Dissertations / Theses: 'Diabète – chirurgie'

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Maanaoui, Mehdi. "La greffe d'îlots pancréatiques chez le patient diabétique transplanté rénal." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2023/2023ULILS071.pdf.

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La greffe d'îlots pancréatiques est une thérapie cellulaire innovante pour la prise en charge du diabète chez le patient diabétique de type 1. A l'heure actuelle, il y a peu d'études s'intéressant à l'impact pronostic de la greffe d'îlots chez le patient diabétique de type 1 transplanté rénal ou aux déterminants du succès de la greffe dans cette population. Par ailleurs, la définition du diabète évolue et la dichotomie entre diabète de type 1 et type 2 s'efface au profit de classifications du diabète basées sur le phénotype clinico-biologique du patient. La greffe d'îlots pancréatiques pourrait donc s'élargir à d'autres profils de patients diabétiques transplantés rénaux, en cas de preuve de déficit d'insulino-sécrétion. L'objectif de cette thèse est donc de déterminer la place de la greffe d'îlots pancréatiques chez les patients diabétiques transplantés rénaux.Dans la première partie, nous présentons les résultats d'une étude de cohorte nationale évaluant l'effet de la greffe d'îlots pancréatiques après transplantation rénale par rapport à une insulinothérapie seule chez des patients diabétiques de type 1. Les patients greffés d'îlots étaient matchés à des patients contrôles grâce à un score de propension dépendant du temps. Après matching, la greffe d'îlots pancréatiques est associée à une réduction du risque composite de mortalité et de retour en dialyse, ainsi qu'au risque isolé de décès. Cette étude souligne l'intérêt de considérer la greffe d'îlots pancréatiques comme une alternative thérapeutique à part entière, notamment dans les régions où elle n'est pas remboursée ou disponible.La deuxième partie explore les déterminants de la perte de fonctionnalité des îlots et notamment les répercussions de l'alloimmunité. Les résultats d'une étude monocentrique suggèrent que les DSA préformés et les DSA de novo précoces impactent peu les résultats de la transplantation d'îlots, mais que les DSA de novo tardifs sont temporellement associés à des résultats métaboliques altérés. Aucun cas de sensibilisation croisée entre les îlots pancréatiques et le rein sous-jacent chez les receveurs n'a été décrit, ni dans l'étude, ni dans la littérature.La dernière partie s'intéresse à l'évaluation du profil insulinique chez le patient diabétique de type 2 transplanté rénal, à travers le calcul des scores HOMA-2, afin d'en extraire l'impact de l'insulino-sécrétion. L'analyse d'une cohorte rétrospective monocentrique montre une association entre l'insulino-résistance évaluée par le HOMA-2 et le risque de perte de greffon, tandis que l'insulino-sécrétion était associée à l'équilibre métabolique. Considérant la relation entre l'équilibre métabolique et la probabilité de mortalité et de perte de greffon chez les patients transplantés rénaux porteurs d'un diabète, la greffe d'îlots pancréatiques pourrait faire partie de l'arsenal thérapeutique dans une approche de médecine personnalisée de ces patients.En conclusion, cette thèse plaide pour une médecine personnalisée du diabète chez les patients transplantés rénaux, en promouvant l'intégration de la greffe d'îlots pancréatiques comme composante fondamentale dans la stratégie thérapeutique pour ces patients
Pancreatic islet transplantation is an innovative cellular therapy for the management of diabetes in patients with type 1 diabetes. Currently, there are few studies that address the prognostic impact of islet transplantation in patients with type 1 diabetes who have received a kidney transplant or the determinants of transplantation success in this population. Furthermore, the definition of diabetes is evolving, with the dichotomy between type 1 and type 2 diabetes fading in favor of diabetes classifications based on the patient's clinical and biological phenotype. Pancreatic islet transplantation could potentially be expanded to other profiles of patients with diabetes and a kidney transplant, especially if there's evidence of insulin secretion deficiency. Thus, the objective of this thesis is to determine the role of pancreatic islet transplantation in patients with diabetes and a kidney transplant.In the first section, we present the results of a nationwide cohort study assessing the effect of pancreatic islet transplantation following kidney transplantation compared to insulin alone in patients with type 1 diabetes. Islet-after-kidney recipients were matched to control patients using a time-dependent propensity score. After matching, pancreatic islet transplantation is associated with a reduction in the combined risk of death and return to dialysis, as well as the isolated risk of death. This study emphasizes the importance of considering islet transplantation as a full-fledged therapeutic alternative, especially in regions where it is not reimbursed or available.The second section explores the determinants of islet loss of functionality, in particular the repercussions of alloimmunity. The results of a single-center study suggest that preformed DSA and early de novo DSA have little impact on islet transplantation outcomes, but late de novo DSA is temporally associated with impaired metabolic results. No cases of cross-sensitization between pancreatic islets and the underlying kidney in recipients were described, neither in the study nor in the literature.The last section focuses on evaluating the insulin profile in patients with type 2 diabetes and a kidney transplant, through the calculation of HOMA-2 scores, to extract the impact of insulin secretion. Analysis of a single-center retrospective cohort shows an association between insulin resistance evaluated by HOMA-2 and the risk of allograft loss, while insulin secretion was only associated with metabolic balance. However, given the relationship between metabolic balance and the likelihood of death and graft loss in kidney transplant patients with diabetes, pancreatic islet transplantation could be part of the therapeutic arsenal in a personalized medicine approach for these patients.In conclusion, this thesis advocates for personalized diabetes medicine in kidney transplant patients, promoting the integration of pancreatic islet transplantation as a key component in the therapeutic strategy for these individuals

2

Rouyer, Olivier. "Dysfonctions endothéliales après transplantation et diabète : Approches expérimentales et cliniques." Strasbourg 1, 2008. http://www.theses.fr/2008STR13075.

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Parmi ses nombreuses fonctions, l’endothélium vasculaire module l’équilibre du tonus vasculaire en secrétant des facteurs vasodilatateurs et vasoconstricteurs. Certaines pathologies altèrent cet équilibre. La dysfonction endothéliale qui en résulte réduit la perfusion des organes et peut compromettre le pronostic vital. Les travaux présentés montrent l’intérêt de technique d’exploration de la dysfonction endothéliale basée sur l’étude de la relaxation endothélium-dépendante, in vitro par l’analyse de la réactivité vasculaire d’anneau aortique en chambre d’organe et in vivo par la mesure de la dilatation flux-dépendante de l’artère humérale en réponse à une hyperhémie post-ischémique. Dans un modèle de rats âgés diabétiques de type 1 induit par streptozotocine, l’introduction tardive d’un IEC est délétère sur la capacité d’exercice. La normalisation de la pression artérielle induite par l’IEC pourrait altérer la perfusion musculaire. La fonction endothéliale n’est pas altérée et n’est pas modifiée quand la durée du diabète est moindre. Dans un modèle génétique de rat Goto-Kakizaki diabétique de type 2, on observe une dysfonction endothéliale liée à la production de prostanoïdes vasoconstricteurs. Celle-ci n’est pas améliorée par l’entraînement, même s’il améliore le profil glycémique. Chez des transplantés cardiaques stables à fonction cardiaque « normale », l’augmentation persistante des valeurs plasmatiques de BNP semble liée à une dysfonction endothéliale. Chez des transplantés hépatiques, la normalité de la «fonction endothéliale» pourrait être liée à la faible prévalence de facteurs de risque cardiovasculaire et à un possible effet protecteur direct du Tacrolimus
Among its many functions, vascular endothelium modulates vascular tone by secreting vasodilators and vasoconstrictors factors. Some diseases alter this balance, causing endothelial dysfunction which reduces organ perfusion and may jeopardizing the life. The work presented shows the interest of exploring endothelial dysfunction through endothelium-dependent relaxation studies, both in vitro through the analysis of aortic vascular ring reactivity in chamber organ and in vivo through flow-dependent dilatation of the humeral artery measurement, in response to a post-ischemic hyperaemia. In a model of aged rats with type 1 diabetes induced by streptozotocin, the late introduction of an IEC is deleterious on the exercise capacity. The normalization of blood pressure induced by the IEC could affect muscle perfusion. Endothelial function was not impaired and was not affected when the term of diabetes was lower. In a genetic model of Goto-Kakizaki rat type 2 diabetes, there was endothelial dysfunction related to the production of vasoconstrictors prostanoids. It was not improved by training even if training improved glycemic profile. In stable heart transplant patients with “normal” cardiac function, the persistent rise of plasma BNP values appeared to be related to endothelial dysfunction. While among hepatic transplant patients, normality of the endothelial function could be linked to the low prevalence of cardiovascular risk factors and a possible direct protective effect of Tacrolimus

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Plourde, Charles-Étienne. "Les mécanismes de résolutions du diabète de type 2 induits par la chirurgie bariatrique." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6038.

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Mélangez obésité, diabète et chirurgie bariatrique et vous obtiendrez ce mémoire. Il y sera question d’obésité, de son étiologie et de ses complications. Parmi celles-ci, nous traiterons majoritairement du diabète de type 2 (DT2) et de sa pathophysiologie. Lorsque nous combinons ces deux maladies, nous nous trouvons devant une combinaison complexe qui demande une intervention thérapeuthique. La plus efficace connue à ce jour est, sans contredit, la chirurgie bariatrique. La résolution du DT2 se produit rapidement après la chirurgie bariatrique, et ce indépendamment de la perte de poids. À ce jour, les mécanismes qui pourraient expliquer ces phénomènes sont mal compris. L’amélioration du DT2 varie selon le type de procédures. La dérivation biliopancréatique (DBP) est la chirurgie qui a le plus grand impact sur le renversement de la résistance à l’insuline, avec une résolution de la maladie jusqu’à 98 % des patients. Différents mécanismes ont été proposés, pour expliquer cet effet, comme la modulation de certaines hormones gastro-intestinales telles que le GLP-1 et le GIP. Ces hormones varient après la chirurgie en raison du réarrangement de l’anatomie intestinale. De plus, la restriction calorique sévère est connue depuis longtemps pour ses effets rapides sur l’homéostasie du glucose. À l’aide de notre étude nous avons voulu déterminer le rôle de la restriction calorique dans l’amélioration rapide de la sensibilité à l’insuline ainsi que la fonction des cellules β suite à la DBP. Pour ce faire nous avons administré un repas test avant et après la DBP soit au jour 3-4-5 post-opératoire afin de mesurer l’apport calorique, les courbes d’excursion glycémique ainsi que la sensibilité et la sécrétion d’insuline. Nous avions un groupe DT2 pairé à des sujets normo glycémiques (NG). Dans une autre étude effectuée parallèlement, un autre groupe de DT2 a subit le même repas test avant et après une restriction calorique identique à celle mesurée en post-opératoire. Ce même groupe était aussi en post opératoire. Les résultats ont démontrés une améloration du HOMA-IR chez les DT2 au jour 3 post DBP ainsi qu’après la restriction calorique. L’index de disposition (ID) s’améliore rapidement chez les DT2 autant après la DBP qu’après la restriction calorique. L’ID était plus haut chex les NG et ne changeait pas suivant la DBP. Les changements du glucagon like peptide-1, du gastric inhibitory peptide, du peptide tyrosine tyrosine, la ghrelin et du polypeptide pancréatique n’étaient pas associés avec la variation de l’ID observé chez les participant Il s’est avéré que l’amélioration de la résistance à l’insuline et de la fonction des cellules β sont similaires après trois jours de restriction calorique comparativement avec la DBP; et ce indépendamment des changements au niveau des incrétines. La restriction calorique est donc un mécanisme majeur dans la résolution du DT2 après la DBP. Mon mémoire fournit les bases physiologiques et cliniques afin de mieux comprendre ces mécanismes.

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Caiazzo, Robert. "Thérapie cellulaire du diabète : facteurs influençant la fonction primaire du greffon." Lille 2, 2009. http://www.theses.fr/2009LIL2S047.

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Notre équipe ayant montré que la fonction primaire du greffon jouait un rôle primordial dans la fonction à long terme des îlots transplantés, nous avons recherché au cours de ce travail de thèse à développer 3 axes de recherche. D'abord, la sélection des préparations en améliorant l'évaluation de la fonction des îlots à l'issue de leur isolement. Pour cela, nous avons mis au point un modèle animal chez la souris nude ou la fonction primaire des îlots greffés sous la capsule rénale est corrélée à celle d'îlots provenant de la même préparation mais greffés chez l'Homme dans le foie par voie intra-portale. Ensuite, nous avons analysé, chez l'Homme, l'impact sur la fonction primaire du greffon des complications liées à la procédure de la greffe. Finalement, nous avons étudié d'autres sites d'implantation des îlots en expérimentant plus particulièrement la greffe d'îlots dans la muqueuse gastrique à partir d'un modèle d'autogreffe chez le mini-porc adulte.

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Arapis, Konstantinos. "Mise au point de modèles précliniques de chirurgie bariatrique chez le rat rendu obèse par un régime hyperlipidique." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC086.

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L'obésité, est un problème de santé publique du fait de ses conséquences pour la santé, l'espérance et la qualité de vie. La gravité de l'obésité morbide et la difficulté d'obtenir et de maintenir une perte pondérale suffisante par un traitement pharmacologique justifient le recours à la chirurgie. Plusieurs bénéfices du traitement chirurgical de l'obésité sont dépendants de la perte pondérale et les mécanismes, très difficiles à étudier chez l'homme, reposent sur une restructuration anatomique et fonctionnelle du tube digestif. Nous avons développé des modèles précliniques de chirurgie bariatrique chez le rat. Ces modèles, sleeve gastrectomie (SG) court-circuit gastrique Roux-en-Y (ou RYGB), très similaires aux procédures chirurgicales pratiquées chez l'homme récapitulaient l'ensemble des bénéfices décrits de la chirurgie de l'obésité morbide. L'analyse des modèles nous a permis montrer, pour la première fois, des changements profonds dans la muqueuse de la glande fundique caractérisée par une hypertrophie et une hyperperplasie des cellules du collet muqueux de la glande fundique. Ces cellules sont dotées de capacités de différenciation des celIules peptiques comme le montre l'augmentation de l'ATPase H+/K+. Cette hyper-trophicité est retrouvée dans l'anse alimentaire chez le rat RYGB et pour la première fois chez l'individu obèse opéré de RYGB. De façon intéressante chez l 'homme obèse RYGB, nous démontrons que l'anse alimentaire présente précocement, un patron d'expression singulier transporteurs de sucres qui n'est plus observé à moyen et long terme. En conclusion, nos modèles précliniques de chirurgie de bariatrique nous ont permis d'acquérir des résultats identifiant de nouvelles voies de recherche dont l'analyse approfondie pourrait aider à une meilleure compréhension des mécanismes impliqués dans les effets bénéfiques de la chirurgie bariatrique.

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Favennec, Marie. "Etude de la voie des kynurénines dans l'obésité humaine." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S037/document.

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Le tryptophane, un acide aminé essentiel, est soit utilisé pour la synthèse protéique et la synthèse de sérotonine, soit dégradé en plusieurs métabolites appelés collectivement les kynurénines. L’expression et l’activité des enzymes de la voie des kynurénines sont stimulées par l’inflammation. La synthèse des kynurénines est donc susceptible d’être augmentée chez les individus obèses. En effet, l’obésité est caractérisée par une inflammation chronique à bas bruit du tissu adipeux, reflétée par l’augmentation de facteurs inflammatoires circulants qui contribuent à l’apparition de l’insulinorésistance et du diabète de type 2. Plusieurs métabolites de la voie des kynurénines pourraient être des facteurs de risque pour le développement de l’insulinorésistance. La chirurgie bariatrique est actuellement le traitement le plus efficace pour l’obésité sévère, elle permet une perte de poids significative ainsi qu’une diminution des facteurs inflammatoires circulantes et une amélioration de l’insulinorésistance et du diabète. Il a été démontré que l’expression d’IDO1, la première enzyme de la voie des kynurénines, est plus élevée dans le tissu adipeux des individus obèses. Le ratio kynurénine sur tryptophane, qui reflète l’activité D’IDO1, est également augmenté chez les individus obèses.Notre objectif a été de caractériser l’expression des enzymes de la voie des kynurénines dans le tissu adipeux et d’évaluer les concentrations des kynurénines dans les sérums de patientes obèses pour rechercher si certains de ces facteurs pouvaient être reliés à l’apparition du diabète. Ces études ont été réalisées dans une cohorte de femmes obèses normoglycémiques et diabétiques. Puis dans un second temps nous avons étudié les conséquences de la perte de poids induite par la chirurgie bariatrique sur les concentrations circulantes des kynurénines et évalué si les variations des concentrations des kynurénines pourraient expliquer en partie l’amélioration du diabète observée après la chirurgie.Dans cette étude, nous avons montré que plusieurs enzymes de la voie sont plus exprimées dans le tissu adipeux des individus obèses que des minces. L’augmentation de l’expression des enzymes dans le tissu adipeux des individus obèses provient d’une part de la présence de macrophages pro-inflammatoires dans le tissu adipeux et également de la réponse des adipocytes aux stimuli pro-inflammatoires. En parallèle, nous avons montré que les concentrations circulantes des kynurénines et le ratio kynurénine sur tryptophane augmentent avec l’IMC et qu’ils diminuent un an après la chirurgie bariatrique. Dans notre étude, comme attendu, la chirurgie bariatrique est associée à une amélioration voire à une rémission du diabète. Nous avons montré également que le maintien des concentrations d’acide kynurénique et d’acide quinolinique sont associés respectivement à la rémission du diabète et à l’amélioration des traits cliniques qui définissent le diabète. La diminution des concentrations en acide xanthurénique après la chirurgie est associée au contraire à une amélioration des traits cliniques qui définissent le diabète
Tryptophan, an essential amino acid, is either used in protein synthesis or metabolized via the serotonin or the kynurenine pathway. The kynurenine pathway is the main route of tryptophan degradation and generates several metabolites collectively called “kynurenines”. The expression of kynurenine pathway enzymes is induced by inflammatory mediators. Consequently kynurenine synthesis could be induced in individuals with obesity. In fact, obesity is characterized by a chronic low grade inflammation of the adipose tissue reflected by increased serum levels of inflammatory factors which are known to contribute to the development of obesity-induced insulino-resistance. Some metabolites of the kynurenine pathway have been proposed to be risk factors for the development of insulin resistance. Bariatric surgery is currently the most effective treatment for severe obesity and results in a significant weight loss, a decreased level of inflammatory factors and an amelioration of glucose homeostasis. The first enzyme of the kynurenine pathway, IDO1, is known to be more expressed in the adipose tissue of individuals with obesity compared to lean individuals. The kynurenine over tryptophan ratio reflects the activity of IDO1 and is also increased in individuals with obesity.Our objective was to characterize the expression of the kynurenine pathway enzymes in the adipose tissue of women with severe obesity and to evaluate serum levels of the kynurenine pathway metabolites to determine whether these factors could be associated with the appearance of diabetes. This study was performed in women with severe obesity with or without type 2 diabetes. Then we investigated the consequences of weight loss induced by bariatric surgery on levels of circulating kynurenines in order to evaluate whether these variations could explain the improvement in glucose control and type 2 diabetes remission after one year follow-up.In this study, we have shown that several kynurenine pathway enzymes were more expressed in the adipose tissue of women with obesity compared to lean controls. This increase is due to the presence of pro-inflammatory macrophages in the adipose tissue and also comes from the adipocyte response to inflammatory stimuli. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. As expected, bariatric surgery is associated with the improvement and even the remission of type 2 diabetes. We have shown that higher levels of kynurenic acid and quinolinic acid one year after the surgery are associated respectively with type 2 diabetes remission and better glucose homeostasis and that lower levels of xanthurenic acid are associated with better glucose homeostasis

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Chavez, Talavera Oscar Manuel. "Rôle des acides biliaires dans la physiopathologie de l'obésité, la résistance à l'insuline, le diabète de type 2, la stéatose hépatique non alcoolique et dans le contexte de la chirurgie bariatrique Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease Bile Acid Alterations in Nonalcoholic Fatty Liver Disease, Obesity, Insulin Resistance and Type 2 Diabetes: What Do the Human Studies Tell?” Bile acids associate with glucose metabolism, but do not predict conversion to diabetes Bile acid alterations are associated with insulin resistance, but not with NASH in obese subjects Roux-en-Y gastric bypass increases systemic but not portal bile acid concentrations by decreasing hepatic bile acid uptake in minipigs The functional relevance of bile acids in the improvement of HDL-mediated endothelial protection after bariatric surgery Metabolic effects of bile acid sequestration: impact on cardiovascular risk factors." Thesis, Lille, 2019. http://www.theses.fr/2019LILUS057.

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En plus de leur rôle dans la solubilisation des lipides alimentaires, les acides biliaires sont des molécules de signalisation régulant leur propre métabolisme, l'homéostasie du glucose et des lipides, la dépense énergétique, la fonction cardiovasculaire et l’inflammation, en modulant le Farnesoid X Receptor (FXR) et le Takeda G protein coupled Receptor 5 (TGR5). En effet, des modifications dans les concentrations des acides biliaires sont associées aux maladies métaboliques et ce sont des candidats pour participer à la pathophysiologie de ces maladies ou prédire leur progression.Dans la première partie de cette thèse nous avons étudié les modifications des acides biliaires dans le contexte de l'obésité, l'insulinorésistance, le diabète de type 2 et la stéatohépatite non alcoolique. Nous avons montré que les acides biliaires sont corrélés avec l’homéostasie du glucose chez l’Homme, mais qu’ils ne sont pas des prédicteurs de la bascule du prédiabète en diabète de type 2 dans un étude de cohorte.La deuxième partie de cette thèse est dédiée à l’étude des acides biliaires dans la chirurgie bariatrique. Nos résultats ont montré que la chirurgie bariatrique réduit la recapture hépatique des acides biliaires, provoquant leur augmentation dans la circulation systémique, et que ce n’est pas l’anse biliaire mais l’anse commune qui est responsable des modifications métaboliques après la chirurgie bariatrique chez le minipig. Ensuite, nous avons montré chez l’Homme que les acides biliaires liés aux lipoprotéines de haute densité (HDL) augmentent après la chirurgie bariatrique, et que cette augmentation est corrélée avec la restauration de leurs fonctions vaso-protectrices
In addition to their role in the solubilization of dietary lipids, bile acids are signaling molecules regulating their own metabolism, glucose and lipid homeostasis, energy expenditure, cardiovascular function and inflammation via the activation of the Farnesoid X Receptor (FXR) and the Takeda G protein coupled Receptor 5 (TGR5). Indeed, changes in bile acid concentrations are associated with metabolic diseases and therefore they are candidates to participate in the pathophysiology of these diseases or predict their progression.In the first part of this thesis, we studied bile acid changes in the context of obesity, insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis. We demonstrated that bile acids are correlated with glucose homeostasis in humans, but that they are not predictors for the progression from prediabetes to type 2 diabetes in a longitudinal cohort study.In the second part of this thesis, we studied the bile acids in the context of bariatric surgery. Our results showed that bariatric surgery reduces the hepatic recapture of certain bile acids, causing them to increase in the systemic circulation. Additionally, we showed that it is not the bile limb but the common limb the one responsible for metabolic changes after bariatric surgery in the minipig. Finally, we showed in humans that bile acids linked to high-density lipoproteins (HDL) increase after bariatric surgery, and that this increase is correlated with the restoration of their vasoprotective functions

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Goncalves, Daisy. "Biodisponibilité de la bile et effets bénéfiques des chirurgies bariatriques de type by-pass." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10171/document.

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Les chirurgies de type by-pass induisent des améliorations spectaculaires de l'homéostasie glucidique indépendamment de la perte de poids chez les patients obèses et diabétiques. Elles provoquent également une diminution de la préférence pour les aliments hypercaloriques. Un mécanisme proposé pour expliquer les effets sur le contrôle glucidique de ces procédures associe une diminution de la production hépatique de glucose et une augmentation de la néoglucogenèse intestinale. Les acides biliaires, décrits comme inhibiteurs de la néoglucogenèse, voient leur biodisponibilité modifiée après ces chirurgies. Ils sont en effet absents de l'anse alimentaire tandis que leur concentration est augmentée dans le sang. Nous avons donc testé l'hypothèse selon laquelle les acides biliaires plasmatiques inhiberaient la production hépatique de glucose alors que leur absence dans l'intestin induirait la néoglucogenèse intestinale. Pour cela, nous avons réalisé des dérivations biliaires chez le rat visant à reproduire le trajet de la bile dans les chirurgies de type by-pass. Nous avons montré que les dérivations biliaires entrainent une augmentation du taux circulant d'acides biliaires. Les dérivations provoquent une forte diminution de la production hépatique de glucose et une induction de la néoglucogenèse dans les portions d'intestin dépourvus de bile. Par ailleurs, la seule modification du trajet de la bile promeut une amélioration du contrôle glucidique et une diminution de l'appétence pour les aliments riches en graisse et en sucre. Ces données nous ont donc permis d'attribuer un rôle clé à la modification du trajet de la bile dans les effets bénéfiques des chirurgies de type by-pass
Gastric bypass procedures have emerged as an effective treatment for morbid obese diabetic patientssince they provoke a rapid remission of diabetes before any weight loss has occurred. Patients also report adisinterest in high calorie food. A suggested mechanism associated a decrease in hepatic glucose production toan enhanced intestinal gluconeogenesis. Bile acids, described as inhibitors of gluconeogenesis, see theirbioavailability changed after these procedures. Indeed, they are absent in the alimentary limb while theirplasmatic concentration is increased. We therefore tested the hypothesis that plasma bile acids may inhibithepatic glucose production while their absence in the gut could induce intestinal gluconeogenesis.For this, we performed bile diversions matching the modified biliary flow occurring after gastric bypassprocedures. We showed that bile diversions lead to an increase in plasma bile acids. Bile diversions promote ablunting in hepatic glucose production whereas intestinal gluconeogenesis is increased in gut segments devoidof bile. Moreover, the modification of bile routing per se improves glucose control and dramatically decreasefood intake due to an acquired disinterest in fatty food. This data shows that bile routing modification is a keymechanistic feature in the beneficial outcomes of gastric bypass procedures

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Amouyal, Chloé. "Restaurer la fonction bêta pancréatique de la souris leptine déficiente par la chirurgie bariatrique." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS010.

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Le bypass gastrique (RYGB) a démontré un effet bénéfique sur le diabète de type 2. L’EGA (entéro-gastro-anastomose) est une procédure de bypass gastrique adaptée au modèle murin. Chez les souris ob-ob (déficientes pour la leptine), l’EGA améliore la tolérance au glucose en augmentant le contenu pancréatique en insuline et la sécrétion d’insuline induite par le glucose in vivo en l’absence de perte de poids, de restriction alimentaire, de modification de composition corporelle, sans modifier le nombre ni dans la taille des ilots. L’expression du gène de l’insuline, la prolifération beta cellulaire et l’infiltration immunitaire insulaire sont également inchangés. De plus, la chirurgie bariatrique régule l’expression de 193 gènes et 27 miRs intra-ilots. Certaines anomalies moléculaires observées dans les îlots pancréatiques des souris ob-ob (régulation négative du canal ionique TRPM5, du transporteur GLUT2, de la glucokinase, de la connexine 36) et fonctionnelles (sensibilité élevée des îlots à de faibles taux de glucose) ont été modulées par la chirurgie bariatrique. La chirurgie a favorisé l’enrichissement de 227 processus biologiques, notamment 21 gènes impliqués dans le transport hormonal et 20 gènes impliqués dans la sécrétion hormonale. Sept des 27 miRs (324-3p, 380-3p, 671-5p, 1927, 6904-5p, 6918-5p et 7682-3p) sont des noyaux dans le réseau de prédiction d’interaction gène-miRs. Globalement, nos données ont mis en évidence de nouveaux mécanismes moléculaires dans la résolution du diabète après une chirurgie bariatrique. De manière importante, notre modèle démontre que la résolution du diabète après la chirurgie bariatrique peut être indépendante de la perte de poids
EGA (entero-gastro-anastomosis) is a gastric bypass procedure adapted to rodent. EGA in leptin deficient ob/ob mice improves glucose tolerance by increasing pancreatic insulin content and glucose stimulated insulin secretion in vivo without persistent body weight loss dietary restriction, modification of body composition / energy expenditure. We do not observe differences in islets ‘number or size after EGA. Insulin gene expression, beta-cell proliferation (Ki67 index) and insular immune infiltration are also unchanged. Transcriptomic analysis of pancreatic islets showed that bariatric surgery differentially regulated 193 genes and 27 miRs. Interestingly, the surgery normalized molecular defects (down regulation of TRPM5, GLUT2, GCK, connexin 36) and functional alteration (high sensitivity of islets to low glucose levels) observed in diabetic ob pancreatic islets. In addition, the surgery promoted the enrichment of 227 biological process, composed of genes with known or undetermined beta cell function, especially 21 genes are involved in the hormone transport and 20 genes in the hormone secretion biological process. Computational analysis predicted that 7 of 27 miRs (324-3p, 380-3p, 671-5p, 1927, 6904-5p, 6918-5p and 7682-3p) are hubs in the miRs-gene interaction network. Altogether, our data highlighted novel molecular mechanisms in the resolution of diabetes after bariatric surgery. Overall, diabetes resolution in our model appears to be totally independent of body weight

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Spinelli, Valeria. "Les acides biliaires et la régulation de l’homéostasie métabolique : rôle du récepteur Farnesoid X Receptor (FXR) dans la cellule bêta-pancréatique : variation du pool des acides biliaires et chirurgie bariatrique Roux-en-Y Gastric Bypass." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S054.

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Les acides biliaires (ABs) sont des molécules produites dans le foie, stockées dans la vésicule biliaire, sécrétées dans l’intestin et retournant au foie via le cycle entéro-hépatique. Une fraction des ABs échappe à la recaptation par le foie et passe dans la circulation systémique par laquelle ils atteignent les organes périphériques dont le pancréas. Outre leur fonction de faciliter l’absorption intestinale des lipides, les ABs sont des molécules de signalisation qui agissent via les récepteurs aux ABs, exprimés dans les tissu clés de la régulation du métabolisme, et dont la modulation par les ABs contribue à réguler l’homéostasie énergétique. Ainsi des variations dans la composition du pool d’ABs peuvent déterminer la modulation du métabolisme via leurs récepteurs.Le récepteur aux ABs Farnesoid-X-receptor (FXR) est impliqué dans la régulation du métabolisme glucidique, lipidique et des ABs par son action dans le foie, l’intestin, les tissus adipeux et le pancréas. La souris déficiente pour FXR dans le corps entier présente une intolérance au glucose et une insulino-résistance dans le foie et dans les tissus périphériques, alors que dans un contexte d’obésité la déficience de FXR améliore ces paramètres. De plus, FXR est exprimé dans la cellule bêta-pancréatique (bcell) où il régule la synthèse et la sécrétion d'insuline, mais les mécanismes moléculaires n’ont pas été complètement élucidés. Pour comprendre 1) la contribution de FXR bcell dans le phénotype métabolique de la souris FXRKO-total, et 2) les mécanismes moléculaires de la régulation de l’insuline par FXR dans la bcell, j’ai développé un modèle murin invalidé pour FXR spécifiquement dans la bcell par la stratégie Cre-LoxP. Le développement du modèle a mis en évidence des phénomènes de recombinaison non-spécifiques et j’ai mis au point une stratégie de génotypage permettant de pallier à cette problématique. J’ai testé différents contextes métaboliques permettant de mettre en évidence le phénotype de la souris FXRKObcell (régime standard et riche en graisses, conditions de jeûne et re-nourriture, variation circadienne). Par rapport au contrôle, la souris FXRKO-bcell développe une intolérance au glucose et présente des insulinémies plus basses, défauts majorés par un régime riche en graisses. L’analyse transcriptomique globale des îlots a permis d’identifier un ensemble de microRNA fortement dérégulés par l’invalidation de FXR bcell qui pourraient expliquer les dysfonctions de sécrétion d’insuline.Outre la modulation de l’activité des récepteurs, des effets métaboliques peuvent être obtenus en modulant la composition du pool de leurs ligands, les ABs. Ainsi, des perturbations métaboliques (comme l’insulino-résistance et le diabète de type 2, l’obésité) sont associées à des variations qualitative et/ou quantitative du pool d’ABs. De plus, des variations du pool d’ABs accompagnent les améliorations métaboliques qui suivent la pratique chirurgicale de Roux-en-Y Gastric Bypass (RYGB) avant la perte de poids, ce que suggère que les ABs puissent être parmi les acteurs des effets métaboliques bénéfiques indépendants de la perte de poids. Pour étudier cette hypothèse, des modèles précliniques de RYGB ont été développés. Au cours de ma thèse j’ai comparé le pool d’ABs pre et post RYGB entre trois espèces (rat, cochon et Homme ; coll. Pr. F. Pattou et Dr. E. Osto) avec l’objectif d’évaluer quel modèle préclinique est le plus approprié pour ces études en termes de caractéristiques du pool d’ABs. La deuxième étude concerne la recherche des causes et mécanismes sous-jacents à l’augmentation des concentrations en ABs circulants induits par le RYGB. Dans le modèle de minipig (coll. Pr. F. Pattou), l’analyse de la composition des pool d’ABs circulants et d’expression génique dans le foie avant et après RYGB, a permis de montrer que des changements de la fonction hépatique sont - au moins en partie - responsables de l’augmentation dans le pool d’AB qui suit le RYGB
Bile acids (BAs) are molecules produced in the liver, stored in the gallbladder, secreted into the intestine and returning to the liver via the enterohepatic circulation. A fraction of BAs escapes the reuptake by the liver and enters the systemic circulation, by which they reach the peripheral organs including the pancreas. Besides their function in facilitating the intestinal absorption of lipids, BAs are signaling molecules that act through receptors for BAs, which are expressed in the key tissues for metabolic regulation, and whose modulation by BAs contribute to regulate energy homeostasis. Thus, variations in the composition of the BAs pool determine the modulation of metabolism via their receptors. The BA-receptor Farnesoid-X receptor (FXR) is involved in the regulation of glucose, lipid and BA metabolism by its action in the liver, intestine, adipose tissue and pancreas. Whole body FXR deficient mice are glucose intolerant and insulin resistant in liver and peripheral tissues, whereas in a context of obesity, FXR deficiency rather improves these parameters. Furthermore, FXR is expressed in the pancreatic beta cell (bcell), where it regulates the synthesis and the secretion of insulin, but the molecular mechanisms have not been fully elucidated yet. To understand 1) the contribution of FXR bcell in the metabolic phenotype of the total FXRKO-mouse, and 2) the molecular mechanisms of the regulation of insulin production by FXR in the bcell, I developed a mouse model invalidated for FXR specifically in the bcell by the Cre-loxP strategy. The development of the model showed nonspecific recombination phenomena, and I developed a genotyping strategy to overcome this problem. To highlight the phenotype of the FXRKObcell mouse I tested various metabolic contexts (standard and high fat diet, fasting and refeeding conditions, circadian variations). Compared to control, FXRKO-bcell mice developed glucose intolerance and has lower insulinémia, defects increased by a high fat diet. The global transcriptomic analysis in the islets identified a set of microRNA strongly deregulated by invalidating FXR in the bcell, which could explain the dysfunctions in insulin secretion. Besides the modulation of the activity of the receptors, metabolic effects can be obtained by varying the composition of the pool of their ligands BAs. Thus, metabolic perturbations (such as insulin resistance and type 2 diabetes, obesity) are associated with qualitative and/or quantitative variations in the BA pool. In addition, variations of the BAs pool are associated to the metabolic improvement that precedes the weight loss after the surgical practice of Roux-en-Y Gastric Bypass (RYGB), which suggests that the BAs can be among the actors of the ‘weight loss-indipendent’ beneficial metabolic effects of RYGB. To investigate this hypothesis, some preclinical models of RYGB have been developed. During my thesis I compared the pool of BAs pre and post RYGB among three species (rat, pig and human; Coll. Prof. F. Pattou and Dr. E.Osto) with the aim of assessing which preclinical model is most suitable for these studies in terms of characteristics of the BAs pool. In a second study, I focused on the causes and mechanisms underlying the increased concentrations of circulating BAs induced by RYGB. In the model of minipig (coll. Pr. F. Pattou), the analysis of the plasma BA pool composition and the hepatic gene expression before and after RYGB, allowed to show that changes in the hepatic function are - at least in part - responsible for the increase of the BA pool following RYGB

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Baud, Grégory. "Modulation de l’absorption intestinale postprandiale du glucose apès Roux-en-Y Gastric Bypass chez le miniporc." Thesis, Lille 2, 2016. http://www.theses.fr/2016LIL2S042/document.

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Le DT2 est caractérise par un défaut combiné de la sécrétion et de l’action de l’insuline. Depuis près d’un demi siècle la chirurgie bariatrique et notamment le Roux-en-Y Gastric Bypass (RYGB) ont montré des effets spectaculaires sur le contrôle glycémique remettant en question le paradigme de la prise en charge médicale du DT2. L’exclusion gastro duodénale induite par le RYGB améliore le métabolisme glucidique indépendemment de la perte de poids. Ainsi les modifications du flux biliaire semblent jouer un rôle, cependant les mécanismes sous-jacents ne sont pas clairs. Nous avons réalisés des RYGB chez le miniporc et nous avons montré que l'absorption intestinale du glucose est diminuée dans l’anse alimentaire (AL) dépourvue de bile. L'absorption du glucose dans l’AL était restaurée par l'ajout de la bile, et cet effet était inhibé lorsque le co transport actif sodium glucose 1 (SGLT1) était bloquée par la phlorizine. SGLT1 restait exprimée dans la AL, cependant la teneur dans la lumière de l’intestin en sodium était nettement diminuée. L’ajout de sodium dans l'AL provoquait le même effet que la bile sur l'absorption du glucose et augmentait également l’excursion glycémique post prandiale chez le miniporc au cours d’un repas test vigil. La diminution de l'absorption intestinale du glucose après RYGB a ensuite été confirmée chez l'homme. Nos résultats démontrent que la l’exclusion biliaire affecte le métabolisme post prandiale du glucose par modulation des co transporteurs intestinaux sodium-glucose
Type 2 diabetes (T2D) is characterized primarily as a combined defect of insulin secretion and insulin action. For nearly a decade, the somewhat mysterious but spectacular benefit of metabolic surgery, and more specifically of Roux-en-Y gastric bypass (RYGB), on glucose control has been caused a questioning the current paradigm of T2D management. Gastro-intestinal exclusion by RYGB improves glucose metabolism, independent of weight loss. Although changes in intestinal bile trafficking have been shown to play a role, the underlying mechanisms are unclear. We performed RYGB in minipigs and showed that the intestinal uptake of ingested glucose is blunted in the bile deprived alimentary limb (AL). Glucose uptake in the AL was restored by the addition of bile, and this effect was abolished when active glucose intestinal transport was blocked with phlorizin. Sodium-glucose cotransporter 1 remained expressed in the AL, while intraluminal sodium content was markedly decreased. Adding sodium to the AL had the same effect as bile on glucose uptake. It also increased postprandial blood glucose response in conscious minipigs following RYGB. The decrease in intestinal uptake of glucose after RYGB was confirmed in humans. Our results demonstrate that bile diversion affects postprandial glucose metabolism by modulating sodium-glucose intestinal cotransport

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Barataud, Aude. "Rôle de la néoglucogenèse intestinale et des récepteurs mu-opioïdes dans les effets bénéfiques du by-pass gastrique chez la souris." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10276/document.

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Le by-pass gastrique Roux-en-Y (BPG) est une chirurgie de l'obésité qui induit des améliorations spectaculaires de l'homéostasie glucidique indépendamment de la perte de poids. Un mécanisme proposé pour expliquer ces améliorations est une augmentation de la production intestinale de glucose (PIG) qui induit des effets bénéfiques sur l'organisme (satiété, amélioration de la sensibilité hépatique à l'insuline). Cette augmentation de la PIG, retrouvée chez la souris ayant subi un BPG simplifié, est également responsable des effets bénéfiques des régimes enrichis en protéines via l'inhibition des récepteurs mu-opioïdes (RMO) par les peptides. Nous avons donc testé l'hypothèse selon laquelle les effets bénéfiques du BPG dépendraient d'une inhibition des RMO par les protéines alimentaires et nous avons également testé le rôle causal de la PIG dans ces améliorations métaboliques. Pour cela, nous avons réalisé un by-pass duodéno-jéjunal (BDJ), ie un BPG sans restriction gastrique, chez des souris sauvages (WT), des souris invalidées pour le gène du RMO (MOR-/-) et des souris dépourvues de PIG (I-G6pc-/-). Chez les souris obèses, Le BDJ induit une forte perte de poids (–30%), en partie expliquée par une malabsorption lipidique, ainsi qu'une amélioration des paramètres glucidiques dépendante de cette perte de poids. Au contraire, chez la souris de poids normal, le BDJ n'induit ni perte de poids ni malabsorption mais améliore la tolérance au glucose. Les effets sont les mêmes chez les souris WT, MOR-/- et I-G6pc-/- ce qui montre que les récepteurs mu-opioïdes et la PIG ne semblent pas avoir de rôle causal dans les améliorations du métabolisme énergétique et glucidique après BDJ
Roux-en-Y gastric bypass procedure (GBP) is an obesity surgery that induces dramatic glucose homeostasis improvements independently of weight loss. A proposed mechanism to explain these glucose homeostasis improvements is an increase in intestinal glucose production (IGP) that induces beneficial effects on metabolism (satiety, improved liver insulin sensitivity). This increase in IGP is found in mice that have undergone a simplified GBP and is also responsible for the beneficial effects of protein-enriched diets through the inhibition of mu-opioid receptors (MOR) by alimentary peptides. We therefore hypothesized that the beneficial effects of GBP could depend on MOR inhibition by dietary proteins and we also tested the causal role of IGP in these metabolic improvements. For this purpose, we performed a duodenal-jejunal bypass surgery (DJB), ie GBP without gastric restriction, in wild-type mice (WT), in mice lacking MOR gene (MOR-/-) and in mice lacking IGP (IG6pc-/-). In obese mice, DJB induced a rapid and substantial weight loss (-30%), partly explained by fat malabsorption, and weight loss-dependent improvements of glucose homeostasis. In contrast, in the non-obese mice, DJB did not induce weight loss nor malabsorption but improved glucose tolerance. Effects were similar in WT, MOR-/- and I-G6pc-/- mice showing that mu-opioid receptors and IGP did not appear to have a causal role in glucose and energy metabolism improvements after DJB

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Sterkers, Adrien. "Evaluation pré-clinique et clinique de l'autogreffe intramusculaire d'îlots de Langerhans." Phd thesis, Université du Droit et de la Santé - Lille II, 2013. http://tel.archives-ouvertes.fr/tel-00951952.

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La transplantation d'îlots permet la restauration d'une insulino-sécrétion endogène chez les patients diabétiques de type 1 par greffe allogénique et limite les conséquences métaboliques d'une pancréatectomie en cas d'autogreffe. Le site de référence intrahépatique présente néanmoins de nombreuses limites. Dans le cadre d'autogreffe, le risque hémorragique accru chez les patients récemment opérés liée à l'injection nécessairement conjointe des îlots et d'héparine en intraportal doit faire privilégier une technique de greffe mini invasive. De nombreux sites d'implantation ont été décrits. L'hypothèse de ce travail de thèse était que la voie intramusculaire offrirait par rapport à la voie portale, l'avantage de simplifier l'acte de transplantation, de réduire le traumatisme pour le patient et d'améliorer la viabilité des îlots en limitant les processus inflammatoires immédiats et en optimisant les processus de néo-vascularisation.Dans une première partie, nous avons pu démontrer, dans un model préclinique, que le site intramusculaire permet la survie, la revascularisation et la sécrétion des îlots autogreffés. Nous avons décrit une technique de greffe permettant d'ameliorer le contrôle glycémique d'animaux autogreffés après pancréatectomie totale. Bien qu'inférieure à la voie intraportale, les tests fonctionnels nous ont permis de valider le site intramusculaire pour la greffe d'îlots autologues. Dans une deuxième partie, nous décrivons un cas clinique original confirmant la possible transposition en clinique de l'autogreffe d'ilots en intramusculaire après pancréatectomie partielle. Ce cas clinique, confirme la faisabilité et suggère son innocuité. Il était cependant difficile dans ce contexte de pancréatectomie partielle d'établir un rapport entre l'absence de développement de diabète et la greffe. Pour ce faire, nous décrivons dans une troisième partie, une étude pilote sur l'évaluation de la fonction des îlots autogreffés dans le muscle chez 8 patients ayant subi une pancréatectomie partielle. Dans ce but nous avons comparé la sécrétion d'insuline après stimulation par l'arginine mesurée simultanément dans le bras greffé et le bras non greffé après l'autogreffe par des tests de stimulation à l'arginine. Malgré une faible quantité d'ilots greffés, nous avons documenté une fonction primaire du greffon chez plus de la moitié des patients, ainsi que sa persistance à plus d'un an. Enfin, nous avons également montré que le gradient d'insulinémie entre le bras greffé et le bras systémique était corrélé avec la masse d'ilots greffés.Le muscle est donc un site phare pour le développement d'un site alternatif lors de greffe d'ilots intramusculaire. Le site intramusculaire permet un formidable site d'évaluation des îlots. Cette procédure, résolument mini-invasive, est particulièrement attractive par son extrême accessibilité aux biopsies, à l'imagerie et aux explantations. Cette accessibilité permet d'élargir les indications de greffe telles que l'autogreffe d'îlots provenant de pancréas tumoraux.

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Payen, Cyrielle. "Implication des troubles métaboliques maternels sur la programmation fœtale des fonctions métabolique hépatique et vasculaire de la descendance." Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0047.

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L’exposition in utero à des pathologies métaboliques maternelles aboutit à une programmation foetale favorisant la survenue de pathologies métabolique, vasculaire et hépatique pour la descendance. Les travaux exposés dans ce manuscrits intéressent à la programmation foetale induite par deux types de pathologies métaboliques maternelles : l’obésité et le diabète. Nous avons ainsi pu mettre en évidence que l’obésité maternelle induisait une programmation foetale directe de la fonction vasculaire de la descendance et ce indépendamment des anomalies métaboliques. De plus, nous avons montré que la perturbation de l’alimentation périnatale, bien que ne modifiant pas la programmation foetale de la fonction vasculaire, conduit à la survenue précoce d’anomalies métaboliques dans la descendance de mère obèse. A court terme, la chirurgie bariatrique n’est pas suffisante pour contrer la programmation foetale des fonctions métabolique et vasculaire décrites pour la descendance de mère obèse. Nous avons également mis en évidence que la programmation foetale des anomalies vasculaires de la descendance de mère diabétique pouvait être transmise de la génération F1 à la génération F2. Finalement, nous avons mis en avant l’importance du dimorphisme sexuel dans la programmation foetale de la fonction vasculaire. Ces résultats démontrent que les maladies vasculaires (hypertension artérielle) et métabolique (obésité, diabète) ne sont pas des maladies exclusivement comportementales mais sont des maladies pouvant trouver leur origine durant la vie foetale et être transmises sur plusieurs générations, contribuant à expliquer la forte augmentation de la prévalence de ces pathologies regroupées au sein du syndrome métabolique au niveau mondial
In utero exposure to maternal metabolic pathologies leads to fetal programming, which increases the occurrence of metabolic, vascular and hepatic diseases in offspring. In this thesis, we focused on fetal programming induced by two types of maternal metabolic dysfunctions : obesity and diabetes. We highlighted that maternal obesity induced direct fetal programming of the vascular function in offspring regardless of metabolic disorders. In addition, we showed that disruption of perinatal nutrition leads to the early occurrence of metabolic disorders in offspring of obese mothers, without modifying the fetal programming of vascular function. Bariatric surgery doesn’t seem tobe able to reverse fetal programming of metabolic and vascular functions as described in obese mothers offspring. We also showed that fetal programming of vascular dysfunction of diabetic mother’s offspring can be transmitted from the F1 to the F2 generation. Finally, we highlighted the importance of sexual dimorphism in the fetal programming of vascular function. These results demonstrate that vascular (arterial hypertension) and metabolic (obesity, diabetes) diseases are not exclusively behavioral diseases but can also have a fetal life origin. They can be transmitted over several generations, thus contributing to explain the worldwide spread of obesity and associated metabolic disorders

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Abdesselam, Inès. "Dépôts de graisse ectopique : étude de leur développement et de leur modulation." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM5005.

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Le projet de cette thèse porte sur le développement de dépôts lipidiques ectopique et leur modulation suite à des intervenions thérapeutiques par imagerie résonance magnétique.Dans notre première étude, nous avons établi l’ordre chronologique d’apparition de graisses ectopiques et d’anomalies cardiaques dans un modèle de souris soumises à un régime riche en graisse et en sucre. Un traitement de courte durée à l’exendine-4 permet une amélioration de tous les paramètres altérés. Dans la deuxième étude, nous avons évalué l’impact d’un traitement de l’obésité sur les dépôts ectopique de graisse cardiaque (TAE et stéatose), hépatique et pancréatique à deux temps (6 mois et 32 mois) après chirurgie bariatrique. Nous avons montré que ce traitement chirurgical permet une réduction de tous ces dépôts, avec une cinétique différente. Enfin, dans la troisième étude, nous nous sommes intéressés à l’effet du poids de naissance sur le développement de tissu adipeux épicardique. Cette étude nous a permis de mettre en évidence qu’il existe une accumulation plus importante de TAE à l’âge adulte lorsque le poids de naissance est augmenté ; et que les paramètres poids de naissance et croissance entre 2 et 12 ans, jouent un rôle important dans la mise en place de ce dépôts de graisse ectopique. En somme, ces résultats permettent une avancée dans la compréhension du développement des dépôts de graisses et de leur modulation
The project of this thesis mainly focuses on ectopic lipid deposition development and their flexibility following therapeutic intervention. In our first study, we set out chronological order of ectopic fat onset and cardiac abnormalities in a high fat high sucrose mice model. Short duration exendin-4 treatment reverses every altered parameter. In the second study, we assessed treatment of obesity effect on cardiac ectopic fat deposition (EAT and steatosis), as well as hepatic and pancreatic fat at two different time points (6 months and 32 months) after bariatric surgery. We show significant reduction of every ectopic fat deposition, however in different kinetic. Finally, in a third study, we investigate birth weight effect on epicardial adipose tissue development. This study demonstrate important EAT accumulation in adulthood when birth weight is increased. Furthermore, birth weight and catch up growth in childhood between 2 and 12 years parameters impact significantly the development of epicardial fat.In summary, these results provide better understanding of ectopic fat deposition development and modulation

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Raucoules-Aimé, Marc. "Administration peroperatoire d'insuline chez le diabetique : influence de la severite de l'acte operatoire, du type de diabete et des modalites d'administration par voie veineuse." Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX22952.

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Chopard-Lallier, Sophie. "Suivi fonctionnel de la greffe d'îlots de Langerhans : interêt de l'imagerie IRM et de l'immuno-monitoring cellulaire." Thesis, Besançon, 2013. http://www.theses.fr/2013BESA3001.

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La greffe d'îlots de Langerhans permet de traiter le diabète de type 1 en restituant une insuline-sécrétion. La moitié des patients reprend l'insuline dans les 5 ans. Cette perte de fonction s'explique par l'absence d'outils de monitoring. Le but de notre travail était de déterminer l'efficacité de l'IRM à diagnostiquer un rejet de greffe, et d'évaluer l'intérêt du monitoring cellulaire chez les patients.Imagerie IRM chez le ratMéthodes : Des îlots syngéniques, allogéniques ou xénogéniques ont été greffés par voie intra-portale à des rats diabétiques après marquage avec une nanoparticule de fer (ferucarbotran). Les IRM étaient réalisées dans une IRM clinique 3T.Résultats : La décroissance du signal était différente suivant les 3 types de greffes. Le signal IRM des greffes allogéniques était significativement plus bas à J4 alors que la glycémie était normale. En prenant un seuil de 84% à J4, l'IRM permet d'obtenir une sensibilité de 91% et une spécificité de 70% Innnuno-monitoring cellulaireMéthodes : Des réactions lymphocytaires mixtes étaient réalisées entre les PBMC des patients greffés, et les splénocytes des donneurs. La réaction immunitaire était évaluée par la sécrétion d'IFNy (ELISpot), par la prolifération cellulaire (cytométrie du flux du Ki67), et par le dosage des cytokines (Bioplex). Le résultat était corrélé à la fonction du greffon évaluée par le (3-score).Résultats : Les patients avec une mauvaise fonction montraient une plus grande réactivité anti-donneur avec l'ELISpot IFNy (p=0,007, r=-0,50) et l'index de prolifération (p=0,006, r=-0,51). Les patients avec une mauvaise fonction avaient des taux d'IFNy, IL-5 et IL-17 plus élevés
Langerhans islet transplantation allows curingtype 1 diabetes by restoring an endogenous insulin secretion. Halfof patients will resume insulin withinyears. This loss of function may be explained by the lack of monitoring tools able to diagnose an ongoing graft failure. The aims of our work were toevaluate the efficiency of MRI to diagnose islet graft rejection, and to assess the feasibility of immune cellular monitoring in transplanted patients.MRI in the rat mortelMethods: Syngeneic, allogeneic and xenogeneic islets were transplanted intra-portally to diabetic rats after labeling with superparamagnetic ironoxide nanoparticles (ferucarbotran). Images were acquired on a clinical 3T MRI scanner.Results: The signal decreasing was different between the 3 types of transplantations. At day 4, the MRI signal in allogeneic group was significantlylower while glycaemia remained normal. With a cut-off value of 84% at day 4, sensitivity of 91% and specificity of 70% were obtained.Cellular immune monitoringMethods: Mixed lymphocyte cultures were performed with peripheral blood mononuclear cells from recipients and splenocytes from donors. Immunereactivity was assessed by the release of IFNy (ELISpot), cell prolifération (flow cytometry of Ki67), and cytokine quantification (Bioplex). Theresults were correlated to the islet graft function assessed by (5-score.Results: Patients with low islet function showed higher cellular reactivity against donor cells assessed by ELISpot IFNy ((p=0,007, r=-0,50) andproliferation index (p=0,006, r=-0,51). Patients with low graft function had higher levels of IFNy, IL-5 and 1L-17

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Cavin, Jean-Baptiste. "Gastrointestinal plasticity in health and diseases : what we have learned from bariatric surgeries." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC143/document.

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Aujourd’hui, face à l’épidémie d’obésité, de plus en plus de personnes ont recours à la chirurgie bariatrique, qui permet une perte de poids importante et une amélioration des conditions métaboliques associées à l’obésité. L’adaptation gastro-intestinale après la chirurgie et ses conséquences métaboliques sont cependant peu connues. Nous avons développé des modèles murins de bypass gastriques et de gastrectomie longitudinale (sleeve) et nous avons caractérisé l’adaptation morphologique et fonctionnelle de l’épithélium gastro-intestinal après ces chirurgies afin de comprendre l’origine des améliorations métaboliques. Nous avons montré que l’estomac était remodelé après les deux chirurgies, suggérant une augmentation de la production acide par les cellules pariétales et une altération de la production de gastrine et de ghréline. Après le bypass, l’anse alimentaire était hyperplasique et la consommation intestinale de glucose était augmentée chez le rat et l’homme; après la sleeve, l’absorption de glucose lors du repas était diminuée. De plus, l’augmentation du nombre de cellules entéroendocrines observée après le bypass, et l’augmentation de leur densité après la sleeve pourraient participer à l’hypersécrétion des hormones incrétines. L’ensemble de ces mécanismes pourrait contribuer à améliorer le contrôle de la glycémie. Enfin, le mini-bypass chez le rat a induit une malabsorption protéique et des fuites énergétiques majeures qui n’étaient pas compensées par l’hyperplasie intestinale ou l’augmentation de l’expression des transporteurs de peptides. Cette thèse montre l’importance du tractus gastro-intestinal dans les conséquences métaboliques de la chirurgie bariatrique
In today’s global epidemic of obesity, more and more people are undergoing bariatric surgery, which is the best known treatment available to lose weight and treat obesity-associated diseases. Yet, little is known about gastrointestinal (GI) adaptation and its metabolic consequences after surgery. We developed original models of Roux-en-Y gastric bypass (RYGB), mini-bypass (MGB) and vertical sleeve gastrectomy (VSG) in rats, and we characterized the morphological and functional adaptations of the GI epithelium after these surgeries in order to understand the origin of the observed metabolic improvements. We reported profound changes in the remaining gastric mucosa of rats having undergone RYGB and VSG, suggesting an increase in acid production by parietal cells and an impaired production of gastrin and ghrelin. In RYGB rats and patients, the alimentary limb was hyperplasic and intestinal glucose consumption was increased. After VSG, the absorption of glucose during meals appeared diminished. These adaptations could participate in the lowering of blood glucose after surgery. In addition, the increased number of enteroendocrine cells observed in RYGB rats and patients, and their increased density in VSG rats, could contribute to the higher secretion of incretin hormone and improved glycemic control in operated individuals. Finally, we demonstrated in rats that the MGB was more malabsorptive than the RYGB. Indeed, we observed an increased fecal loss of nitrogen and energy despite intestinal overgrowth and higher expression of peptide transporters. This thesis brings new insight to the role of the GI tract in the metabolic outcomes of bariatric surgeries

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Olivi, Elena <1982&gt. "Adipose-derived stem cells and tissue revascularization: enhancing islet survival and performance for diabetes care." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5603/1/Olivi_Elena_tesi.pdf.

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Pancreatic islet transplantation represents a fascinating procedure that, at the moment, can be considered as alternative to standard insulin treatment or pancreas transplantation only for selected categories of patients with type 1 diabetes mellitus. Among the factors responsible for leading to poor islet engraftment, hypoxia plays an important role. Mesenchymal stem cells (MSCs) were recently used in animal models of islet transplantation not only to reduce allograft rejection, but also to promote revascularization. Currently adipose tissue represents a novel and good source of MSCs. Moreover, the capability of adipose-derived stem cells (ASCs) to improve islet graft revascularization was recently reported after hybrid transplantation in mice. Within this context, we have previously shown that hyaluronan esters of butyric and retinoic acids can significantly enhance the rescuing potential of human MSCs. Here we evaluated whether ex vivo preconditioning of human ASCs (hASCs) with a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids may result in optimization of graft revascularization after islet/stem cell intrahepatic cotransplantation in syngeneic diabetic rats. We demonstrated that hASCs exposed to the mixture of molecules are able to increase the secretion of vascular endothelial growth factor (VEGF), as well as the transcription of angiogenic genes, including VEGF, KDR (kinase insert domain receptor), and hepatocyte growth factor (HGF). Rats transplanted with islets cocultured with preconditioned hASCs exhibited a better glycemic control than rats transplanted with an equal volume of islets and control hASCs. Cotransplantation with preconditioned hASCs was also associated with enhanced islet revascularization in vivo, as highlighted by graft morphological analysis. The observed increase in islet graft revascularization and function suggests that our method of stem cell preconditioning may represent a novel strategy to remarkably improve the efficacy of islets-hMSCs cotransplantation.

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Olivi, Elena <1982&gt. "Adipose-derived stem cells and tissue revascularization: enhancing islet survival and performance for diabetes care." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5603/.

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Abstract:

Pancreatic islet transplantation represents a fascinating procedure that, at the moment, can be considered as alternative to standard insulin treatment or pancreas transplantation only for selected categories of patients with type 1 diabetes mellitus. Among the factors responsible for leading to poor islet engraftment, hypoxia plays an important role. Mesenchymal stem cells (MSCs) were recently used in animal models of islet transplantation not only to reduce allograft rejection, but also to promote revascularization. Currently adipose tissue represents a novel and good source of MSCs. Moreover, the capability of adipose-derived stem cells (ASCs) to improve islet graft revascularization was recently reported after hybrid transplantation in mice. Within this context, we have previously shown that hyaluronan esters of butyric and retinoic acids can significantly enhance the rescuing potential of human MSCs. Here we evaluated whether ex vivo preconditioning of human ASCs (hASCs) with a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids may result in optimization of graft revascularization after islet/stem cell intrahepatic cotransplantation in syngeneic diabetic rats. We demonstrated that hASCs exposed to the mixture of molecules are able to increase the secretion of vascular endothelial growth factor (VEGF), as well as the transcription of angiogenic genes, including VEGF, KDR (kinase insert domain receptor), and hepatocyte growth factor (HGF). Rats transplanted with islets cocultured with preconditioned hASCs exhibited a better glycemic control than rats transplanted with an equal volume of islets and control hASCs. Cotransplantation with preconditioned hASCs was also associated with enhanced islet revascularization in vivo, as highlighted by graft morphological analysis. The observed increase in islet graft revascularization and function suggests that our method of stem cell preconditioning may represent a novel strategy to remarkably improve the efficacy of islets-hMSCs cotransplantation.

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Muccini, Natascia <1980&gt. "Diabete ed ischemia critica degli arti inferiori. Valutazione degli indicatori sierologici di danno di parete: determinazione quantitativa delle cellule endoteliali circolanti mature." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6611/1/TESI_MUCCINI.pdf.

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OBIETTIVO : Quantificare le CECs/ml nei pazienti affetti da ischemia critica (IC) degli arti inferiori, eventuali correlazioni tra i fattori di rischio, lo stadio clinico con l’ aumento delle CECs. Valutare i cambiamenti strutturali (calcificazione ed infiltratto infiammatorio) e l’ angiogenesi (numero di capillari /sezione) della parete arteriosa. MATERIALI E METODI: Da Maggio 2006 ad Aprile 2008 in modo prospettico abbiamo arruolato paziente affetti da IC da sottoporre ad intervento chirurgico. In un data base abbiamo raccolto : caratteristiche demografiche, fattori di rischio, stadiazione dell'IC secondo Leriche-Fontaine (L-F), il tipo di intervento chirurgico. Per ogni paziente abbiamo effettuato un prelievo ematico di 2 ml per la quantificazione immunomagnetica delle CECs e prelievo di parete arteriosa. RISULTATI: In modo consecutivo abbiamo arruolato 33 pazienti (75.8% maschi) con età media di 71 aa (range 34-91aa), affetti da arteriopatia ostruttiva cronica periferica al IV stadio di L-F nel 84.8%, da cardiopatia ischemica cronica nel 60.6%, da ipertensione arteriosa nel 72.7% e da diabete mellito di II tipo nel 66.6%. Il valore medio di CECs/ml è risultato significativamente più elevato (p= 0.001) nei soggetti affetti da IC (CECs/ml =531.24 range 107- 3330) rispetto ai casi controllo (CECs/ml = 125.8 range 19-346 ). Le CECs/ml nei pazienti diabetici sono maggiori rispetto alle CECs/ml nei pazienti non diabetici ( 726.7 /ml vs 325.5/ml ), p< 0.05 I pazienti diabetici hanno presentato maggior incidenza di lesioni arteriose complesse rispetto ai non diabetici (66% vs 47%) e minor densità capillare (65% vs 87%). Conclusioni : Le CECs sono un marker sierologico attendibile di danno vascolare parietale, la loro quantità è maggiore nei pazienti diabetici e ipertesi. La minor capacità angiogenetica della parete arteriosa in presenza di maggior calcificazioni ed infiltrato infiammatorio nei diabetici, dimostra un danno istopatologico di parete maggiore .
OBJECTIVE: To quantify the number of circulating endothelial mature cells (EMC) in patients with critical limb ischemia (CI), and if correlations exit with risk factors, clinical stage and the number of cEMC. Evaluate the vascular structure changes (calcification and inflammatory infiltrate) and angiogenesis (number of capillary/arterial slice) of arterial wall. METHODS: Between 2006, may, and 2008, april, we’ve enrolled in a prospective study patients with CI scheduled for surgery. Demographic data, risk factors, clinical stage according to Leriche-Fontaine, type of surgery have been collected and stored in a database. For every patient 2 ml of blood have been sampled for immunomagnetic quantification of cEMC, so as a sample of the arterial wall. RESULTS: Thirtythree patients (25 males, 75,8%), aged 34-91, average 71years old, with CI underwent surgical revascularization have been enrolled. Twentyeight patients (84.8%) had a IV stage PAOD, chronic heart ischemia (60.6%), hypertension (72.7%) and diabetes mellitus type II (66.6%). The average concentration of cEMC/ml is significant higher (p=0.001) in patients with CI (cEMC=531.24, range 107-3330) than in control cases (cEMC =125.8, range 19-346). Also patients with diabetes type II have a higher concentration of cEMC than the non-diabetic patients (726.7/mm vs 325.5/ml vs.), with a p<0.05. Arterial wall of pts. with diabetes , compared with control group, revealed a higher incidence of complex arterial lesions (66% vs. 47%) and a lower capillary density (65% vs. 87%). CONCLUSION: cEMC are a reliable marker of vascular wall damage. Their concentration is higher in patients with diabetes, hypertensive disease. In patients with diabetes type 2 we’ve found a minor angiogenic capability with more calcifications and inflammatory infiltrate, showing a more serious damage

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Muccini, Natascia <1980&gt. "Diabete ed ischemia critica degli arti inferiori. Valutazione degli indicatori sierologici di danno di parete: determinazione quantitativa delle cellule endoteliali circolanti mature." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6611/.

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Abstract:

OBIETTIVO : Quantificare le CECs/ml nei pazienti affetti da ischemia critica (IC) degli arti inferiori, eventuali correlazioni tra i fattori di rischio, lo stadio clinico con l’ aumento delle CECs. Valutare i cambiamenti strutturali (calcificazione ed infiltratto infiammatorio) e l’ angiogenesi (numero di capillari /sezione) della parete arteriosa. MATERIALI E METODI: Da Maggio 2006 ad Aprile 2008 in modo prospettico abbiamo arruolato paziente affetti da IC da sottoporre ad intervento chirurgico. In un data base abbiamo raccolto : caratteristiche demografiche, fattori di rischio, stadiazione dell'IC secondo Leriche-Fontaine (L-F), il tipo di intervento chirurgico. Per ogni paziente abbiamo effettuato un prelievo ematico di 2 ml per la quantificazione immunomagnetica delle CECs e prelievo di parete arteriosa. RISULTATI: In modo consecutivo abbiamo arruolato 33 pazienti (75.8% maschi) con età media di 71 aa (range 34-91aa), affetti da arteriopatia ostruttiva cronica periferica al IV stadio di L-F nel 84.8%, da cardiopatia ischemica cronica nel 60.6%, da ipertensione arteriosa nel 72.7% e da diabete mellito di II tipo nel 66.6%. Il valore medio di CECs/ml è risultato significativamente più elevato (p= 0.001) nei soggetti affetti da IC (CECs/ml =531.24 range 107- 3330) rispetto ai casi controllo (CECs/ml = 125.8 range 19-346 ). Le CECs/ml nei pazienti diabetici sono maggiori rispetto alle CECs/ml nei pazienti non diabetici ( 726.7 /ml vs 325.5/ml ), p< 0.05 I pazienti diabetici hanno presentato maggior incidenza di lesioni arteriose complesse rispetto ai non diabetici (66% vs 47%) e minor densità capillare (65% vs 87%). Conclusioni : Le CECs sono un marker sierologico attendibile di danno vascolare parietale, la loro quantità è maggiore nei pazienti diabetici e ipertesi. La minor capacità angiogenetica della parete arteriosa in presenza di maggior calcificazioni ed infiltrato infiammatorio nei diabetici, dimostra un danno istopatologico di parete maggiore .
OBJECTIVE: To quantify the number of circulating endothelial mature cells (EMC) in patients with critical limb ischemia (CI), and if correlations exit with risk factors, clinical stage and the number of cEMC. Evaluate the vascular structure changes (calcification and inflammatory infiltrate) and angiogenesis (number of capillary/arterial slice) of arterial wall. METHODS: Between 2006, may, and 2008, april, we’ve enrolled in a prospective study patients with CI scheduled for surgery. Demographic data, risk factors, clinical stage according to Leriche-Fontaine, type of surgery have been collected and stored in a database. For every patient 2 ml of blood have been sampled for immunomagnetic quantification of cEMC, so as a sample of the arterial wall. RESULTS: Thirtythree patients (25 males, 75,8%), aged 34-91, average 71years old, with CI underwent surgical revascularization have been enrolled. Twentyeight patients (84.8%) had a IV stage PAOD, chronic heart ischemia (60.6%), hypertension (72.7%) and diabetes mellitus type II (66.6%). The average concentration of cEMC/ml is significant higher (p=0.001) in patients with CI (cEMC=531.24, range 107-3330) than in control cases (cEMC =125.8, range 19-346). Also patients with diabetes type II have a higher concentration of cEMC than the non-diabetic patients (726.7/mm vs 325.5/ml vs.), with a p<0.05. Arterial wall of pts. with diabetes , compared with control group, revealed a higher incidence of complex arterial lesions (66% vs. 47%) and a lower capillary density (65% vs. 87%). CONCLUSION: cEMC are a reliable marker of vascular wall damage. Their concentration is higher in patients with diabetes, hypertensive disease. In patients with diabetes type 2 we’ve found a minor angiogenic capability with more calcifications and inflammatory infiltrate, showing a more serious damage

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Hildenbrand-Joie, Céline Ziegler Olivier. "Plaie chirurgicale du talon chez le diabétique quels sont les facteurs pronostiques /." [S.l.] : [s.n.], 2003. http://www.scd.uhp-nancy.fr/docnum/SCDMED_T_2003_HILDENBRAND_JOIE_CELINE.pdf.

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24

Orrico, Catia <1972&gt. "Diabete ed ischemia critica degli arti inferiori. Studio del danno della parete arteriosa e del ruolo dell'endotelio circolante nella riparazione tessutale e nella neoangiogenesi." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/1739/1/Orrico_Catia_tesi.pdf.

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Objectives In diabetic and non diabetic patients with peripheral artery obstructive disease (PAOD), we sought to establish whether the vascular wall damage, the mature circulating endothelium and the "in situ" neoangiogenesis are related with each other. Design In the peripheral blood of diabetic patients suffering critical ischaemia associated with peripheral artery disease, low levels and poor function of circulating endothelial progenitor cells (EPCs) were observed. Moreover, circulating endothelial cells (CECs) have been described in different conditions of vascular injury. In this type of disorders, which are all characterized by endothelial damage, neoangiogenesis plays a key role. Materials In the study we recruited 22 diabetic and 16 non diabetic patients, all of them suffering PAOD and critical ischaemia; healthy subjects and multiorgan donors have also been considered like controls. Methods Histopathologic characterization was performed on arterial tissue samples under a light microscope. Flow cytofluorimetric analysis was used to quantify CECs in peripheral blood samples. "In situ" expression of the Vascular Endothelial Growth Factor (VEGF) and Metalloproteinase 9 (MMP-9) transcripts was quantified in a Real Time-PCR analysis. Circulating VEGF concentration was determined by an ELISA assay. Results Arterial wall from diabetic patients, compared with non diabetic subjects, revealed a higher incidence of serious lesions (60% vs 47%) and a lower number of capillaries (65% vs 87%). Mean number of CECs/ml was significantly increased in all patients, compared to healthy controls (p=0.001). Compared to healthy subjects, VEGF transcripts expression resulted significantly higher in diabetic patients and in all patients (p<0.05) and a similar result was obtained in the MMP-9 transcripts expression. Serum VEGF concentration was significantly increased in PAOD patients correlated with controls (p=0.0431). Conclusions Our study demonstrates that in all patients considered, probably, regressive phenomenons prevail on reparative ones, causing an inesorable and progressive degeneration of the vascular wall, worse by diabetes. The vascular damage can be monitored by determining CECs number and its severity and development are emphasized by the MMP-9 transcripts expression. The "in situ" VEGF increased expression seems to be the evidence of a parietal cells bid to induce local angiogenesis. This reparing mechanism could induce the EPCs mobilitation by means the release of VEGF from the arterial wall. The mechanism, however, is ineffective like demonstrated by the EPCs reduced number and activities observed in patients suffering PAOD and critical ischaemia.

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Orrico, Catia <1972&gt. "Diabete ed ischemia critica degli arti inferiori. Studio del danno della parete arteriosa e del ruolo dell'endotelio circolante nella riparazione tessutale e nella neoangiogenesi." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/1739/.

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Objectives In diabetic and non diabetic patients with peripheral artery obstructive disease (PAOD), we sought to establish whether the vascular wall damage, the mature circulating endothelium and the "in situ" neoangiogenesis are related with each other. Design In the peripheral blood of diabetic patients suffering critical ischaemia associated with peripheral artery disease, low levels and poor function of circulating endothelial progenitor cells (EPCs) were observed. Moreover, circulating endothelial cells (CECs) have been described in different conditions of vascular injury. In this type of disorders, which are all characterized by endothelial damage, neoangiogenesis plays a key role. Materials In the study we recruited 22 diabetic and 16 non diabetic patients, all of them suffering PAOD and critical ischaemia; healthy subjects and multiorgan donors have also been considered like controls. Methods Histopathologic characterization was performed on arterial tissue samples under a light microscope. Flow cytofluorimetric analysis was used to quantify CECs in peripheral blood samples. "In situ" expression of the Vascular Endothelial Growth Factor (VEGF) and Metalloproteinase 9 (MMP-9) transcripts was quantified in a Real Time-PCR analysis. Circulating VEGF concentration was determined by an ELISA assay. Results Arterial wall from diabetic patients, compared with non diabetic subjects, revealed a higher incidence of serious lesions (60% vs 47%) and a lower number of capillaries (65% vs 87%). Mean number of CECs/ml was significantly increased in all patients, compared to healthy controls (p=0.001). Compared to healthy subjects, VEGF transcripts expression resulted significantly higher in diabetic patients and in all patients (p<0.05) and a similar result was obtained in the MMP-9 transcripts expression. Serum VEGF concentration was significantly increased in PAOD patients correlated with controls (p=0.0431). Conclusions Our study demonstrates that in all patients considered, probably, regressive phenomenons prevail on reparative ones, causing an inesorable and progressive degeneration of the vascular wall, worse by diabetes. The vascular damage can be monitored by determining CECs number and its severity and development are emphasized by the MMP-9 transcripts expression. The "in situ" VEGF increased expression seems to be the evidence of a parietal cells bid to induce local angiogenesis. This reparing mechanism could induce the EPCs mobilitation by means the release of VEGF from the arterial wall. The mechanism, however, is ineffective like demonstrated by the EPCs reduced number and activities observed in patients suffering PAOD and critical ischaemia.

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Lugrin, Didier. "Réponse endocrino-métabolique à l'anesthésie générale et à la chirurgie chez le diabétique comparée au sujet sain." Bordeaux 2, 1989. http://www.theses.fr/1989BOR23071.

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Belligoli, Anna. "Adipose tissue and insulin secretion in the pathophysiology of obesity and its complications." Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3421917.

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Type 2 diabetis mellitus (T2DM) and obesity are global health care problems that are closely linked together. The precise mechanisms linking the two conditions remain unclear. Indeed, while the close relationship between T2DM and weight gain is well established, not all obese subjects are diabetic and this paradox is still unexplained. Impaired tissue perfusion has been proposed as one of the common metabolic defects, but little is known about adipose tissue (AT) microangiopathy and its possible role in T2DM. In animal models of obesity and diabetes, expanding AT microvasculature appears structurally altered and the angiogenetic potential of adipose derived stem cells impaired. Several studies, in humans, suggest that obesity leads to an impaired angiogenesis and AT hypoxia, inducing an inflammatory and a profibrotic response that plays a pivotal role in the pathogenesis of metabolic complications related to weight gain, first of all insulin resistance and diabetes. Moreover, from a pathophysiological point of view it is well established that dysfunctional visceral adipose tissue (VAT) is one of the major determinants of metabolic complications of obesity, while subcutaneous depots has been considered metabolically healthy. Nevertheless it could be hypothesized that in the progress of obesity through the metabolic impairment, SAT could become dysfunctional as VAT. On the basis of these data, we planned to study both subcutaneous and visceral adipose tissue in terms of adipocytes size, capillary density, adipose tissue stem cells (ASCs), endotelial precursor of AT and adipogenic potential, in obese subjects compared to lean subjects and in obese patients with a different glyceamic profile. We collected subcutaneous (SAT) and/or visceral (VAT) adipose tissue (AT) from 249 patients divided in 5 different groups: 18 lean normal weight and normoglycemic subjects (18.5 < BMI < 24,9 kg/m2) as control group, 68 normoglycemic obese subjects (ob N), 65 pre-diabetic obese subjects (ob pre-T2DM), 57 diabetic obese subjects (ob T2DM) and 41obese patients after underwent to a relevant weight loss (ob WL), corresponding to at least 10% of body weight. In different representative subgroups of these samples we performed: 1) immunohistochemical analysis to evaluate the morphometry of adipocyte and capillary density; 2) flow cytofluorimetric analysis of stromal vascular fraction (SVF) in order to quantify adipose tissue stem cells (ASCs), defined as CD45-CD34+CD31-, and endothelial precursors cells (EPs) defined as CD45-CD34+CD31+; 3) in vitro culture of ASCs obtained from SVF, in order to estimate the adipogenic potential in the different groups and different depot of AT; 4) gene expression profile by RT-Real Time PCR of PPRγ, Leptin, VEGFA, VEGF2, HIF1α to correlate their expression with previous findings. Our study confirm that obese AT is less vascularized than lean AT but T2DM does not represent an aggravating factor to the vascular reduction already present in obesity. On the contrary, T2DM and also prediabetic condition are able to further modify AT architecture, remodeling mature adipocyte size and adipogenic potential mediated by ASCs, importantly reducing AT hyperplastic growth capacity. Moreover our results allow us to assume that primum movens in development of T2DM must be searched in AT architecture and that both depots, SAT and VAT, play a pivotal role in the development of this disease. Furthermore, considering the continuous increase in bariatric procedures to treat both weigh gain and associated co-morbidities, we plan to evaluate the effects of laparoscopic sleeve gastrectomy (LSG) after one year. Indeed, whereas the beneficial effects of this bariatric procedure are well known, side effects are lesser known. In particular, postprandial hypoglycaemia is a well described side effect after RYGB, but few data are available for LSG.. We enrolled a total of 197 consecutive non-diabetic morbidly obese who underwent to LSG in our Center for the Study and the Integrated Treatment of Obesity (Ce.S.I.T.O.). All patients were studied 12 months before and after LSG and, anthropometrics parameters, medical history, clinical examination, complete blood count and complete metabolic panel including a 3- hour OGTT, were collected. One year after LSG, all patients had a significant reduction in weight and BMI, a significant improvement in glucose and insulin profile, and a significant decrease in inflammatory markers. We found an high incidence of severe hypoglycaemia (32,8%) after a provocative test (OGTT). Patients with hypoglycaemic events had a lower weight and BMI and a greater %EBML after LSG. compared to patients without hypoglycemic events. Hypoglycaemia was more frequent in patients having lower age, lower fasting blood glucose levels and higher triglycerides levels before LSG.
L’obesità e il diabete mellito tipo 2 (T2DM) sono due patologie strettamente correlate tra loro e, insieme, rappresentano una delle maggiori emergenze sanitarie a livello mondiale. I meccanismi fisiopatologici che legano le due patologie, non sono ancora stati completamente spiegati. Infatti, mentre sono abbastanza note le alterazioni che portano dall’aumento del peso corporeo alla comparsa di T2DM, meno noti sono i motivi per cui non tutti i pazienti obesi sviluppano la patologia diabetica. Per spiegare tale paradosso, alcuni studi si sono concentrati sulla possibile diversa capacità di espansione del tessuto adiposo (TA). Come tutti i tessuti, anche il TA, per poter espandersi, necessita di un’adeguata consensuale vascolarizzazione. E’ stato ipotizzato che un’alterata angiogenesi durante l’espansione del TA in alcuni soggetti, e la presenza di un danno a livello del microcircolo dello stesso TA, possano influire negativamente sul peggioramento del profilo glicemico. In alcuni modelli di animali, affetti da diabete e obesità, si sono evidenziate alterazioni a carico del microcircolo del TA e a carico del potenziale adipogenico. Consensualmente, alcuni studi sul TA dell’uomo, hanno suggerito che l’obesità porta ad una alterazione dell’angiogenesi a livello del TA con contemporanea comparsa di uno stato ipossico a sua volta responsabile della risposta infiammatoria e profibrotica. Infiammazione e fibrosi, hanno un ruolo fondamentale nello sviluppo dell’insulino-resistenza e quindi del T2DM. Inoltre, è noto che il tessuto adiposo viscerale (VAT) rappresenta il deposito di TA con maggior grado di infiammazione, mentre il tessuto adiposo sottocutaneo (SAT) è considerato un tessuto meno infiammato e in grado di avere un ruolo protettivo nei confronti dello sviluppo delle patologie metaboliche. Nonostante ciò, è possibile ipotizzare che con l’aumento progressivo del peso corporeo anche il SAT acquisisca caratteristiche disfunzionali come il VAT. Sulla base di questi presupposti, abbiamo deciso di analizzare le possibili variazioni in termini di morfologia, di densità capillare, di quantità di precursori adipogenici, di potenziale adipogenetico sia nel SAT che nel VAT di pazienti obesi e di pazienti normopeso normoglicemici. Inoltre, tra i pazienti obesi, sulla base delle caratteristiche cliniche e biochimiche, abbiamo selezionato coloro che erano normoglicemici (ob N), pre-diabetici (ob pre-T2DM) e diabetici (ob T2DM). Sono, quindi, stati raccolti campioni di SAT e/o il VAT da 249 pazienti divisi nei 4 gruppi sopra descritti: 18 pazienti normopeso e normoglicemici (18.5 < BMI < 24,9 kg/m2), 68 ob N, 65 ob pre-T2DM e 57 ob T2DM. Abbiamo, inoltre, avuto l’opportunità di analizzare il SAT di 41 pazienti obesi dopo significativo calo ponderale (ob WL). I campioni di TA sono stati studiati (1) mediante analisi immunocitochimica, al fine di valutare la morfologia degli adipociti e la densità capillare, (2) mediante analisi citofluorimetrica della frazione vasculo stromale (FVS) per quantificare la presenza di precursori adipocitari (CD45-CD34+CD31-) e di precursori endoteliali (CD45-CD34+CD31+), (3) attraverso la coltura dei preadipociti estratti dalla FVS, per valutare il potenziale adipogenetico; (4) mediante espressione genica di leptina, PPRγ, VEGFA, VEGF2 e HIF1-α. L’analisi dei nostri dati ci ha permesso di confermare che il tessuto adiposo dei soggetti obesi è significativamente meno vascolarizzato, sia nel SAT che, dato ad oggi non noto, nel VAT, rispetto al tessuto adiposo dei soggetti magri. Diversamente da quanto ipotizzato, la presenza di un alterato profilo glicemico, come quello presente nel pre-diabete, o la presenza di un diabete franco, non peggiorano ulteriormente la vascolarizzazione del TA, né nel SAT, né nel VAT. Ciò che si modifica in maniera significativa e precoce è l’architettura del TA. Infatti, già nei pazienti ob pre-T2DM e, anche nei pz ob T2DM, abbiamo osservato un progressivo aumento del diametro degli adipociti. Inoltre, nel TA dei pazienti con alterato profilo glicemico abbiamo osservato una significativa riduzione sia nella percentuale dei preadipociti presenti nella FVS sia nella loro capacità di differenziare in vitro. Questi dati ci permettono di ipotizzare che il TA dei pazienti con alterato profilo glicemico cresce maggiormente per ipertrofia che per iperplasia e che il ”primum movens” nello sviluppo della patologia diabetica è da ricercare nelle modificazioni a carico della cellula adiposa più che nelle modificazioni del microcircolo del tessuto adiposo sia nel VAT ma, anche nel SAT. Inoltre, considerando il progressivo incremento nell’utilizzo della chirurgia bariatrica per trattare sia l’aumento di peso ma anche le complicanze metaboliche a esso correlate, è stato eseguito uno studio sugli effetti della sleeve gastrectomy per via laparoscopica (LSG) a distanza di un anno dall’intervento. Mentre gli effetti positivi di questa procedura chirurgica sono ormai noti, meno noti sono gli effetti collaterali; in particolare, l’ipoglicemia post prandiale è stata ben descritta dopo intervento di by pass gastrico ma resta ancor poco indagata dopo intervento di LSG. Abbiamo, pertanto, reclutato 197 pazienti obesi non diabetici sottoposti a LSG e li abbiamo studiati prima e a distanza di un anno dall’intervento bariatrico. In tutti i pazienti è stata raccolta la storia clinica, è stato eseguito esame obiettivo e sono stati eseguiti gli esami bioumorali comprensivi di screening endocrino-metabolico completo, incluso OGTT prolungato a 180 minuti, e dosaggio delle citochine infiammatorie. Un anno dopo l’intervento, tutti i pazienti hanno avuto una significativa riduzione del peso corporeo e del BMI, un significativo miglioramento dei parametri metabolici, compreso il profilo glicemico e insulinemico, e una significativa riduzione delle citochine infiammatorie. Il 32,8% dei pazienti ha sviluppato un’ipoglicemia severa dopo test provocativo (OGTT). I pazienti con ipoglicemie hanno mostrato un peso e un BMI significativamente minore rispetto ai pazienti che non hanno sviluppato ipoglicemia e una percentuale di perdita di BMI significativamente maggiore. L’ipoglicemia si è dimostrata essere più frequente in quei pazienti che, prima dell’intervento, erano più giovani, con un peso e un BMI inferiore e con livelli di trigliceridemia superiori ai pazienti che non avevano sviluppato ipoglicemie dopo LSG.

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Hartmann, Dorothea Regina [Verfasser], and Christian [Gutachter] Jurowich. "Untersuchung früh-postoperativer Effekte bariatrischer Chirurgie auf Diabetes mellitus Typ 2 – Identifizierung von Non-Respondern / Dorothea Regina Hartmann ; Gutachter: Christian Jurowich." Würzburg : Universität Würzburg, 2018. http://d-nb.info/1154386589/34.

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Schiller, Julia Virginie. "Venöse Revaskularisation bei Vorliegen einer Mikro- und Makroangiopathie." Doctoral thesis, Universitätsbibliothek Leipzig, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-71990.

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In der vorliegenden Arbeit wurde die venöse Revaskularisation bei Vorliegen einer Mikro- und Makroangiopathie untersucht. Die Zielgruppe dieser Methodik sind Patienten, die aus kardiologischer und herzchirurgischer Sicht austherapiert sind, für die weder ein Stent noch eine konventionelle Bypassoperation in Frage kommt. Das betrifft Patienten mit disseziierten Gefäßen, mit schwerer diffuser koronarer Herzerkrankung oder small vessel disease. Für diese Patienten ist derzeit keine optimale Therapie vorhanden. Es handelt sich somit um eine ultima ratio-Therapie. Zur Prüfung der Effektivität der Methode bei beschriebenem Krankheitsbild wurde in Minipigs eine Mikroangiopathie durch Injektion von Mikrosphären (Durchmesser 100µm) in den linken Hauptstamm erzeugt. Nach 7 Wochen Krankheitsentwicklung der Mirkoangiopahtie wurde eine hochgradige Stenose des Ramus interventricularis anterior (RIVA) hervorgerufen, welches die Makroangiopathie simulieren sollte. Anschließend wurden die Tiere der Therapiegruppe mit einem Bypass von der Arteria mammaria auf die Begleitvene des RIVA versorgt. Dabei wurde die Begleitvene proximal der Anastomose ligiert. Die Kontrollgruppe blieb ohne Therapie. Die Stenose und der Bypass wurden angiographisch dargestellt. Nach 17 Wochen wurde bei allen Tieren eine Herzkatheteruntersuchung durchgeführt, um die Stenose und den Bypass zu beurteilen. Als Maß für die Herzleistung wurde zu allen 3 Versuchsteilen die Ejektionsfraktion bestimmt. Anhand der Ejektionsfraktion konnte die Überlegenheit der venösen Revaskularisation als Therapie gezeigt werden. 7 Wochen nach Injektion der Mikrosphären fielen die Werte der Ejektionsfraktion beider Gruppen ab. Nach 17 Wochen nahm die Ejektionfraktion der Therapiegruppe, die in der Zwischenzeit mit einem Bypass versorgt wurden, wieder deutlich zu und die der Kontrollgrupppe sank weiter ab. Zusätzlich wurden die entnommenen Herzen histologisch untersucht. Dabei zeigte sich ein Umbau des Gefäßsystems im Bereich der angeschlossenen Vene
Objective: Many patients with significant arterioclerosis of the heart cannot benefit from a coronary artery bypass and other methods because they have macroangiopathy combined with microangiopathy. We evaluated the efficiency of venous revascularization in minipigs with macroangiopathy combined with microangiopathy in a chronic model of 3 months. Histological analysis of arterial and venous vessels of the heart was conducted. Methods: In left anterior descending artery (LAD) microspheres (diameter 100µm) were injected in 24 minipigs (12 control group, 12 therapy group). 7 weeks later a stenosis of the LAD was performed in both groups with an average of 84,6 ± 4,3%. In therapy group left internal thoracic artery was anastomosed to the concomitant vein of the LAD in beating heart surgery. The flow of bypass was proved in angiography and the flow rate was measured by ultrasound. 10 weeks later bypass of therapy group and stenosis of both groups were verified in angiography. At the beginning of every part of the experiment the ejection fraction in both groups was evaluated with echocardiography. Hemodynamic monitoring was performed throughout the experiment. In histological analysis arterial and venous vessels in left atrium, right atrium, septum and area of anastomosis were evaluated in the thickness of wall and area of lumen. Results: In ejection fraction a significant difference between control and therapy group was seen. After performing the bypass, the ejection fraction in therapy group increased, while it decreased in control group in the same period of time of 10 weeks. In the histological analysis a non-classifiable type of vessel was found only in the area of the anastomosis. The vessel had a a large area of lumen and a thick wall due to media hyperplasia. Conclusion: Venous revascularization of the concomitant vein of the LAD via bypass of the left thoracic artery in a chronic model improves cardiac funcion and is therefore an effective method when having microangiopathy and macroangiopathy combined. The non-classifiable type of vessel are most likely arterialized veins which underwent a structural change of the wall due to the arterial blood pressure

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GIRIBONO, Anna Maria. "Trattamento endovascolare con nuovi materiali in pazienti diabetici affetti da ischemia critica e lesioni trofiche degli arti inferiori: risultati a medio termine." Doctoral thesis, Università degli studi del Molise, 2021. http://hdl.handle.net/11695/100849.

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Obiettivo: Il diabete mellito è una delle cause principali di amputazione dell’arto inferiore in tutto il mondo. Si tratta di una patologia attualmente molto diffusa, più di 425 milioni di persone ne sono affette e si prevede che questo numero raddoppierà dopo il 2045. Un soggetto diabetico ha un rischio significativo, fino al 25% in più rispetto ai non diabetici, di sviluppare ulcere trofiche durante tutta la sua vita. Negli ultimi anni grazie allo sviluppo di nuove tecnologie e nuovi materiali, il trattamento endovascolare è diventato ormai l’opzione terapeutica ormai di prima scelta. Lo scopo di questa tesi è quello di analizzare i risultati a breve e medio termine del trattamento endovascolare eseguito con diverse tipologie di materiali nei pazienti affetti da ischemia critica degli arti inferiori. In particolare sono state valutate la pervietà primaria, primaria assistita e secondaria il tasso di restenosi/occlusione e di salvataggio d’arto. Materiali e Metodi: Sono stati arruolati in due differenti centri di chirurgia vascolare rispettivamente del Sud e Nord Italia, AOU Federico II di Napoli e AOU Maggiore della Carità di Novara, 80 pazienti diabetici con concomitante arteriopatia periferica trattati mediante diverse tipologie di devices, in particolare in un sottogruppo di pazienti è stato utilizzato una nuova tipologia di stent: SUPERA® (Abbott Vascular, Santa Clara, CA, USA). Tutti i pazienti sono stati sottoposti preoperatoriamente ad un ecocolordoppler degli arti inferiori, calcolo dell’indice caviglia-braccio, radiografia del piede, tampone microbiologico ed antibiotico terapia mirata in caso di lesioni trofiche, calcolo del BMI. Risultati: Tutte le procedure di rivascolarizzazione sono state eseguite in anestesia locale. Sono stati trattati, da Febbraio 2018 a Marzo 2020, presso i due centri di riferimento 80 pazienti (69 M/11 F). È stato effettuato un ecocolordoppler di controllo a 3,6,12,18 e 24 mesi. Il successo tecnico è stato del 100%. La pervietà primaria, primaria assistita e secondaria complessiva di tutta la popolazione in esame sono state rispettivamente del 73,8%, 86% e 90% a 24 mesi. Nel sottogruppo di pazienti trattati con stent Supera® sono state rispettivamente del 75%, 90,6% e 87,5% a 24 mesi. Il tasso di salvataggio d’arto per tutti i pazienti è stato superiore al 90%. Conclusioni: Il trattamento endovascolare nei pazienti affetti da piede diabetico ischemico è ormai l’opzione terapeutica di prima scelta, grazie allo sviluppo di nuove tecnologie e nuovi materiali. Tali procedure di rivascolarizzazione endovascolare, eseguiti utilizzando svariati materiali, hanno mostrato buoni tassi di pervietà a breve e medio termine e nella maggior parte dei casi in cui si è verificata la complicanza, il trattamento endovascolare è risultato essere ripetibile ed efficace. Nella nostra casistica, infatti, Il tasso di salvataggio d’arto è stato superiore al 90%.
Objective: Diabetes mellitus is a main cause of lower limb amputation worldwide. It is currently a very common disease, more than 425 million people are affected and this number is expected to double after 2045. A person with diabetes has a significant risk, up to 25% more than non-diabetics, of developing trophic ulcers throughout his life. In recent years, thanks to the development of new technologies and new materials, the endovascular treatment has now become the therapeutic option of first choice. The purpose of this thesis is to analyze the short and medium term results of endovascular treatment performed with different types of materials in patients suffering from critical ischemia of the lower limbs. In particular, the primary, primary assisted and secondary patency, the restenosis / occlusion and limb salvage rate were assessed. Methods: Eighty diabetic patients with concomitant peripheral arterial disease were enrolled in two different vascular surgery centers respectively in South and North Italy, AOU Federico II in Naples and AOU Maggiore della Carità in Novara and treated with different types of devices; in a group of these a new type of stent was used: SUPERA® (Abbott Vascular, Santa Clara, CA, USA). All patients underwent preoperative an ultrasound Doppler of the lower limbs, a calculation of the ankle-arm index, foot x-ray, microbiological swab and targeted antibiotic therapy in case of trophic lesions, calculation of the BMI. Results: All revascularization procedures were performed under local anesthesia. From February 2018 to March 2020, 80 patients (69M/11F) were treated at the two reference centers. A control echocolordoppler was performed at 3,6,12,18 and 24 months. Technical success was 100%. The primary, primary assisted and secondary patency of the entire population under examination were respectively 73.8%, 86% and 90% at 24 months. In the subgroup of patients treated with Supera® stents, they were 75%, 90.6% and 87.5% at 24 months, respectively. The limb salvage rate for all patients was over 90%. Conclusions: The endovascular treatment in patients with ischemic diabetic foot is now the first choice therapeutic option, thanks to the development of new technologies and new materials.

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Signac, Angélique. "Bilan de deux années de réadaptation de patients amputés vasculaires du membre inférieur." Bordeaux 2, 1997. http://www.theses.fr/1997BOR2M110.

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Cunin, Claude. "Greffes intracérébroventriculaires de noyaux hypothalamiques : Études histophysiologiques chez le rat brattleboro déficient génétique en vasopressine." Nancy 1, 1986. http://www.theses.fr/1986NAN10009.

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L'étude immunocytochimique du développement du greffon a mis en évidence de la vasopressine, de l'ocytocine des neurophysines I et II associées. Examen des paramètres de la fonction rénale. La technique de greffe serait susceptible de recréer une restauration fonctionnelle au niveau du système nerveux diencéphalique

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Pietramaggiori, Giorgio. "Integrazione di forze meccaniche, fattori circolanti e matrici extracellulari: un nuovo paradigma in ingegneria dei tessuti." Doctoral thesis, Università degli studi di Padova, 2007. http://hdl.handle.net/11577/3425015.

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New therapeutical strategies are needed to face the dramatic increases in the prevalence of difficult to heal ulcers. Using new in vivo models and a wound staging system developed ad hoc, in these studies we propose an important role of mechanical forces as non pharmacological healing inductors. Results demonstrate that controlled regimens of mechanical forces in vivo may be used to stimulate cell proliferation and vascular remodeling, alone or in combination with more traditional approaches based on soluble factors and extracellular matrices.

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Taleb, Nadine. "L’efficacité du pancréas artificiel externe durant l’exercice chez les adultes atteints de diabète de type 1." Thèse, 2016. http://hdl.handle.net/1866/18885.

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Problématique : l’activité physique est évitée par les patients atteints de diabète de type 1 (DbT1) malgré ses bénéfices et ce par crainte du risque d’hypoglycémie majoré par l’exercice. Le pancréas artificiel externe est une nouvelle technologie de trois composantes qui fonctionnent en boucle fermée, un système de surveillance continue du glucose (SSCG), un algorithme et une pompe à insuline. Peu d’études ont été conçues spécifiquement pour tester le pancréas artificiel pendant l’exercice. De plus, la précision des SSCG pourrait être compromise par les changements rapides du glucose au cours de l’exercice. Objectifs : 1) Tester et comparer l’efficacité des deux versions du pancréas artificiel, simple-hormone (insuline seule) et double-hormone (insuline et glucagon), pour prévenir l’hypoglycémie durant deux types d’exercice, en continu et par intervalles, chez les patients DbT1. 2) Comparer la performance de deux SSCG, Dexcom et Enlite, au repos et pendant l’exercice. Résultats : 1) Avec le système à simple-hormone comparé au double-hormone, 31,2% des participants ont eu au moins un épisode d’hypoglycémie nécessitant un traitement par glucides vs. 9% (p=0,02) et 24,4 ± 27,6 % de temps était passé en hypoglycémie (glucose plasmatique < 4 mmol/l) vs. 4,4 ± 14,3% (p=0,0001), respectivement. 2) Les moyennes de différence relative absolue par rapport au glucose plasmatique pour Dexcom vs. Enlite étaient comparables au repos 13,8 vs. 12,4% (p=0,53) et pendant l’exercice 22,5% vs. 20,4% (p=0,58). La comparaison repos vs exercice était significatif pour Dexcom (p=0,005) et Enlite (p=0,007). Conclusions : le pancréas artificiel à double-hormone engendre un moindre risque d’hypoglycémie et permet un meilleur contrôle de la glycémie que le système à simple-hormone. Les deux SSCG, Dexcom et Enlite ont une bonne performance, sont comparables, mais sont tous les deux moins précis durant l’exercice qu’au repos.
Background: Physical activity is often avoided by patients with Type 1 diabetes (T1D) despite its health benefits due to fear of its elevated hypoglycemic risk. The external artificial pancreas is a new technology that controls glucose via a closed-loop strategy of three components; a continuous glucose monitoring system (CGMS), an algorithm and an insulin pump. Studies of the artificial pancreas included physical activity sessions but were rarely designed to specifically assess its efficacy during exercise. Moreover, the precision of the CGMS can be affected by the rapidly changing blood glucose levels during exercise. Objectives: 1) To test and compare the efficacy of the two versions of the artificial pancreas, single-hormone (insulin only) and dual-hormone (insulin plus glucagon) during two types of exercise, continuous and interval, in patients with T1D. 2) To compare the performance of two CGMS, Dexcom and Enlite, at rest and during exercise. Results: 1) During single-hormone artificial pancreas in comparison to dual-hormone, 31.2% of the participants had at least one hypoglycemic episode necessitating treatment vs. 9% (p=0,02) and 24.4 ± 27.6 % of the time spent in hypoglycemia (plasma glucose < 4 mmol/l) vs. 4.4 ± 14.3% (p=0.0001), respectively. 2) The mean relative absolute differences (MARD) in reference to plasma glucose for Dexcom vs. Enlite were at rest 13.8 vs. 12.4% (p=0.53) and during exercise 22.5% vs. 20.4% (p=0.58). The comparison of mean ARD`s at rest vs. exercise were significant for Dexcom (p=0.005) and Enlite (p=0.007). Conclusions: The dual-hormone artificial pancreas was shown to be better than single-hormone at achieving hypoglycaemia-free control during exercise in adults with T1D. Dexcom and Enlite demonstrated comparable overall performances during rest and physical activity with a lower accuracy for both sensors during exercise.

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Leroux-Stewart, Josée. "Effets cardiométaboliques de la restriction calorique seule ou en combinaison avec l’activité physique dans le diabète de type 2." Thèse, 2016. http://hdl.handle.net/1866/18871.

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Le diabète de type 2 (DbT2) est une maladie chronique caractérisée par des taux sanguins élevés de glucose pouvant engendrer de multiples complications, sources de morbidité et mortalité importantes. De façon alarmante, la prévalence mondiale est en augmentation due en grande partie au vieillissement de la population et à l’adoption d’habitudes de vie (HDV) malsaines. La sédentarité et la mauvaise qualité alimentaire sont à la base d’une épidémie d’obésité qui joue un rôle crucial dans la pathogénèse du DbT2. La modification des HDV en visant une balance calorique négative demeure un traitement primordial dans la prise en charge de cette maladie. Toutefois, il persiste un doute par rapport à la thérapie à privilégier entre une restriction calorique (RC) ou une combinaison d’une thérapie à base de RC et d’activité physique (AP), afin de favoriser une perte de masse grasse et de gras épicardique. Ce dernier représente le gras viscéral du cœur et est un marqueur émergent qui pourrait aider dans la stratification du risque cardiovasculaire. Le but général de ce mémoire est de caractériser les effets indépendants de la RC et de l’AP sur le gras total, le gras épicardique et le profil cardiométabolique des personnes atteintes de DbT2. Pour ce faire, une étude randomisée contrôlée de 16 semaines fut menée avec 73 patients répartis en 3 groupes de randomisation (Contrôle, RC, RC+AP) en visant un déficit calorique similaire dans les 2 groupes d’intervention. Les résultats ont démontré que la combinaison RC+AP favorise une réduction plus significative de la masse grasse totale et de l’épaisseur du gras épicardique. Toutefois, il n’y a pas eu d’amélioration additionnelle du profil cardiométabolique. Ces résultats doivent maintenant être validés dans de plus grosses études.
Type 2 diabetes (T2D) is a chronic disease characterized by high blood sugar that can lead to many complications with potential morbid outcomes. Alarmingly, the worldwide prevalence is increasing at a high rate mainly du to aging and harmful lifestyle habits. In fact, inactivity and poor food choices are at the heart of an obesity epidemic that plays a crucial role in the pathogenesis of T2D. Lifestyle modifications thus play an important role in patient care. However, it remains uncertain which therapy between a caloric restriction (CR) alone or a combination of CR plus physical activity (PA) should be encouraged to achieve better reduction in fat mass and in epicardial fat thickness. The latter represents the visceral fat depot of the heart and is emerging as an important marker for predicting and stratifying cardiovascular risk. The objective of this Master’s thesis is to better characterize the independent effects of CR and PA on total fat mass, epicardial fat, and overall cardiometabolic profile of patients with T2D. To achieve this, a randomized controlled 16-week trial was performed, with 73 patients randomized to 1 of 3 groups (Control, CR, or CR+PA), while aiming for a similar caloric deficit in both intervention groups. Results showed that the combination of CR+PA allows a larger reduction of fat mass and epicardial fat thickness. However, these findings did not translate into significant differences in cardiometabolic improvements between groups. These results now need to be validated in larger cohorts with longer follow-ups.

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Patková, Barbora. "Bariatrická chirurgie a kompenzace diabetu." Master's thesis, 2018. http://www.nusl.cz/ntk/nusl-387229.

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Introduction: Obesity and type 2 diabetes mellitus (hereinafter referred to as DM2T) are called the greatest epidemic of the 21st century. Its occurrence is on the rise not only in the Czech Republic but all around the world. Overweight and obesity are the key factors in developing DM2T, they are affecting the occurrence of the disease in men in 64 % and 77 % in women. Based on the observations, nearly 60 % of the population in the Czech Republic are considered obese or overweight. Bariatric/Metabolic surgery is one of the most effective treatments of the DM2T. Objectives: The objective of this thesis is to describe and analyze the effect of each bariatric surgery on the patients of 3rd Internal Clinic of Endocrinology and Metabolism, General University Hospital and 1st Medical Faculty, Charles University in Prague within the first two years post-surgery. The same time period is observed to monitor the DM2T compensation depending on the type of bariatric surgery. Methodology: 128 patients were observed (including 52 patients diagnosed with DM2T), that underwent the bariatric surgery. The data were gathered from the medical records in the hospital's information system Medea. These data were further analyzed, processed and assessed in Microsoft Excel and also together with the agency STEM/MARK a.s....

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Benjamim, de Oliveira Adriana. "Évolution échocardiographique et prédicteurs de progression de la sténose valvulaire aortique." Thèse, 2014. http://hdl.handle.net/1866/11795.

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Manolescu, Daniel-Constantin. "Impacts métaboliques et thérapeutiques de la vitamine A, sous forme d’acide rétinoïque, dans l’obésité, la résistance à l’insuline et le diabète de type 2 chez la souris ob/ob = Metabolic and Therapeutic Impacts of Vitamin A as Retinoic Acid on Obesity, Insulin Resistance, and Type 2 Diabetes in ob/ob Mice." Thèse, 2018. http://hdl.handle.net/1866/21808.

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Hartmann, Dorothea Regina. "Untersuchung früh-postoperativer Effekte bariatrischer Chirurgie auf Diabetes mellitus Typ 2 – Identifizierung von Non-Respondern." Doctoral thesis, 2018. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-156714.

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Hintergrund: Metabolische Chirurgie bei normal- oder übergewichtigen Patienten ist ein brisantes Thema. Die Identifikation von präoperativen Faktoren, die das Outcome bezüglich Diabetes nach bariatrischen Operationen beeinflussen, ist daher notwendig. Methoden: Zwischen 2005 und 2011 wurden 235 morbid adipöse Patienten mit einer bariatrischen Operation versorgt. 82 der 235 Patienten hatten Diabetes mellitus Typ 2 (T2DM). Die Daten dieser Subgruppe wurden in uni- und multivariaten Analysen untersucht um Faktoren zu identifizieren, die bereits präoperativ anzeigen, dass keine Verbesserung der diabetischen Stoffwechsellage (Non-Response) eintreten wird. Ergebnisse: 3 Monate postoperativ verbesserte sich bei 17 von 82 Patienten die diabetische Stoffwechsellage nicht. Es konnte kein Zusammenhang zwischen ausbleibendem Gewichtsverlust und Diabetes-Non-Response gezeigt werden. In der univariaten Analyse war die präoperative Dauer der Diabetes-Erkrankung signifikant länger (9.146 vs. 6.270 Jahre; *p = 0.016) und der präoperative HbA1c signifikant höher (8.341 vs. 7.781 %; *p = 0.033) in der Gruppe der Non-Responder gegenüber den Patienten, deren Diabetes sich ausreichend verbessert hatte. Ebenso waren unter den Non-Respondern mehr Patienten auf eine medikamentöse Therapie mittels oraler Antidiabetika und Insulin angewiesen (*p = 0.045). In der multivariaten Analyse zeigten Patientenalter zum Zeitpunkt der Operation, präoperative Insulindosis und die Dosis oraler Antidiabetika eine positive Korrelation zu postoperativer Diabetes-Non-Response (*p = 0.04; *p = 0.021; *p = 0.021). Eine ausbleibende Verbesserung der diabetischen Stoffwechsellage war seltener nach Roux-en-Y Magenbypass-Operation verglichen mit anderen bariatrischen Eingriffen (**p = 0.008). Zusammenfassung: Eine lange präoperative Diabetes-Dauer, hohe HbA1c-Werte und eine präoperative Diabetestherapie bestehende aus oralen Antidiabetika und Insulin können eine ausbleibende Verbesserung der diabetischen Stoffwechsellage in der früh postoperativen Phase nach bariatrischer Chirurgie anzeigen. Alter, präoperative Insulintherapie und orale Antidiabetika können als unabhängige signifikante prädiktive Faktoren angesehen werden
Background: Diabetes surgery in nonobese or moderately obese patients is an emerging topic. The identification of preoperative factors predicting diabetes outcome following bariatric surgery, especially for metabolic nonresponders, is imperative. Methods: Between 2005 and 2011, 235 patients underwent bariatric surgery for morbid obesity. Eighty-two of 235 patients had type 2 diabetes mellitus (T2DM). Data from this subgroup were investigated with univariate and multivariate analyses to identify predictors for metabolic nonresponse after surgery. Results: Diabetes did not improve in 17/82 patients within 3 months after surgery. No correlation between excess body weight loss and metabolic response was detected. In univariate analysis, preoperative duration of diabetes was significantly longer in the nonresponder group (9.146 vs. 6.270 years; *p 0.016), preoperative HbA1c levels were significantly higher among the nonresponders than among the responders (8.341 vs. 7.781 %; *p 0.033), and more patients in the nonresponder group were reliant on a multi-drug approach preoperatively (*p 0.045). In multivariate analysis, age, preoperative doses of insulin, and preoperative oral antidiabetics showed positive correlation to metabolic nonresponse after surgery (*p 0.04; *p 0.021; *p 0.021). Metabolic failure rate was lower after Roux-en-Y gastric bypass compared to other bariatric procedures (**p 0.008). Conclusions: A long history of preoperative T2DM, high preoperative HbA1c levels, and a preoperative therapy consisting of diverse approaches to diabetes treatment may be factors predicting failure of diabetes improvement in the early postoperative course after bariatric surgery. Age, preoperative insulin, and oral antidiabetic medication can be regarded as independent, significant predictors for metabolic outcome after bariatric surgery

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Nosso, Gabriella. "REMISSIONE DEL DIABETE MELLITO DI TIPO 2 DOPO CHIRURGIA BARIATRICA: MECCANISMI FISIOPATOLOGICI E SIGNIFICATO CLINICO." Tesi di dottorato, 2015. http://www.fedoa.unina.it/10362/1/Tesi%20Dottorato%20GabriellaNosso.pdf.

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La chirurgia bariatrica rappresenta una valida opzione terapeutica nel trattamento dell'obesità, essendo in grado di indurre una significativa e stabile perdita di peso con miglioramento o scomparsa delle co-morbidità associate all'obesità. In particolare, numerose evidenze scientifiche documentano un drammatico miglioramento dell'omeostasi glicemica dopo interventi di chirurgia bariatrica, sebbene sia difficile stabilire se si tratti di risoluzione o remissione del diabete. Inoltre restano ancora da chiarire i precisi meccanismi fisiopatologici alla base del miglioramento del diabete. Durante il triennio del Corso di Dottorato in "Fisiopatologia Clinica e Medicina Sperimentale" la mia attività di ricerca ha riguardato gli effetti di differenti interventi di chirurgia bariatrica sui meccanismi fisiopatologici alla base del miglioramento dell'omeostasi glico-lipidica, con particolare riguardo allo studio degli ormoni entero-insulari e dell'andamento glicemico in condizioni di vita reale in soggetti in risoluzione clinica del diabete dopo chirurgia bariatrica allo scopo di definire criteri più appropriati di remissione. A tal fine sono stati condotti quattro studi: Studio 1. Obiettivo. Valutare la sensibilità insulinica, la secrezione insulinica e la risposta postprandiale degli ormoni entero-insulari in pazienti con diabete mellito di tipo 2 (DM2) ed obesità sottoposti a bypass gastrico (BPG) o gastrectomia verticale (SG). Materiali e Metodi. In 33 pazienti obesi con DM2 [14 sottoposti a BPG; 6M, età: 49±7 anni, BMI: 42±6 Kg/m2 ed HbA1C: 8.1±2.2 %, (M±DS) e 19 sottoposti a SG; 8M, età: 44±10 anni, BMI: 46±9 Kg/m2 ed HbA1C: 7.6±2 %] sono state valutate sensibilità e secrezione insulinica e la risposta degli ormoni gastrointestinali (GIP, GLP-1 e grelina) ad un pasto misto liquido (305 kcal) prima ed 1 anno dopo chirurgia bariatrica. Risultati. Ad 1 anno dall'intervento chirurgico si è osservato un decremento ponderale di circa 40 kg dopo entrambe le procedure. La remissione del DM2, valutata come glicemia a digiuno < 126 mg/dl ed HbA1C < 6.5%, si verificava nel 86% dei pazienti dopo BPG e nel 74% dei soggetti dopo SG. La sensibilità insulinica, espressa come indice OGIS (Oral Glucose Insulin Sensitivity), aumentava significativamente a 12 mesi, senza differenze tra le due procedure chirurgiche. La secrezione insulinica, sia precoce ed espressa come IGI30 (Indice insulinogenico), che totale (IGI180) aumentava significativamente in entrambi i gruppi (p<0.05). Il picco di GLP-1 dopo pasto misto, pressoché assente nel preoperatorio, raddoppiava ad 1 anno dopo SG (p<0.05) mentre incrementava di 7 volte 1 anno dopo BPG (p<0.001); la secrezione del GIP (valutata come AUC) e il picco a 60 minuti si riducevano ad 1 anno con una soppressione di circa il 50% rispetto ai valori pre-intervento dopo entrambe le procedure (p<0.05). La secrezione di grelina si riduceva significativamente solo dopo SG (p<0.05), mentre rimaneva invariata dopo BPG. Conclusioni. Lo studio mostra che secrezione e sensibilità insulinica migliorano della stessa entità con le due procedure chirurgiche (BPG e SG) mentre il profilo degli ormoni gastrointestinali presenta significative differenze. La perdita di peso, piuttosto che le modifiche entero-ormonali, sembra costituire il determinante chiave del miglioramento dello stato metabolico un anno dopo chirurgia bariatrica. Studio 2. Obiettivo. Valutare gli effetti a lungo termine della chirurgia bariatrica sul metabolismo lipidico a digiuno e postprandiale in soggetti con DM2 ed obesità e le possibili relazioni con le modifiche degli entero-ormoni. Materiali e Metodi. Sono stati studiati 19 pazienti con DM2 ed obesità in assenza di terapia ipolipidemizzante (età:46±8 anni, BMI:42±6 kg/m²) di cui 10 sottoposti a BPG e 15 sottoposti ad SG. Prima e 24 mesi dopo l'intervento sono stati valutati i parametri clinici e la risposta lipidica ed entero-ormonale ad un pasto misto liquido (305 kcal). Risultati. I due gruppi avevano simili caratteristiche pre-operatorie. Due anni dopo l'intervento si osservava una riduzione significativa del peso corporeo, della glicemia e dell' insulinemia a digiuno rispetto al pre-operatorio (p<0.05 per tutti) e senza differenze tra le due procedure. Durante il follow-up post-operatorio i trigliceridi a digiuno si riducevano significativamente (p<0.05) e il colesterolo HDL aumentava similmente in entrambi i gruppi. Di contro, il colesterolo LDL a digiuno si riduceva solo dopo BPG (p<0.05). La risposta dei trigliceridi plasmatici al pasto misto, si riduceva marcatamente dopo entrambe le procedure (p<0.001) mentre i livelli postprandiali del colesterolo LDL si riducevano significativamente solo dopo BPG (p<0.05). La risposta del GLP-1 al pasto misto era significativamente aumentata dopo entrambe le procedure rispetto al pre-operatorio ma in misura maggiore dopo BPG (p<0.001). La riduzione della trigliceridemia a digiuno osservata 2 anni dopo chirurgia bariatrica si associava positivamente con la perdita di peso (R=0.470, p=0.049) e con la riduzione dell' HOMA-IR (R=0.679, p=0.001), mentre il colesterolo LDL post-intervento correlava con la risposta del GLP-1 al pasto misto solo dopo BPG (R=-0.733, p=0.007). Conclusioni: Lo studio dimostra che entrambe le procedure bariatriche inducono un marcato miglioramento della trigliceridemia, sia a digiuno che post-prandiale, ed un significativo incremento dei livelli di HDL-colesterolo. Il colesterolo LDL si riduce solo dopo BPG attraverso un meccanismo probabilmente mediato dal recupero del GLP-1. Studio 3. Obiettivo. Valutare l'efficacia clinica della chirurgia bariatrica vs terapia medica con liraglutide sul decremento ponderale, controllo glicemico e profilo di rischio cardiovascolare in pazienti con DM2 ed obesità severa. Materiali e Metodi. Sono stati studiati retrospettivamente 31 pazienti con DM2 ed obesità severa sottoposti ad intervento di chirurgia bariatrica e 31 soggetti con DM2 e comparabile peso corporeo in terapia con liraglutide in aggiunta alla terapia medica. In tutti i partecipanti sono stati valutati prima e 12 mesi dopo il trattamento i principali parametri antropometrici, controllo glicemico, trattamento ipoglicemizzante e delle altre comorbidità, sicurezza ed effetti collaterali. Risultati. L'età media era rispettivamente di 47 ± 8 e 56 ± 9 anni nel gruppo bariatrico e nei soggetti in terapia medica (p<0.001); il BMI prima del trattamento era 44 ± 7 e 40 ± 4 kg/m2 nel gruppo chirurgico e nel gruppo in terapia medica, rispettivamente (p = 0.03). Un anno dopo il trattamento, la perdita di peso media era di 38 ± 15 kg nel gruppo bariatrico e di 5 ± 8 kg nel gruppo in terapia con liraglutide (p<0.001). Il controllo glicemico migliorava in entrambi i gruppi ma con un migliore risultato dopo chirurgia bariatrica. L' UKPDS risk score si riduceva in entrambi i gruppi, sebbene in misura maggiore nel gruppo chirurgico (p<0.001). In aggiunta, circa il 60 % dei pazienti in terapia con liraglutide raggiungeva il target di HbA1c <7 % perdendo almeno il 5 % del peso corporeo. Conclusioni. In pazienti con DM2 ed obesità severa, la chirurgia bariatrica induce una riduzione ponderale ed un miglioramento metabolico complessivo significativamente maggiori rispetto alla terapia medica. Da notare tuttavia che l'aggiunta di liraglutide alla terapia medica è in grado di indurre una perdita di peso clinicamente rilevante e di ottimizzare il controllo glicemico in più della metà dei pazienti. Questo dato sottolinea la necessità di implementare interventi intensivi sullo stile di vita in associazione alla terapia con incretino-mimetici come possibile strategia terapeutica in pazienti con DM2 ed obesità severa che hanno accesso limitato, o rifiutano, l'approccio chirurgico. Studio 4. Obiettivo. La remissione del diabete (RD) dopo chirurgia bariatrica viene definita sulla base del raggiungimento di specifici targets di glicemia a digiuno ed HbA1c in assenza di terapia ipoglicemizzante. Pochi studi hanno valutato l'andamento giornaliero della glicemia in condizioni di vita reale. Scopo. Valutare il profilo glicemico mediante monitoraggio in continuo (CGM) in pazienti obesi in RD. Materiali e metodi. I gruppi di studio includono 19 pazienti obesi (10M, età: 48±8 anni, IMC: 32 ± 6 kg/m2) in RD da almeno 2 anni dopo chirurgia bariatrica di cui 9 sottoposti a BPG e 10 sottoposti a SG, ed un gruppo di controllo di 9 soggetti non operati con simili caratteristiche antropometriche (M: 4; età: 49 ± 10 anni, IMC: 35 ± 8 kg/m2). Tutti i partecipanti sono stati sottoposti a 2-h OGTT e CGM (IG; Dexcom G4 PLATINUM). Al momento dello studio, i pazienti bariatrici avevano ottenuto una riduzione ponderale di ~28% (IMCpre: 42±8, IMCpost: 32±6 Kg/m2, p<0.0001) e dell'HbA1c di 1.9% (da 7.6±2 a 5.7±0.6 %, p=0.0001). Risultati. All'OGTT, nessun soggetto mostrava una glicemia > 200 mg/dl a 120'. Al CGM, la glicemia media era simile in entrambi i gruppi (117 e 106 mg/dl, rispettivamente nel gruppo bariatrico e di controllo, p=0.07); tuttavia entrambi i gruppi chirurgici avevano valori di IG massimo significativamente maggiori rispetto al gruppo di controllo (p<0.05); i soggetti del gruppo BPG presentavano un picco medio statisticamente più elevato rispetto ai pazienti SG e trascorrevano un maggior tempo in ipoglicemia. La variabilità glicemica era significativamente più alta nei bariatrici vs controlli, con valori significativamente maggiori in BPG rispetto a SG (p<0.05). Nessuna differenza era riscontrata in termini di età, durata del DM2 e BMI post-operatorio tra i soggetti con e senza evidenza di ipoglicemia al CGM. I soggetti con ipoglicemia mostravano un più cospicuo decremento ponderale, un maggiore miglioramento della sensibilità insulinica, un più elevato picco post-operatorio di GLP-1 e livelli al picco di GIP più bassi dopo l'intervento (p<0.05, per tutti). Conclusioni. I pazienti in RD dopo chirurgia bariatrica presentano, a fronte di normali valori di HbA1c, glicemia a digiuno e glicemiaOGTT-2h, un'elevata variabilità glicemica con picchi iperglicemici e un'alta percentuale di ipoglicemie, soprattutto dopo BPG. Studi a più lungo termine chiariranno gli effetti cardiovascolari della elevata variabilità glicemica.

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ZENTI, MARIA GRAZIA. "Effetti di diverse tecniche di Chirurgia Bariatrica sull’Omeostasi Metabolica in pazienti Obesi." Doctoral thesis, 2014. http://hdl.handle.net/11562/693959.

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Abstract:

La chirurgia bariatrica si è dimostrata efficace nel determinare la remissione del diabete tipo 2 nei soggetti obesi, tuttavia il meccanismo con cui le diverse tecniche chirurgiche agiscono sulla secrezione β-cellulare e sulla modulazione dell’insulino-resistenza non è ancora completamente chiarito. Scopo: valutare in modo prospettico gli effetti di diverse tecniche di chirurgia bariatrica (bendaggio gastrico, sleeve gastrectomy, bypass gastrico) sul calo ponderale e sul compenso glicometabolico in pazienti obesi diabetici, e individuare, in un sottogruppo di questi pazienti, i meccanismi attraverso cui l’intervento di chirurgia bariatrica modifica l’omeostasi del glucosio. Metodi: Sono stati arruolati 104 obesi diabetici, (66 F; 38 M) sottoposti consecutivamente a chirurgia bariatrica; 11 pazienti sono stati sottopostia a Bendaggio Gastrico Regolabile (LAGB) (età 47,3±2,9 anni; BMI 42,3±2,5 kg/m2), 77 a Bypass Gastrico (RYGB) (età 49.0± 0,1 anni; BMI 45,7±0,76 kg/m2) e 16 a Sleeve gastrectomy (SG) (età 50,0±2,3 anni; BMI 50,7±2,2 kg/m2). I pazienti erano eterogenei per durata di malattia e per trattamento antidiabetico. 5 soggetti (2M; 3F), età media 48,2±4,3 anni, peso 112,5±7,9 kg, BMI 40,9±2,7 kg/m2, durata di diabete: 5,6 anni (range 3-12 aa), HbA1c 7,6± 0,6%, sono stati sottoposti a test pasto-misto (186 Kcal: 53% carboidrati, 17% proteine, 30% grassi) prima e 1 mese dopo chirurgia (RYBP), con dosaggio di glicemia, C-peptide, insulina, lattato, e GIP per 5 ore. La funzione β-cellulare è stata valutata mediante analisi modellistica delle curve glucosio/C-peptide durante pasto e costruzione della curva stimolo (glicemia)-risposta (secrezione di insulina). La valutazione di massa grassa e massa magra negli arti e nel tronco, prima e 1 mese dopo chirurgia, è stata eseguita mediante DEXA. Risultati: I 104 pazienti hanno presentato un calo ponderale medio a 12 mesi del 26,5±1,46 % che si è mantenuto a 24 e 36 mesi. La remissione del diabete a 36 mesi è stata evidenziata nel 56,5% dei pazienti (nel 50,0% dei pazienti sottoposti a LAGB, 56% dei pazienti sottoposti a RYGB, e 100% dei pazienti sottoposti a SG). La durata di malattia è risultato l’unico predittore della persistenza del diabete a 24 e 36 mesi. Nei 5 pazienti sottoposti a test con pasto misto (secondo protocollo pubblicato su ClinicalTrials.gov NCT 01767441), dopo un mese dall’intervento è stato evidenziato un significativo calo ponderale: Δmassa-totale -10,62±0,61 kg p<0,001, ΔBMI -4,07±0,26 kg/m2 p<0,001, Δgrasso-tot -5,58±0,74 kg p<0,007; Δgrasso del torso (-4,13±0,69 p<0,04). Dopo un mese dall’intervento, glicemia e insulina a digiuno calavano (glicemia 9,6±1,18 vs 5,5±0,47 mmol/L, p=ns; insulina 231,36±21,17 vs 64,92±4,41 pmol/L, p=0,02), come anche HOMA-IR (17,2±4,8 vs 2,7±0,61 p=0,04). Si riduceva inoltre l’area sotto la curva insulinemica (66,43±10.5 vs 28.67±7.4 nmol/l in 4 ore; p=0,039) e l’area sotto la curva del lattato (256,03±34,76 vs 183,77±32,89 mmol/l in 4 ore; p=0,02) mentre la risposta del GIP al pasto misto ha mostrato una tendenza all’aumento (AUC 19,14±5,14 vs 23,72±3,4 ng/ml in 4 ore, p=ns). Infine, la funzione β-cellulare migliorava significativamente (p<0.04) come dimostrato dallo spostamento a sinistra della curva stimolo-risposta. Conclusioni: Nella maggior parte dei nostri pazienti, il calo ponderale dopo chirurgia bariatrica si mantiene fino a 3 anni di follow-up e la remissione completa del diabete a 3 anni riguarda oltre il 50 % dei diabetici, senza evidenza di recidive. I dati preliminari del test pasto misto, dopo 30 giorni dall’intervento di RYBP, suggeriscono che il miglioramento dell’omeostasi glucidica sia attribuibile a concomitanti incrementi della funzione β-cellulare e della sensibilità insulinica, con contemporanea riduzione della glicolisi anaerobia. Tali miglioramenti sono ottenuti in presenza di una significativa riduzione dell’impegno biochimico della β-cellula.
Bariatric surgery can lead to improvement or even resolution of type 2 diabetes Mellitus (T2DM) with the spectrum of responses depending also on operation procedures. However, many underlying mechanisms of metabolic action of different surgical techniques are still unclear. The aim of this study was evaluate the long-term effects of bariatric surgery on weight loss and T2DM remission and to provide a better understanding of the effects of surgery on β-cell function and incretin secretion. METHODS: The study included 104 obese T2DM patients (66 women and 38 men, ) who were wait-listed for laparoscopic gastric banding (LAGB, 11 subjects, age 47,3±2,9 y, BMI 42,3±2,5 kg/m2), or for laparoscopic Roux-en-Y gastric bypass (RYBP , 77 subjects, age 49,7±0,1 y, BMI 45,7±0,7 kg/m2), or for sleeve gastrectomy (SG, 16 subjects, age 50,9±2,3 y, BMI 50,7±2,2 kg/m2) In 5 patients a mixed meal tolerance test (MMT: 186 Kcal; 53% carbohydrate, 30% fat, 17% protein) was performed before and 1 and 12 months after RYBP to assess hormonal changes. During MMT blood samples were collected for 300 minutes for the measurement of plasma glucose, insulin, C-peptide, lactate and GIP. β-cell function parameters were derived from mathematical modelling of plasma glucose, insulin and C-peptide concentrations. Body composition, fat mass and fat-free mass were evaluated before and 1 and 12 months after RYBP by means of DEXA. RESULTS: The average percentage of weight loss after surgery in the 104 patients was 26,5±1,46% and it was maintained at 24 and 36 months follow-up. Diabetes remission at 3 years follow-up occurred in 56,5% of study participants (in 50,0% of LAGB, 56% of RYBP and 100% of SG). Duration of diabetes was the only significant predictor of diabetes remission at 2 and 3 years. The 5 patients who underwent MMT (according to ClinicalTrials.gov protocol NCT 01767441), showed, 1 month after RYBP, a significant weight loss: ΔBMI=- 4,07±0,26 kg/m2 p<0,001, Δtotal mass= -10,62±0,61 kg, Δtotal-fat= -5,58±0,74 kg p<0,007. HOMA-IR and plasma insulin decreased (HOMA-IR 17,2±4,8 vs 2.7±0.61 p=0,04; plasma insulin 231,36±21,17 vs 64,92±4,41 pmol/L, p=0,02) as well as insulin AUC and lactate AUC (respectively 66,43±10,5 vs 28,67±5,51 nmol/l in 4 hour; p=0,039 and 258,03±34,76 vs 183,77±32,89 mmol/l in 4 hour; p=0,02). Insulin secretion rate significantly improved (p<0,04). CONCLUSIONS Bariatric Surgery appears to be a viable option for the treatment of severe obesity, resulting in long term weight loss and frequent diabetes remission. Our preliminary data suggest that amelioration in glucose homeostasis, evaluated by a physiological stimulus (MMT), could be related to improvement in β-cell function and insulin sensitivity.

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Schlinkert, Pia. "Charakterisierung des Einflusses bariatrischer Chirurgie auf die β-adrenerge Signalkaskade und damit verbundene Adaptationsprozesse im Glukose- und Fettsäuremetabolismus." 2019. https://tud.qucosa.de/id/qucosa%3A75418.

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Übergewicht und Diabetes werden zunehmend zum globalen Gesundheitsproblem, eine vielversprechende Behandlungsmöglichkeit der therapieresistenten Adipositas stellen bariatrische Eingriffe dar. Ein positiver Effekt bariatrischer Chirurgie auf die Herzfunktion und das kardiovaskuläre Risiko wurde beobachtet, molekularbiologische Erklärungen dieses Zusammenhanges fehlen bislang. Material und Methoden. Es wurden zwei verschiedene Tiermodelle genutzt, um den Auswirkungen von Übergewicht und bariatrischer Chirurgie auf das Herz nachzugehen: ein HFD-Mausmodell und ein HFD-Rattenmodell mit duodenojejunalem Bypass (DJB). Linksventrikuläres Gewebe beider Modelle wurde mittels quantitativer Real-Time-PCR und Western Blot auf Expression der Zielgene und -proteine untersucht. Aus dem linksventrikulären Gewebe des DJB-Rattenmodells wurde RNA für eine differentielle Genexpressionsanalyse gewonnen. Die Genexpressionsanalyse wurde von der Deep Sequencing Group am CRTD Dresden durchgeführt. Die Analyse der Sequenzierungsdaten erfolgte mittels Ingenuity Pathway Analyse. Ergebnisse. Die zwölfwöchige Hochfettfütterung führte bei den Mäusen zu keiner echokardiographisch darstellbaren Einschränkung des Herzens. Die Tiere wiesen allerdings eine prä- bzw. diabetische Stoffwechsellage auf. Das linksventrikuläre Gewebe der HFD- Mäuse zeigte eine Herabregulation der Glukosetransporter Glut1 und Glut4. Die bariatrische Intervention führte im linksventrikulären Gewebe der Ratten zu einer Heraufregulation des Glukosetransporters Glut1, die Proteinexpression war unverändert. Die Expression des β1-, des β2-Rezeptors und ausgewählter Calcium-handling Proteine war zwischen den beiden Gruppen ebenfalls nicht verschieden. Repräsentative Gene des kardialen Fettsäurestoffwechsels zeigten keine Beeinflussung durch die bariatrische Intervention. Die Analyse der differentiellen Genexpressionsanalyse zeigte für die DJB-Gruppe Veränderungen innerhalb der oxidativen Phosphorylierung und innerhalb adrenerger Signalwege. Zusammenfassung. Es konnte gezeigt werden, dass es durch Übergewicht und eine (prä-) diabetische Stoffwechsellage im linken Ventrikel zur Herabregulation der Glut1- und Glut4- Expression kommt. Nach bariatrischer Chirurgie zeigten Herzen der Interventionsgruppe eine vermehrte Glut1-Expression. Ausgewählte Gene und Proteine der adrenergen Signalkaskade zeigten keine Veränderung innerhalb der DJB-Gruppe, die Pathway-Analyse lässt allerdings vermuten, dass andere Proteine innerhalb dieses Signalweges durchaus differentiell exprimiert vorliegen. Die Überrepräsentation von Genen der oxidativen Phosphorylierung und die protektive Heraufregulation von Glut1 könnten neue Ansatzpunkte für die Therapie kardiovaskulärer Erkrankungen liefern.

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Stingl, Maria-Theresa. "Kurz- und Langzeitergebnisse des laparoskopischen Gastric Banding (eine retrospektive Studie an 127 Patienten)." Doctoral thesis, 2009. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-38672.

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Die laparoskopische Implantation eines Magenbandes gilt als etabliertes Verfahren der bariatrischen Chirurgie. Im Rahmen der vorliegenden retrospektiven Studie an 127 Patienten wurden die Kurz- und Langzeitergebnisse des Laparoskopischen Gastric Banding (LAGB) untersucht. 60 Patienten wurden in Pergastrischer Technik, 67 Patienten in Pars flaccida Technik operiert. Untersucht wurde Sicherheit, Effizienz und Qualität des LAGB insbesondere im Hinblick auf die Art der angewandten Operationstechnik. Die mittlere Nachbeobachtungszeit betrug 63 Monate. Der mittlere prozentuale Übergewichtsverlust (EBWL %) war 50,6 %. Bei 39 Patienten traten ein oder mehrere Komplikationen auf. Die häufigsten Komplikationen waren Slippage und Pouchdilatation. Die Mortalitätsrate lag bei 0 %. Über 2/3 der Patienten dokumentierten eine Steigerung der subjektiven Lebensqualität durch das LAGB. Im Vergleich der Ergebnisse zweier verschiedener Operationstechniken stellte sich heraus, dass die Wahl des operativen Zugangsweges weder einen Einfluss auf die Effektivität der Gewichtsabnahme noch auf die Reduktion der körpergewichtsbedingten Komorbidität hat. In Übereinstimmung mit Ergebnissen anderer Studien zeigten sich Vorteile der Pars flaccida Technik im Sinne einer niedrigeren postoperativen Komplikationsrate. Insbesondere die sehr häufigen Komplikationen Pouchdilatation und Slippage traten in der Pars flaccida Gruppe signifikant seltener auf als bei den Patienten, die in Pergastrischer Technik operiert wurden. Zur Erhöhung der Effizienz sowie Reduktion der Komplikationsrate des LAGB ist - über die Optimierung operativ-technischer Aspekte hinaus- eine professionelle, interdisziplinäre und langfristige Nachbetreuung der Patienten unabdingbar
The Laparoscopic Adjustable Gastric Banding (LAGB) has become a common bariatric procedure. Within this study 127 patients were analysed retrospectively after LAGB in terms of preoperative characteristics, weight loss, co-morbidities, short and long-term complications and quality of life. 60 patients were operated using the pergastric pathway (PG), 67 patients were operated using the pars flaccida technique (PF). The median follow-up was 63 month. Mean excess body weight loss (EBWL %) was 50.6 %. 39 patients experienced one ore more postoperative complications. The most frequent complications were slippage and pouch dilatation (34 %). Mortality rate was 0 %. Two-thirds of the patients reported an increase in quality of life after LAGB. Comparing the two different operation techniques (PF and PG-technique) there was no difference in weight loss or reduction of co-morbidities. In accordance with similar studies we documented a lower postoperative complication rate in the pars flaccida group. Especially the very frequent complications slippage and pouch dilatation occurred significantly less often using the pars flaccida technique

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CACCIABAUDO, Francesco. "STUDIO SPERIMENTALE SU PANCREAS DI MAIALE PER L’OTTENIMENTO DI CELLULE PRODUCENTI INSULINA." Doctoral thesis, 2014. http://hdl.handle.net/10447/85546.

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L’obiettivo del mio studio è stato quello di standardizzare delle tecniche per prelevare, mantenere e transdifferenziare la componente sia esocriche sia endocrine del pancreas in cellule producenti insulina; per poter realizzare tale lavoro sono state seguite diverse fasi. Nella fase preliminare furono prelevate e trans-differenziate cellule provenienti dal dotto di Wirsung di maiale in cellule-ß producenti isulina. Nella seconda fase le ß-cellule furono ottenute dalla componente esocrina di pancreas in toto di maiale dopo exsaguinazio e con l’impiego di due diverse soluzioni di conservazione, al fine di valutare quale delle due potesse mantenere meglio l’organo e potesse dare una successivamente una migliore resa cellulare; inoltre l’altro obiettivo di questa seconda fase del mio studio fu quella di confrontare la vitalità e la capacità di produrre insulina delle cellule prima e dopo crioconservazione. Nella fase finale furono prelevate direttamente le cellule ß-pancreatiche da maiale a cuore non battente con l’impiego delle due soluzioni di conservazione prima citate, al fine di valutare ancora una volta le differenze nelle capacità conservative delle due soluzioni direttamente sulle cellule ß e di valutare la vitalità e la capacità di produrre insulina delle suddette ß-cellule direttamente prelevate dal maiale prima e dopo criopreservazione. Questo studio è stato condotto presso il laboratorio di Chirurgia Sperimentale e presso il reparto di Virologia Sperimentale dell’Istituto Zooprofilattico della Sicilia “A.Mirri”, in collaborazione con il Consorzio Interuniversitario per i Trapianti d’Organo di Roma.

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Rikkala, Prashanth Reddy. "Regulation of the Na+-D-glucose cotransporter SGLT1 in the small intestine in response to bariatric surgery and peptides derived from protein RS1 (RSC1A1)." Doctoral thesis, 2015. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-130608.

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Bariatric surgery represents the first-line treatment for morbid obesity, resulting in weight loss and improved diabetes control. The positive effect of bariatric surgery on type-2 diabetes is unclear. Increased secretion of insulin regulating enterohormone glucagon-like-peptide 1 (GLP-1) has been observed in rats with experimental type 2-like diabetes following duodenal-jejunal bypass (DJB) and ileal transposition (IT). Sodium dependent glucose co-transporter (SGLT1) is involved in the secretion of GLP-1 that in turn regulates insulin secretion. In the present study, an attempt was made to elucidate the impact of DJB and IT on SGLT1 mediated glucose transport. Transport measurements using phlorizin inhibited uptake of SGLT1-specific glucose analogue [14C] α-Methyl-D-glucopyranoside (AMG) were performed to determine the changes in SGLT1 transport upon these surgical procedures. The data indicated that DJB decreased SGLT1-mediated glucose absorption in the small intestine which contributes to the body-weight independent improvement of type 2 diabetes. However, IT did not change the SGLT1-mediated glucose transport. Immunohistochemical analysis revealed that in IT, the transposed ileum showed increased diameter, increased villi length and increased number of GLP-1 secreting L-cells. The weight-independent improvement in glycemic control after IT is not related to SGLT1-mediated glucose absorption but may be linked to increased GLP-1 secretion. Along with this, the study also focused on the regulation of SGLT1 by several RS1 derived tripeptides in mouse and human intestinal tissues (ex vivo). Phlorizin inhibited uptake of AMG was measured without and with tripeptides. QEP and thiophosphorylated QSP down-regulated SGLT1 activity in small intestine in a concentration-dependent manner. Among the tested tripeptides, QEP showed higher activity and further analysis in various species demonstrated its universal role in SGLT1 regulation. The data thus indicates that RS1 derived tripeptides QEP and thiophosphorylated QSP may be employed for the treatment of type 2 diabetes
Bariatrische Operationen repräsentieren die Behandlung erster Wahl bei krankhafter Fettleibigkeit, resultierend in Gewichtsverlust und verbesserter Diabetes-Kontrolle. Der positive Effekt bariatrischer Operationen auf den Typ-2 Diabetes ist unklar. Erhöhte Sekretion von Insulin, welches das Enterohormon „Glucagon-like-peptide 1“ (GLP-1) reguliert, wurde beobachtet bei Ratten mit experimentellem Typ 2-ähnlichem Diabetes nach duodenalem-jejunalem Bypass (DJB) und ilealer Transposition (IT). Der Natrium-abhängige Glucose Cotransporter (SGLT1) ist beteiligt an der Sekretion von GLP-1, das wiederum die Insulin-Sekretion reguliert. In der vorliegenden Studie wurde der Versuch unternommen, die Bedeutung von DJB und IT für den durch SGLT1 vermittelten Glucose-Transport aufzuklären. Transportmessungen der durch Phlorizin hemmbaren Aufnahme des SGLT1-spezifischen Glucose-Analogs [14C] α-Methyl-D-glucopyranosid (AMG) wurden durchgeführt, um die durch diese chirurgischen Eingriffe bedingten Änderungen des Transports durch SGLT1 zu bestimmen. Die Daten deuten darauf hin, dass DJB die SGLT1-vermittelte Glucose Absorption im Dünndarm verringert, was zu einer körpergewichts-unabhängigen Verbesserung des Diabetes Typ 2 beiträgt. Aber IT veränderte den SGLT1-vermittelten Glucose-Transport nicht. Immunhistochemische Analysen zeigten, dass bei IT das transponierte Ileum einen vergrößerten Durchmesser, eine erhöhte Länge der Villi und eine erhöhte Anzahl der GLP-1 sekretierenden L-Zellen aufwies. Die gewichtsunabhängige Verbesserung der glykämischen Kontrolle nach IT steht nicht im Zusammenhang mit der durch SGLT1-vermittelten Glucose-Absorption, sondern könnte verbunden sein mit einer erhöhten GLP-1 Sekretion. Damit einhergehend fokussiert sich die Studie auch auf die Regulation des SGLT1 durch verschiedene, von RS1 abgeleitete Tripeptide in Darm-Gewebe von Maus und Mensch (ex vivo). Die phlorizin-hemmbare Aufnahme von AMG wurde gemessen mit und ohne Tripeptide. QEP und thiophosphoryliertes QSP regulierten die SGLT1-Aktivität herunter im Dünndarm auf eine konzentrationsabhängige Weise. Unter den getesteten Tripeptiden zeigte QEP eine höhere Aktivität und weitere Analysen in verschiedenen Spezies zeigten seine universelle Rolle in der SGLT1-Regulation.Die Daten zeigen daher, dass die von RS1 abgeleiteten Tripeptide QEP und thiophosporyliertes QSP eingesetzt werden könnten zur Behandlung von Typ2 Diabetes

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Griffo, Ettore. "ASSE ENTERO-INSULARE E METABOLISMO GLICO-LIPIDICO NEL DIABETE DI TIPO 2 E NELL’OBESITÀ: EFFETTI DELLA CHIRURGIA BARIATRICA E DI DIVERSI INTERVENTI NUTRIZIONALI." Tesi di dottorato, 2014. http://www.fedoa.unina.it/9678/1/Ettore_Griffo_26.pdf.

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Le evidenze scientifiche attribuiscono agli ormoni dell’asse entero-insulare (GLP-1 e GIP), molteplici azioni che vanno dalla regolazione dell’omeostasi glicemica e lipidica al controllo del senso di fame, dell’assunzione di cibo e, quindi, dell’introito energetico. Molte funzioni svolte dagli ormoni dell’asse entero-insulare si sono evidenziate solo dopo gli interventi di chirurgia bariatrica attuati per la terapia dell’obesità morbigena. Durante il triennio del corso di dottorato in “Scienza dell’Alimentazione e della Nutrizione” la mia attività di ricerca ha riguardato lo studio dell’asse entero-insulare dopo diversi interventi nutrizionali e dopo interventi di chirurgia bariatrica effettuati con differenti tecniche chirurgiche. A tal fine sono stati condotti tre studi: Studio 1. Obiettivo: valutare gli effetti di acidi grassi n-3 e/o polifenoli sulla risposta lipidica ed entero-ormonale in soggetti ad alto rischio cardio-metabolico. Materiali e metodi: 78 soggetti, di età compresa tra i 35 e i 70 anni, sovrappeso/obesi, con circonferenza vita elevata ed almeno una delle componenti della sindrome metabolica, sono stati randomizzati a seguire per 8 settimane una tra le seguenti diete: (A) controllo, povera in polifenoli e acidi grassi n-3, (B) ricca in acidi grassi n-3, (C) ricca in polifenoli, (D) ricca in acidi grassi n-3 e polifenoli. Le diete erano isocaloriche e simili per contenuto in acidi grassi saturi, monoinsaturi, colesterolo, carboidrati, fibre, proteine e vitamine. Prima e dopo le 8 settimane d’intervento, sono state determinate le concentrazioni di GLP-1, dei lipidi e dell’apo-lipoproteina B48 (apo-B48) nel plasma e nelle subfrazioni lipoproteiche ricche in trigliceridi (chilomicroni e VLDL grandi), sia a digiuno che dopo somministrazione di un pasto ricco in grassi che rifletteva la stessa composizione delle diete assegnate. Risultati: In fase acuta, la concentrazione postprandiale dei trigliceridi e del colesterolo dei chilomicroni dopo pasto test ricco in n-3 era significativamente maggiore rispetto al pasto controllo (p<0.05). Non sono state osservate differenze significative nei livelli di lipidi postprandiali dopo la somministrazione degli altri pasti test. Per quando riguarda la concentrazione del colesterolo, trigliceridi ed apo-B48 nelle VLDL grandi, non si sono osservate variazioni dopo ogni pasto test somministrato. Il GLP-1 mostrava una tendenza alla riduzione soltanto dopo pasto test ricco in PUFA n-3. Dopo 8 settimane la concentrazione postprandiale dei trigliceridi e del colesterolo nei chilomicroni, si riduceva dopo la dieta ricca in n-3, ma non in modo significativo. L’AUC (area under the curve) dei trigliceridi e del colesterolo delle VLDL grandi era diminuita significativamente solo dopo la dieta ricca in polifenoli (p<0.05). L’AUC del GLP-1 si riduceva significativamente dopo dieta ricca in n-3 (p<0.001). Conclusioni. Dallo studio si deduce che, in fase acuta, la risposta ad un pasto grasso ricco in n-3 determina un aumento del contenuto di colesterolo e trigliceridi dei chilomicroni rispetto al pasto di controllo; questi effetti si modificano nel medio termine. Studio 2. Obiettivo: Valutare la sensibilità, la secrezione insulinica e la risposta degli ormoni gastrointestinali in pazienti con DM2 e obesità sottoposti a bypass gastrico (BPG) o gastrectomia verticale (SG). Materiali e Metodi. In 33 pazienti obesi con DM2 (14 sottoposti a BPG, 6M, età: 49±7 anni; BMI 42±6 Kg/m2 ed HbA1C 8.1±2.2 %, M±DS e 19 sottoposti a SG, 8M; 44±10 anni; BMI 46±9 Kg/m2 e HbA1C 7.6±2 %) sono state valutate sensibilità e secrezione insulinica e la risposta degli ormoni gastrointestinali (GIP, GLP-1 e grelina) ad un pasto misto liquido (305 kcal) prima, 2 settimane ed 1 anno dopo CB. Risultati. Ad 1 anno dall’intervento chirurgico si è osservato un decremento ponderale di 40±15 kg dopo BPG e 39±18 kg dopo SG. La remissione del diabete, valutata come glicemia a digiuno < 100 mg/dl ed HbA1C < 6.5%, si verificava nel 64% dei pazienti dopo BPG e nel 68% dei pazienti dopo SG. La sensibilità insulinica, espressa come indice OGIS (Oral Glucose Insulin Sensitivity) ed indice ISI (Insulin Sensitivity Index), aumentava in egual misura dopo i due interventi sia a 2 settimane che a 12 mesi, senza differenze tra le due procedure chirurgiche. La secrezione insulinica precoce, espressa come AIR (Acute Insulin Response), aumentava significativamente in entrambi i gruppi (p<0.05). Il picco di GLP-1 dopo pasto misto, pressoché assente nel preoperatorio, raddoppiava 1 anno dopo SG (GLP-1t30 da 4±1 a 9±7 pmol/l, p<0.05) e incrementava di ~7 volte dopo BPG (da 7±5 a 44±18 pmol/l, p<0.001); la secrezione del GIP (valutata come AUC) e il picco a 60 minuti si riducevano significativamente dopo entrambi gli interventi (p<0.05). La secrezione di grelina si riduceva significativamente solo dopo SG (p<0.05), mentre rimaneva invariata dopo BG. Conclusioni. Lo studio mostra che la secrezione e sensibilità insulinica migliorano della stessa entità con le due procedure chirurgiche (BPG e SG) mentre il profilo degli ormoni gastrointestinali presenta significative differenze. Il ripristino della risposta del GLP-1 e la riduzione dei livelli di GIP sembrano essere implicati nella remissione del DM2 dopo BPG mentre la soppressione della grelina e la riduzione dei livelli di GIP potrebbero contribuirvi dopo SG. Studio 3. Obiettivi: Valutare gli effetti a breve e a medio-lungo termine della chirurgia bariatrica sul metabolismo lipidico a digiuno e postprandiale in soggetti con DM2 ed obesità e le possibili relazioni con le modifiche degli entero-ormoni. Metodi: Sono stati studiati 25 pazienti con DM2 ed obesità (età:48±8 anni, BMI:44±7 kg/m²) di cui 10 sottoposti a BPG e 15 sottoposti a SG. Poiché le variazioni di peso e dei principali parametri metabolici sono risultate simili con i due interventi, l’analisi è stata effettuata sull’intero campione. Abbiamo valutato la risposta lipidica ed entero-ormonale ad un pasto misto liquido (305 kcal) somministrato prima, 2 settimane, 12 e 24 mesi dopo chirurgia bariatrica. Risultati. Dopo 2 settimane, 12 e 24 mesi dall’intervento chirurgico si osservava una riduzione significativa del peso corporeo, glicemia e insulinemia a digiuno e dell’insulino-resistenza (HOMA-IR) (p<0.05 per tutti). Durante il follow-up post-operatorio i lipidi a digiuno (colesterolo totale e trigliceridi) si riducevano significativamente (p<0.05), mentre il colesterolo HDL, dopo una transitoria caduta a 2 settimane (p<0.05), aumentava significativamente dopo 12 e 24 mesi. La risposta dei trigliceridi plasmatici, valutata come IAUC (incremental area under the curve), si riduceva del 64%, 52% e 61% rispettivamente dopo 2 settimane, 12 e 24 mesi dall’intervento bariatrico. La risposta del GLP-1 al pasto misto era significativamente aumentata durante il follow-up, rispetto ai valori pre-intervento (p<0.001), mentre la risposta del GIP si riduceva progressivamente. Comunque non vi era alcuna relazione tra le variazioni degli entero-ormoni e della trigliceridemia postprandiale. La riduzione dei trigliceridi a digiuno correlava positivamente solo con la riduzione dell’insulino-resistenza (p<0.05). Conclusioni: Lo studio suggerisce che la chirurgia bariatrica induce un miglioramento molto precoce del metabolismo lipidico sia a digiuno che post-prandiale, che permane nel periodo di follow-up. La riduzione dei trigliceridi a digiuno è associata ad una riduzione della resistenza all'insulina mentre la riduzione della lipemia postprandiale è, probabilmente, correlata al ridotto assorbimento intestinale dei lipidi e potrebbe essere in relazione anche con l’aumento del GLP-1.

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Schiller, Julia Virginie. "Venöse Revaskularisation bei Vorliegen einer Mikro- und Makroangiopathie." Doctoral thesis, 2010. https://ul.qucosa.de/id/qucosa%3A11241.

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In der vorliegenden Arbeit wurde die venöse Revaskularisation bei Vorliegen einer Mikro- und Makroangiopathie untersucht. Die Zielgruppe dieser Methodik sind Patienten, die aus kardiologischer und herzchirurgischer Sicht austherapiert sind, für die weder ein Stent noch eine konventionelle Bypassoperation in Frage kommt. Das betrifft Patienten mit disseziierten Gefäßen, mit schwerer diffuser koronarer Herzerkrankung oder small vessel disease. Für diese Patienten ist derzeit keine optimale Therapie vorhanden. Es handelt sich somit um eine ultima ratio-Therapie. Zur Prüfung der Effektivität der Methode bei beschriebenem Krankheitsbild wurde in Minipigs eine Mikroangiopathie durch Injektion von Mikrosphären (Durchmesser 100µm) in den linken Hauptstamm erzeugt. Nach 7 Wochen Krankheitsentwicklung der Mirkoangiopahtie wurde eine hochgradige Stenose des Ramus interventricularis anterior (RIVA) hervorgerufen, welches die Makroangiopathie simulieren sollte. Anschließend wurden die Tiere der Therapiegruppe mit einem Bypass von der Arteria mammaria auf die Begleitvene des RIVA versorgt. Dabei wurde die Begleitvene proximal der Anastomose ligiert. Die Kontrollgruppe blieb ohne Therapie. Die Stenose und der Bypass wurden angiographisch dargestellt. Nach 17 Wochen wurde bei allen Tieren eine Herzkatheteruntersuchung durchgeführt, um die Stenose und den Bypass zu beurteilen. Als Maß für die Herzleistung wurde zu allen 3 Versuchsteilen die Ejektionsfraktion bestimmt. Anhand der Ejektionsfraktion konnte die Überlegenheit der venösen Revaskularisation als Therapie gezeigt werden. 7 Wochen nach Injektion der Mikrosphären fielen die Werte der Ejektionsfraktion beider Gruppen ab. Nach 17 Wochen nahm die Ejektionfraktion der Therapiegruppe, die in der Zwischenzeit mit einem Bypass versorgt wurden, wieder deutlich zu und die der Kontrollgrupppe sank weiter ab. Zusätzlich wurden die entnommenen Herzen histologisch untersucht. Dabei zeigte sich ein Umbau des Gefäßsystems im Bereich der angeschlossenen Vene.:1. Einleitung 7 1.1. Patienten ohne therapeutische Option 7 1.2. Das therapeutische Dilemma bei gleichzeitigem Vorliegen einer Mikro- und Makroangiopathie 8 1.3. Therapieoption - venöse Revaskularisation 10 1.4. Vorversuch 12 1.5. Fragestellung 14 2. Methodik 15 2.1. Versuchskonzept 15 2.2. Versuchsbeschreibung 16 2.2.1. Vorgehensweise vor der Operation 16 2.2.1.1. Vorbereitung 16 2.2.1.2. Narkose 17 2.2.2. Medikation 17 2.2.3. Versuchsprotokoll 19 2.2.3.1. Versuchsteil 1: Induktion der Mikroangiopathie durch Mikropsphären 19 2.2.3.2. Versuchsteil 2: Herzinfarkt, venöse Revaskularisation (Therapiegruppe) 20 2.2.3.3. Versuchsteil 3: Herzkatheteruntersuchung, Herzexplantation 24 2.3. Erhobene Parameter und Untersuchungen 26 2.3.1. Echokardiographie 26 2.3.2. Herzkatheteruntersuchung 27 2.3.3. Ultraschallflussmessung 28 2.3.4. Bestimmung der Enzyme 29 2.3.5. Elektrokardiographie 29 2.3.6. Messung des mittleren arteriellen Blutdrucks 29 2.3.7. Blutgasanalyse 30 2.3.8. Entnahme Herz 30 2.4. Histologische Methodik und Auswertung 30 2.4.1. Herstellung der histologischen Schnitte 30 2.4.2. Protokoll der Hämatotoxilin Eosin- Färbung für Paraffinschnitte 31 2.4.3. Auswertung Histologie 31 2.5. Lyse 32 2.6. Statistik 33 3. Materialien 34 3.1. Versuche 34 3.1.1. Minipigs 34 3.1.2. Medikamente 34 3.1.3. Materialien 35 3.1.4. Geräte 35 3.2. Histologische Aufarbeitung 36 3.2.1. Materialien 36 3.2.2. Geräte 36 3.3. Lyse 37 3.3.1. Materialien 37 3.3.2. Geräte 37 3.4. Statistische Datenanalyse 37 4. Ergebnisse 38 4.1. Allgemeine Charakteristika der Versuchstiere 38 4.1.1. Vergleich Therapiegruppe und Kontrollgruppe 38 4.1.2. Komplikationen/Ausfälle 39 4.2. Funktionelle Ergebnisse 40 4.2.1. Auswertung Mikroangiopathie 40 4.2.1.1. Herzkatheteruntersuchung 40 4.2.1.2. Funktionelle Befunde 43 4.2.1.3. Ergebnisse Lyse 43 4.2.2. Echokardiographie - Ejektionsfraktion 44 4.2.3. Herzkatheteruntersuchung - Auswertung Makroangiopathie 45 4.2.4. Ultraschallflussmessung 45 4.2.5. Enzymbestimmung 45 4.2.6. Elektrokardiographie und hämodynamische Parameter 47 4.2.6.1. Elektrokardiographie – ST-Veränderungen 47 4.2.6.2. Herzfrequenz 48 4.2.6.3. Mittlerer arterieller Blutdruck 49 4.2.6.4. Systolischer und diastolischer Blutdruck 49 4.3. Histologische Ergebnisse 51 4.3.1. Vergleich Gefäße in verschiedenen Bereichen des Herzens 51 4.3.2. Nicht klassifizierter Gefäßtyp 53 5. Diskussion 58 5.1. Versuchsmodell 58 5.1.1. Auswahl der Versuchstiere 58 5.1.2. Mikroangipathie 58 5.1.3. Makroangiopathie 59 5.1.4. Operationskonzept 60 5.1.4.1. Auswahl des Bypassgrafts 60 5.1.4.2. Beating heart Chirurgie 61 5.1.5. Auswertung der Ergebnisse 62 5.2. Umbau des Gefäßsystems 67 5.3. Limitationen des Modells 71 5.3.1. Anzahl Versuchstiere 71 5.3.2. Methodik und funktionelle Parameter 72 5.4. Mögliche klinische Anwendungen der Operationstechnik 74 6. Zusammenfassung der Arbeit 77 7. Literaturverzeichnis 79 8. Anhang 87 9. Danksagung 92
Objective: Many patients with significant arterioclerosis of the heart cannot benefit from a coronary artery bypass and other methods because they have macroangiopathy combined with microangiopathy. We evaluated the efficiency of venous revascularization in minipigs with macroangiopathy combined with microangiopathy in a chronic model of 3 months. Histological analysis of arterial and venous vessels of the heart was conducted. Methods: In left anterior descending artery (LAD) microspheres (diameter 100µm) were injected in 24 minipigs (12 control group, 12 therapy group). 7 weeks later a stenosis of the LAD was performed in both groups with an average of 84,6 ± 4,3%. In therapy group left internal thoracic artery was anastomosed to the concomitant vein of the LAD in beating heart surgery. The flow of bypass was proved in angiography and the flow rate was measured by ultrasound. 10 weeks later bypass of therapy group and stenosis of both groups were verified in angiography. At the beginning of every part of the experiment the ejection fraction in both groups was evaluated with echocardiography. Hemodynamic monitoring was performed throughout the experiment. In histological analysis arterial and venous vessels in left atrium, right atrium, septum and area of anastomosis were evaluated in the thickness of wall and area of lumen. Results: In ejection fraction a significant difference between control and therapy group was seen. After performing the bypass, the ejection fraction in therapy group increased, while it decreased in control group in the same period of time of 10 weeks. In the histological analysis a non-classifiable type of vessel was found only in the area of the anastomosis. The vessel had a a large area of lumen and a thick wall due to media hyperplasia. Conclusion: Venous revascularization of the concomitant vein of the LAD via bypass of the left thoracic artery in a chronic model improves cardiac funcion and is therefore an effective method when having microangiopathy and macroangiopathy combined. The non-classifiable type of vessel are most likely arterialized veins which underwent a structural change of the wall due to the arterial blood pressure.:1. Einleitung 7 1.1. Patienten ohne therapeutische Option 7 1.2. Das therapeutische Dilemma bei gleichzeitigem Vorliegen einer Mikro- und Makroangiopathie 8 1.3. Therapieoption - venöse Revaskularisation 10 1.4. Vorversuch 12 1.5. Fragestellung 14 2. Methodik 15 2.1. Versuchskonzept 15 2.2. Versuchsbeschreibung 16 2.2.1. Vorgehensweise vor der Operation 16 2.2.1.1. Vorbereitung 16 2.2.1.2. Narkose 17 2.2.2. Medikation 17 2.2.3. Versuchsprotokoll 19 2.2.3.1. Versuchsteil 1: Induktion der Mikroangiopathie durch Mikropsphären 19 2.2.3.2. Versuchsteil 2: Herzinfarkt, venöse Revaskularisation (Therapiegruppe) 20 2.2.3.3. Versuchsteil 3: Herzkatheteruntersuchung, Herzexplantation 24 2.3. Erhobene Parameter und Untersuchungen 26 2.3.1. Echokardiographie 26 2.3.2. Herzkatheteruntersuchung 27 2.3.3. Ultraschallflussmessung 28 2.3.4. Bestimmung der Enzyme 29 2.3.5. Elektrokardiographie 29 2.3.6. Messung des mittleren arteriellen Blutdrucks 29 2.3.7. Blutgasanalyse 30 2.3.8. Entnahme Herz 30 2.4. Histologische Methodik und Auswertung 30 2.4.1. Herstellung der histologischen Schnitte 30 2.4.2. Protokoll der Hämatotoxilin Eosin- Färbung für Paraffinschnitte 31 2.4.3. Auswertung Histologie 31 2.5. Lyse 32 2.6. Statistik 33 3. Materialien 34 3.1. Versuche 34 3.1.1. Minipigs 34 3.1.2. Medikamente 34 3.1.3. Materialien 35 3.1.4. Geräte 35 3.2. Histologische Aufarbeitung 36 3.2.1. Materialien 36 3.2.2. Geräte 36 3.3. Lyse 37 3.3.1. Materialien 37 3.3.2. Geräte 37 3.4. Statistische Datenanalyse 37 4. Ergebnisse 38 4.1. Allgemeine Charakteristika der Versuchstiere 38 4.1.1. Vergleich Therapiegruppe und Kontrollgruppe 38 4.1.2. Komplikationen/Ausfälle 39 4.2. Funktionelle Ergebnisse 40 4.2.1. Auswertung Mikroangiopathie 40 4.2.1.1. Herzkatheteruntersuchung 40 4.2.1.2. Funktionelle Befunde 43 4.2.1.3. Ergebnisse Lyse 43 4.2.2. Echokardiographie - Ejektionsfraktion 44 4.2.3. Herzkatheteruntersuchung - Auswertung Makroangiopathie 45 4.2.4. Ultraschallflussmessung 45 4.2.5. Enzymbestimmung 45 4.2.6. Elektrokardiographie und hämodynamische Parameter 47 4.2.6.1. Elektrokardiographie – ST-Veränderungen 47 4.2.6.2. Herzfrequenz 48 4.2.6.3. Mittlerer arterieller Blutdruck 49 4.2.6.4. Systolischer und diastolischer Blutdruck 49 4.3. Histologische Ergebnisse 51 4.3.1. Vergleich Gefäße in verschiedenen Bereichen des Herzens 51 4.3.2. Nicht klassifizierter Gefäßtyp 53 5. Diskussion 58 5.1. Versuchsmodell 58 5.1.1. Auswahl der Versuchstiere 58 5.1.2. Mikroangipathie 58 5.1.3. Makroangiopathie 59 5.1.4. Operationskonzept 60 5.1.4.1. Auswahl des Bypassgrafts 60 5.1.4.2. Beating heart Chirurgie 61 5.1.5. Auswertung der Ergebnisse 62 5.2. Umbau des Gefäßsystems 67 5.3. Limitationen des Modells 71 5.3.1. Anzahl Versuchstiere 71 5.3.2. Methodik und funktionelle Parameter 72 5.4. Mögliche klinische Anwendungen der Operationstechnik 74 6. Zusammenfassung der Arbeit 77 7. Literaturverzeichnis 79 8. Anhang 87 9. Danksagung 92

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PERBELLINI, Filippo. "Adipose and cardiac progenitor cells for regenerative medicine." Doctoral thesis, 2014. http://hdl.handle.net/11562/694159.

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Le malattie cardiovascolari e il loro evoluzione in arresto cardiaco, sono una della principali cause di morte a livello mondiale. Il diabete è spesso associato all'alterazione dei substrati metabolici i quali sono in grado di modificare l'omeostasi dei tessuti ed alterare le popolazioni di precursori cellulari. La maggior parte dei tessuti adulti presenta delle sotto-popolazioni di progenitori mesenchimali che, a causa delle loro proprietà rigenerative, sono un'interessante fonte di cellule per la medicina rigenerativa e la terapia cellulare. Recentemente è stato dimostrato che, in seguito ad un arresto cardiaco, l'iniezione di cellule mesenchimali può migliorare la contrattilità cardiaca in topo e ratto. Lo scopo di questa tesi è stato di isolare, caratterizzare e differenziare cellule mesenchimali di tessuto adiposo (ADMSCs) e cellule derivate da cardiosfere (CDCs) e determinare l'effetto di una dieta ad alto contenuto di grassi su queste due popolazioni cellulari. Da tessuto atriale di topo sono state isolate EDCs (Explant-derived cells) e CDCs, mentre dal tessuto adiposo inguinale, dopo digestione con collagenasi di tipo2, sono state isolate ADMSCs. Quest'ultime, dopo espansione in vitro, contengono un numero maggiore di cellule CD90+ (47% vs 87%) e minore di DDR2+ and CD45 rispetto a cellule appena isolate (rispettivamente 9% e 20% vs 38% e 42%). Alcuni medium sono stati testati per verificare la capacità differenziativa delle ADMSCs, di questi solo il medium con TGFβ è stato in grado di aumentare l espressione di geni cardiaci. L'espansione di ADMSCs in ipossia ha aumentato la velocità di proliferazione e ha modificato il profilo di marker cellulari espresso dalle ADMSCs. E' stato inoltre notato un numero più elevato di cellule positive per DDR2 e minore di CD45+ e CD90+ rispetto a ADMSCs espanse in normali condizioni di ossigeno. L'espansione di fibroblasti cardiaci in vitro e CDCs ha rivelato una similarità tra queste due popolazioni, entrambe aumentano la velocità di proliferazion e la capacità clonogenica con l'aumentare dei passaggi in cultura ed esprimono marker mesenchymali e marker espressi da fibroblasti come CD90 e DDR2. Le CDCs hanno dimostrato di essere in grado di acquisire un fenotipo cardiaco in vitro, aumentando l'espressione di cardiac actin e troponin T, tuttavia non sono state osservate cellule con spontanea attività contrattile. Dopo quattro mesi di dieta ad alto contentuto di grassi (55% grasso, HFD) i topi presentano aumentati livelli plasmatici di glucosio, colesterolo e insulina e diminuiti livelli di lattato. Un numero significativamente maggiore di ADMSCs sono stae isolate da animali HFD e il numero di ADMSCs correla con i livelli pasmatici di glucosio, colesterolo e lattato. I livelli di espressione di CD45, DDR2 e CD105 sono aumentati in ADMSCS da topi con dieta ad alto contenuto di grassi e la loro funzionalità e capacità differenziativa è risultata essere leggermente diminuita. Nelle CDCs non sono state riscontrate differenze nè nell'espressione di marker nè nella loro funzionalità. Per concludere, 4 mesi di dieta HFD sono in grado di indurre un fenotipo diabetico in topi C57 Black 6. La dieta HFD ha aumentato il numero di ADMSCs ma ha modificato le percentuali di sottopopolazioni all interno di questa popolazione, inoltre è stata registrata un diminuzione nella loro capacità differenziativa. Al contrario, le CDCs non sono state influenzate dal fenotipo diabetico.
Cardiovascular diseases, and the progression to heart failure, are one of the leading cause of death. Diabetes is often associate with cardiovascular complications because of the disturbed substrate metabolism that can alter the homeostasis of the tissues and modify the progenitor cell populations. Most adult tissues have a mesenchymal progenitor cell subpopulation that represents a proportion of the total cell number and which, because of its regenerative properties, is an attractive source for cell therapy. Recently it has been proved that injection of mesenchymal cells improve contractile function in rodents following myocardial infarction. The aim of this study was to isolate, characterize and differentiate adipose-derived mesenchymal stem cells (ADMSCs), and cardiosphere-derived cells (CDCs), and to determine the effect of simply a high fat diet on these two mesenchymal populations. Cardiac explant-derived and cardiosphere-derived cells (EDCs, CDCs) were cultured from atrial tissue and adipose stem cells were cultured from epididymal fat depots after collagenase digestion. Cultured ADMSCs contained more CD90+ cells (47% vs 87%) and fewer DDR2+ and CD45+ cells compared to freshly isolated ADMSCs (respectively 9% and 20% vs 38% and 42%). Various media were tested to validate the differentiation capacity of adipose mesenchymal cells, but only the TGFβ-supplemented medium was able to increase the expression of cardiac specific genes. Hypoxia increased cell proliferation and changed the surface marker profile of ADMSCs; more DDR2+ cells and fewer CD45+ and CD90+ cells were found compared to normoxic ADMSCs. In vitro expansion of neonatal cardiac fibroblasts and cardiosphere-derived cells revealed a similarity between these two cell populations, both increased proliferation and clonogenic capacity with time in culture and expressed mesenchymal/fibroblast markers such as CD90 and DDR2. CDCs were able to acquire a cardiac phenotype in vitro, increasing gene expression of cardiac actin and troponin T, however no beating cells were observed. After 4 months of high-fat diet (55% fat; HFD,) mice had raised fed plasma glucose, cholesterol and insulin levels and decreased plasma lactate. Significantly more ADMSCs were obtained from high fat fed animals and ADMSC numbers correlated with plasma glucose, cholesterol and lactate. Expression of CD45, DDR2 and CD105 were increased in ADMSCs from high fat fed mice and the functional properties and differentiation capacity were slightly decreased. No differences in surface marker expression and functional properties were detected between high fat and chow diet mice CDCs. In conclusion, four months of HFD induced a diabetic phenotype in C57 Black 6 mice. The high fat diet increased ADMSCs yield but modified the balance of ADMSCs populations and decreased their differentiation capacity. In contrast, cardiac progenitor cells were unaffected by induction of the diabetic phenotype.

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COCCIA, FEDERICA. "Obesità severa e nafld in pazienti con e senza diabete tipo 2 prima e dopo chirurgia bariatrica: studio degli indici non invasivi di steatosi e fibrosi e dei livelli plasmatici di acidi biliari come predittori di severità dell’istologia epatica." Doctoral thesis, 2020. http://hdl.handle.net/11573/1363031.

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Background Obese subjects are at high risk of nonalcoholic fatty liver disease (NAFLD) and diabetes (T2D) due to insulin resistance (IR). Since high glucose levels are as toxic as lipids for hepatic metabolism, we hypothesize that altered response to oral glucose tolerance test (OGTT) is associated to more severe NAFLD with significant/advanced liver damage. Methods and Results We studied 90 subjects with morbid obesity (73F/17M, BMI=43.2±5,9Kg/m2) undergoing bariatric surgery and intraoperative liver biopsy, and measured HbA1c, HOMA-IR (fasting Glucose x Insulin/22.5), OGTT glucose and insulin profile, and calculated OGIS (muscle insulin sensitivity), hepatic-IR (glucose[AUC0-30] x insulin[AUC0-30]) during OGTT, insulin response as (insulin[dAUC0-120] /glucose[dAUC0-120] or Insulinogenic Index (IGI= (I30-I0)/(G30-G0)). Patients were divided in 3 groups according to liver biopsy: A (no-NAFLD, 23%), B (simple steatosis (SS), 53%) and C (NASH, 24%) with similar age, gender and BMI. Diabetes was 0% in no-NAFLD, 13% in SS, 35% in NASH. During OGTT, OGIS decreased from A to C (422 vs 360 vs 338, p<0.01). Increased insulin concentrations, HbA1c, HOMA-IR and OGIS, not Hep-IR, were strongly associated to hepatic steatosis (p0.03, p0.0001 and p0.01 respectively) Hepatic fibrosis stage was mild as most of the patients had fibrosis grade-1 (69% vs. 8% no fibrosis) and associated to fasting insulin, HbA1c and HOMA-IR. Total insulin response was similar in the 3 groups, while IGI was strongly associated to steatosis (r=0.48, p<0.0001), but not to fibrosis. Conclusions: in morbid obesity OGTT-indexes of IR, and not of insulin response, are markers of histological severity of liver disease
Purpose: in morbid obesity nonalcoholic fatty liver disease (NAFLD) is endemic. Aim of this study is to evaluate the diagnostic accuracy of the most common noninvasive methods for identify NAFLD and fibrosis in a cohort of morbid obese population. Methods 90 morbid obese patients undergoing bariatric surgery (BS) and intraoperative liver biopsy were evaluated preoperatively with Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and serum biomarkers for steatosis and fibrosis and liver stiffness measurement (LSM) using acoustic radiation force impulse (ARFI) elastography. All non diabetic patient (n=77) underwent OGTT and calculation of Oral Glucose Insulin Sensitivity index (OGIS). Results: In the entire cohort prevalence of NAFLD was 77%, NASH 24%, moderate/severe steatosis 50% and significant fibrosis 14%. New cutoffs were evaluated for all steatosis score assessed in this population. In all patients with moderate/severe steatosis HOMA IR was significantly greater than 3.5. ALT, GGT, Triglycerides, HOMA IR and ARFI increased with fibrosis grade (p0.03, p 0.008, p 0.04, p 0.05 respectively) and AST to Platelet ratio (APRI) was the only noninvasive fibrosis score significantly increased in significant fibrosis (p 0.04). A combination of 1/OGIS and VAI was able to discriminate NASH from simple steatosis (NAFL) (p 0.02). Conclusions: In morbid obese subjects, we calculated new cutoffs of the most common steatosis indexes and found that a score based on insulin resistance (1/OGIS) and abdominal obesity (VAI) could represent a way to identify morbid obese subjects at risk of NASH.

Dissertations / Theses on the topic 'Diabète – chirurgie'

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