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Elamin, Ahmed Abu Baker. "Studies on the short-acting insulin analogue lispro." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310125.
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PEROTTI, MARIO. "EFFICACIA DEL PASSAGGIO A DEGLUDEC DA UN’ALTRA INSULINA BASALE (GLARGINE/ DETEMIR) IN UNA COORTE DI PAZIENTI CON DIABETE MELLITO TIPO 1 ( DMT1) IN CONDIZIONI DI REALE PRATICA CLINICA." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241121.
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La terapia del diabete tipo 1 può oggi essere più flessibile e personalizzata grazie alla disponibilità di numerosi tipi di insulina che differiscono tra loro per la farmacocinetica (inizio, picco e durata di azione). Il miglior controllo glicometabolico può essere ottenuto attraverso una terapia multiniettiva secondo uno schema basal-bolus, il quale prevede 3 somministrazioni preprandiali di un analogo rapido, che esprime meglio la fisiologica secrezione insulinica determinata dai pasti e da 1 iniezione di insulina ad azione lenta, necessaria per rispondere al fabbisogno insulinico nei periodi di digiuno (interprandiale e notturno).
Il raggiungimento di un controllo glicemico ottimale mediante trattamento insulinico intensivo determina un riduzione del rischio di complicanze micro e macrovascolari, ma conduce inevitabilmente a un incremento dell’incidenza di ipoglicemie, con conseguenze potenzialmente negative per il sistema cardiovascolare e neurologico.
Ottimizzare la terapia farmacologica mediante l’utilizzo di nuovi analoghi dell’insulina ad azione lenta in grado di offrire un minore rischio di ipoglicemia rappresenta un punto di fondamentale importanza.
Insulina degludec presenta molte delle caratteristiche che definiscono il profilo ideale di un’insulina basale. Dopo la somministrazione nel sottocute, grazie alla particolare ingegneria chimica, degludec viene assorbita in modo continuo e uniforme con un effetto ipoglicemizzante stabile e una durata di azione che supera le 42 ore. Dopo circa tre giorni di terapia è possibile raggiungere lo steady state condizione farmacocinetica in cui i livelli circolanti di insulina si mantengano stabili riducendo così la variabilità day-to day
L'utilizzo di degludec è stato ampiamente analizzato nel corso di studi clinici randomizzati ( RCT) sia in pazienti con diabete mellito tipo I sia in pazienti con diabete mellito tipo II. I risultati mostrano una non inferiorità di degludec rispetto a glargine in termine di target glicemici, ma una superiorità di degludec rispetto a glargine in termini di riduzione degli episodi di ipoglicemia soprattutto notturni. Tuttavia il contesto clinico di uno studio randomizzato può non essere completamente riproducibile nella pratica clinica quotidiana. Obiettivo di questo studio retrospettivo è la valutazione dell’efficacia clinica di degludec in una coorte di pazienti affetti da diabete mellito tipo 1 precedentemente trattati con diverso analogo lento ( glargine o detemir) nella pratica clinica quotidiana di real-life.
I risultati di questo studio mostrano un impatto positivo di degludec nella gestione terapeutica di pazienti con diabete mellito tipo 1 in linea con precedenti studi clinici randomizzati . Il passaggio a degludec da un altro analogo basale ( glargine o detemir) è in grado di migliorare il controllo glicemico, con una riduzione media dei valori di HbA1c di 0,20 % [-0,24;-0.17] a 6 mesi rispetto al basale (p <0.001). Inoltre i dati descritti in questo lavoro hanno evidenziato una riduzione del rischio di ipoglicemia sia totale ( rate ratio 0,79 [0,69: 0,89]), sia notturna (rate ratio 0,54 [0,42; 0,69]) sia grave (rate ratio 0,15 [0,09; 0,24]) a 6 mesi dalla modifica di terapia (p <0.001). Tale significatività rimane per tutto il periodo di follow-up di 12 mesi. Infine dopo 6 mesi di terapia con degludec, la dose totale di insulina giornaliera è diminuita del 11% rispetto al basale (p <0,001). Sulla base di questi dati, possiamo affermare che la terapia insulinica con degludec rappresenta un valido strumento terapeutico nella pratica clinica quotidiana, in grado di migliorare il compenso glicemico e la qualità di vita dei pazienti, favorendo così il raggiungimento di obiettivi glicemici più ambiziosi.Type 1 diabetes (DMT1) leads to absolute insulin deficiency due to immunologic destruction of the islet cells. Therefore affected patients need lifelong insulin treatment. Newer therapies for type 1 diabetes are aimed at developing insulin delivery systems that mimick normal physiology, identifying newer insulins that mimick endogenous insulin. To reproduce physiologic insulin secretion, both long- and short-acting insulins are used. Long-acting insulin, given at bedtime, suppresses glucose output from the liver overnight and provides basal insulin between meals; bolus doses of short-acting insulin modulate glucose excursions associated with carbohydrate consumption. Optimal glycemic control is necessary to reduce the risk for diabetes complications. However, tight glucose control carries a risk for hypoglycemia. Hypoglycemia may accelerate the vascular complications of diabetes by increasing platelet aggregation, leading to higher cardiovascular risk and all-cause mortality. Even brief hypoglycemia can cause profound dysfunction of the brain. Insulin administration by subcutaneous route has intrinsic limitations that, together with the pharmacokinetic (PK) profile of insulin formulations, do not reproduce the physiological patterns of insulin secretion. Insulin degludec (IDeg) is an ultra-long insulin analog that has unique pharmacokinetic and pharmacodynamic properties with a half-life of more than 24 h and a duration of action of more than 42 h. Compared to insulin glargine , the insulin degludec glucose-lowering action at steady state shows four time lower day-to day variability. Randomized clinical studies of degludec have shown a reduction in nocturnal hypoglycemia compared to insulin glargine. Given this background, IDeg is an ultra-long insulin analog that exhibits low intra-individual variability and whose efficacy is comparable to IGlar, but which presents as advantages flexibility in dose timing and lower risk of hypoglycemia, benefits that may impact quality of life and adherence to therapy. In Europe data on the use or effect of degludec in the general diabetes population not exist yet. Thus collection of data under routine clinical practice is highly warranted in order to access the effectiveness of degludec in real-life clinical setting. Aim of this retrospective non interventional study is to evaluate the clinical effectiveness of switching to IDeg in insulin treated patients with DMT1 under condition of routine clinical care. In all patients (n: 900), basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are presented as mean [95%CI]. HbA1c decreased by -0.20 % [-0.24; -0.17%] at 6 months vs baseline (P < .001). Rate ratio of overall (0.79 [0.69; 0.89]), non-severe nocturnal (0.54 [0.42; 0.69]) and severe (0.15 [0.09; 0.24]) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period (P < .001 for all). Total daily insulin dose decreased by -4.88 [-5.52; -4.24] U (-11%) at 6 months vs baseline (P < .001). This study demonstrates that switching patients to IDeg from other basal insulins improves glycaemic control and significantly reduces the risk of hypoglycaemia in routine clinical practice.
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Louafi, Fethi. "Role of retinoic acid or vitamin D analogue in models of human keratinocyte apoptosis : interactions with the IGF system." Thesis, University of Warwick, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269235.
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Moolman, Lukas Johannes. "The effect of snacking on continuously monitored glucose concentrations in analogue insulin basal bolus treatment regimens." Diss., University of Pretoria, 2013. http://hdl.handle.net/2263/40694.
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Gagnon-Auger, Maude. "Améliorer la pharmacocinétique de l’insuline analogue ultrarapide chez des sujets obèses et diabétiques de type 2." Thèse, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/11616.
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Résumé: Comparées aux classiques insulines humaines régulières (IHR), les insulines analogues ultrarapides (IAUR) ont été conçues pour mieux synchroniser le pic insulinémique avec l’absorption du repas. Le progrès a été démontré chez les patients diabétiques de type 1, mais le contrôle glycémique s’est peu ou pas amélioré chez les patients diabétiques de type 2 (DT2), qu’ils soient sous IAUR ou IHR. Or ces patients constituent 75 % des utilisateurs d’insuline. L’utilité des IAUR est donc toujours débattue. La dose (donc le volume) injectée et le flot sanguin dans le tissu adipeux sous-cutané (FSTA) sont les facteurs majeurs de l’absorption de l’insuline. Les patients DT2, résistants à l’insuline, s’injectent des doses importantes et leur FSTA est de 50 à 70 % plus faible que celui des sujets sains de poids normal (PN). Nous avons montré que l’absorption sous-cutanée des IAUR est diminuée chez les sujets obèses et DT2 (ODT2) par rapport aux sujets PN, que le volume injecté avait un effet délétère additionnel et que le FSTA peut être augmenté de façon pharmacologique avec un agent vasoactif (AV) chez des sujets résistants à l’insuline. Nous suggérons que l’ajout d’un AV à une IAUR va augmenter le FSTA au site d’injection et donc améliorer sa pharmacocinétique (PK) et sa pharmacodynamie (PD). Pour vérifier cette hypothèse, nous avons 1) évalué la réponse du FSTA à 4 AV chez des sujets PN, obèses non-diabétiques et ODT2; 2) évalué la PK/PD et la biodisponibilité de l’IAUR lispro ± AV chez des sujets ODT2; et 3) caractérisé l’expression des cibles des AV dans le tissu adipeux sous-cutané chez les sujets énumérés en 1). Les 4 AV ont augmenté le FSTA des sujets ODT2, mais moins que celui des autres sujets. L’occurrence de la raréfaction et/ou dysfonction microvasculaire chez les sujets ODT2 pourrait expliquer l’hyporéactivité vasculaire aux AV testés. Le plus actif des AV chez les sujets ODT2 a été ajouté à l’IAUR lispro pour améliorer sont absorption sc. Les PK/PD ont été améliorées seulement chez les sujets ODT2 avec une hémoglobine glycosylée A1c ≥ 8 %; c’est-à-dire 4 sujets sur 8. Chez ces derniers, l’absorption de 30 U + AV a été plus rapide de 14 et 71 min à 20 et 80 % de l’aire sous la courbe totale de la lispro plasmatique, respectivement. Chez les 4 autres sujets ODT2, l’absorption de la lispro semble s’être détériorée avec l’AV. Une interaction chimique a peut-être eu lieu entre l’AV et la lispro, ce qui aurait perturbé son absorption. Selon nos résultats, le niveau de contrôle du diabète, le volume d’injection et les caractéristiques chimiques de l’AV seraient des modulateurs de l’efficacité du concept IAUR + AV. Il nous faut maintenant déterminer l’impact de ces facteurs sur la capacité d’un AV à améliorer l’absorption sc de l’IAUR chez les sujets ODT2.Abstract: Compared to classic regular human insulin (RHI), short-acting insulin analogues were designed to better synchronize plasma insulin increase to food absorption. Although improvements were noted in subjects with type 1 diabetes, slight to no improvement in glycemic control were observed in subjects with type 2 diabetes (T2D) using SAIA instead of RHI. Nevertheless, they represent 75 % of all insulin users. Consequently, the relative useful-ness of SAIA in T2D patients is currently hotly debated. Injected volume and subcutaneous (sc) adipose tissue blood flow (ATBF) are two main factors involved in insulin absorption. In fact, T2D patients use large doses of insulin because of their resistance to insulin and have an ATBF 50 to 70 % lower than lean healthy subjects. We already showed that SAIA absorption is decreased in obese T2D (OT2D) subjects compared to normal weight healthy subjects and that volume has additional detrimental effects. We also showed that ATBF can be increased pharmacologically with vasoactive agents (VA) in healthy and insulin-resistant subjects. Then we suggest that in OT2D subjects, addition of VA to SAIA preparations will locally increase ATBF, improve insulin sc absorption (Pharmacokinetic - PK) and bioavailability, thus insulin hypoglycemic effect (Pharmacodynamic - PD). To test this hypothesis, we 1) assessed ATBF response of 4 selected VA within three experimental groups (normal weight, obese non-diabetic and OT2D subjects); 2) evaluated insulin PK/PD and bioavailability improvement in OT2D subjects after the addition of the best VA to SAIA lispro and 3) characterized expression of selected VA targets in sc adipose tissue biopsies, within equivalent experimental groups, and compared results with ATBF responses. All 4 VA were able to increase ATBF of OT2D subjects but in a less extend than other subjects. The occurrence of microvascular rarefaction and/or dysfunction in OT2D subjects can explain the hyporeactivity to tested VA. Nevertheless, one VA among others was shown more effective to increase ATBF in OT2D subjects and was then tested (mixed) with SAIA lispro. With the AV, PK/PD were improved only in OT2D subjects with A1c glycated hemoglobin ≥ 8 %; 4 subjects on 8. The sc absorption of 30 U + VA was faster by 14 and 71 min for respectively 20 and 80 % of the total area under the lispro plasmatic curve. But the sc absorption with VA appeared blunted with the other subjects. Maybe detrimental chemical interactions occurred between the VA and lispro, which could impede absorption. Our results suggest that diabetes control state, injection volume, and VA chemical characteristics influence the efficacy of our SAIA + VA concept. Further tests are needed to seize the impact of these factors on VA effectiveness in sc absorption improvement of SAIA in OT2D subjects.
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LEPERRE, ARMELLE. "Etude des effets de l'insulin-like growth factor i (igf-i, facteur analogue a l'insuline i) sur les fibroblastes en cultures monocouches et tridimensionnelles." Reims, 1992. http://www.theses.fr/1992REIMM037.
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Watson, Christopher John. "Insulin analogues for insulin receptor studies and medical applications." Thesis, University of York, 2012. http://etheses.whiterose.ac.uk/3797/.
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The structure of insulin molecule was determined by Dorothy Hodgkin in 1969. Subsequently, it has been established that insulin must rearrange upon binding to its receptor (Insulin Receptor – IR). However, all known structures of the hormone depict its storage or inactive form. It has been shown that some residues, key for IR binding, are buried inside the insulin molecule and must be exposed for an efficient insulin-IR complex formation. It has been postulated that the C-terminal region of the B-chain (~B20-B30) is dynamic in this process, and that the detachment of the B20-B30 β-strand leads to the activation of insulin. However, the understanding of the molecular basis of the insulin regulatory role is hindered by the lack of the structure of the insulin-IR complex; only 3-D description of the apo-form of the IR ectodomain is known. The very complex molecular biology behind expression and production of IR fragments also hampers progress in this field. In order to facilitate progress towards determination of the insulin-IR complex crystal structure this work delivered: (i) structural characterisation of highly-active insulin analogues for stable hormone-IR complexes, (ii) development of various attempts for an alternative production of L1 domain of human IR, (iii) structural characterisation of the role of residues B24 and B26 for insulin function, (iv) clarification of individual contributions of hydrogen bonds stabilising the insulin dimer, (v) understanding of the structural basis of different functionality of click-chemistry based novel insulin analogues. This work established that: (i) the structural signature of the highly active insulin analogues is new -turn at the Cterminus of the B-chain (the B26 turn) achieved by trans-to-cis isomerisation of the PheB25- TyrB26 peptide bond. This conformational change exposes residues responsible for IR binding, (ii) the production of the L1 domain in E. coli, instead of the usual mammalian expression system, is not feasible, (iii) the structural invariance of the PheB24 is fundamental to the formation of the insulin-IR complex. It acts as an anchoring and side-chain pivot for the B26 turn, (iv) removal of the NHB25-COA19 dimer interface hydrogen bond is sufficient for a complete disruption of the dimer, whilst the other four hydrogen bonds had a less marked effect in this process, (v) the formation of the B26 turn can be efficiently mimicked by click-chemistry based intra-B-chain crosslinks. These results provide a wealth of information about the active form of insulin, they provide important tools towards the first insulin-IR complex, and deliver novel insulin analogues.
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Shojaee-Moradie, Fariba. "Hepatic and peripheral effects of four insulin analogues." Thesis, King's College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338643.
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Bagley, Christopher James. "Analogues of Insulin-Like Growth Factor-1 / Christopher James Bagley." Title page, table of contents and summary only, 1989. http://web4.library.adelaide.edu.au/theses/09PH/09phb146.pdf.
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Milner, Steven John. "The oxidative folding of insulin-like growth factor-I analogues /." Title page, table of contents and summary only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phm65945.pdf.
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Verchere, Cameron Bruce. "Control of insulin secretion from the perfused rat pancreas : effects of acetylcholine and a somatostatin analog, SMS 201-995." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/26657.
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The effect of varying concentrations of glucose or the gastrointestinal hormones, gastric inhibitory polypeptide (GIP) and somatostatin (SS-14), on the in vitro immunoreactive insulin (IRI) response to the parasympathetic neurotransmitter, acetylcholine (ACh) was investigated. The isolated, vascularly perfused rat pancreas was used in all experiments.
Acetylcholine (1.0 µM) did not stimulate IRI secretion in the presence of 2.2 mM glucose. However, in the presence of 4.4, 6.6, or 8.9 mM glucose, ACh (1.0 µM) potently stimulated IRI secretion (approximately fourfold). At a higher glucose concentration (17.8 mM), the IRI response to ACh was reduced. GIP also potentiated the IRI response to 1.0 µM ACh. This potentiation was most marked in the presence of 1.0 nM GIP, whereas the effect of concomitant infusion of 0.2 nM GIP and 1.0 µM ACh was only slightly greater than additive. SS-14 potently inhibited ACh-stimulated IRI secretion. These results demonstrated the glucose dependency of cholinergically stimulated IRI secretion, and that physiological levels of glucose and GIP increased B-cell sensitivity to cholinergic stimulation. It was suggested that the parasympathetic stimulation of IRI secretion associated with food intake could be affected by postprandial increases in glucose, GIP, and SS-14.
The idea that endogenously released somatostatin may have influenced glucose or GIP-stimulated IRI secretion was not supported by the present experiments, since neither glucose (8.9 mM) nor GIP (2.0 nM) were found to have a significant effect on the release of pancreatic somatostatin-like immunoreactivity (SLI). Both atropine (1.0 µM) and hexamethonlum (100 µM) inhibited the IRI response to ACh. This suggested that the parasympathetic stimulation of IRI secretion was mediated not only by muscarinic receptors on the B-cell, but also by nicotinic receptors on intrapancreatic ganglia. Neither atropine nor hexamethonlum had a significant effect on glucose- or GIP-stimulated IRI secretion, indicating that the IRI response to these stimuli was not mediated by cholinergic receptors.
Both SS-14 and the synthetic somatostatin analog SMS 201-995 (SMS; Sandostatin®) inhibited IRI secretion stimulated by 8.9 mM glucose, 2.0 nM GIP, or 1;.0 µM ACh, but not 17.8 mM glucose. The most potent inhibition by both SS-14 and SMS was observed in the presence of the weakest IRI stimuli (8.9 mM glucose and 1.0 µM ACh). These results suggested that the inhibitory effects of somatostatin on the B-cell could be overcome by the presence of strong stimuli. In addition, the inhibitory effects of the native hormone and the analog were found to be approximately equipotent (weight basis), indicating that the increased potency of SMS previously observed in vivo was due to its longer half-life in plasma, and not due to a more potent direct effect on the B-cell.Medicine, Faculty of
Cellular and Physiological Sciences, Department of
Graduate
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Liu, Hui-Kang. "Modification of the function of insulin-secreting cells by beta-cell toxins, differentiation drugs, insulin mimetics, steroids, and incretic hormones and their stable analogues." Thesis, University of Ulster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399055.
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Agin, Arnaud. "Dosage des analogues de l'insuline à l'aide de deux immunodosages de l'insuline humaine : Evaluation analytique et application à l'étude de la biotransformation de la glargine." Université Louis Pasteur (Strasbourg) (1971-2008), 2006. https://publication-theses.unistra.fr/public/theses_doctorat/2006/AGIN_Arnaud_2006.pdf.
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Agin, Arnaud Sapin Rémy. "Dosage des analogues de l'insuline à l'aide de deux immunodosages de l'insuline humaine évaluation analytique et application à l'étude de la biotransformation de la glargine /." Strasbourg : Université Louis Pasteur, 2008. http://eprints-scd-ulp.u-strasbg.fr:8080/875/01/AGIN_Arnaud_2006.pdf.
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Marshall, Nicholas John. "The influence of insulin-like growth factor 1 and its analogues on fibroblasts and dermal wound healing." Title page, table of contents and synopsis only, 1998. http://web4.library.adelaide.edu.au/theses/09MD/09mdm3685.pdf.
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Includes bibliography (leaves 191-219). Examines the levels of insulin-like growth factor and the presence of IGF binding proteins in human wound fluid. Tests the potency of IGF-1 and 2 analogues in in vitro models of fibroblast activity and their effect on healing in normal and diabetic rodent wounds. Shows that IGF-1, IGF-2 and their binding proteins are present in fluid from a partial thickness cutaneous wound; that the binding proteins negatively modulate the activity of insulin-like growth factors in vitro, but that the IGFs do not necessarily show enhanced activity in vivo at the wound site if binding protein affinity is decreased. Discusses possible roles of these binding proteins in wound repair.
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Gagnon-Auger, Maude. "Réévaluation de la pharmacocinétique d'une insuline analogue ultrarapide chez des sujets obèses et diabétiques de type 2." Mémoire, Université de Sherbrooke, 2010. http://savoirs.usherbrooke.ca/handle/11143/4004.
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Les caractéristiques pharmacocinétiques des insulines analogues ultra-rapides (IAUR) furent établies chez des sujets de poids normal, sains ou diabétiques de type 1, et à partir de petites doses d'insuline (4-12 U). La taille de la dose injectée et le flot sanguin dans le tissu adipeux (FSTA) sont des facteurs très importants qui affectent l'absorption sous-cutanée de l'insuline. Cependant, chez les patients obèses et diabétiques de type 2 (DT2), les doses d'insulines injectées sont beaucoup plus importantes et leur FSTA de base est 50 à 70 % plus faible que chez un sujet sain de poids normal. Ce qui porte à croire que l'absorption de l'insuline est moins efficace chez ces patients. Notre objectif est de déterminer la pharmacocinétique et la pharmacodynamie d'une IAUR chez les patients DT2 obèses. Six sujets témoins sains et de poids normal reçurent 10 U d'IAUR lispro et 7 sujets DT2 obèses 10, 30 et 50 U. Après injection sous-cutanée, nous avons procédé à un clamp euglycémique. La lispro plasmatique fut mesurée par RIA spécifique.Les paramètres de cinétique et de dynamique obtenus chez nos sujets sains confirment ceux publiés précédemment. Nos résultats sont donc pleinement en accord avec la littérature. Lors de l'injection de petites doses (10 U) chez les sujets DT2 obèses, l'absorption de la lispro ne semble pas être altérée par rapport aux témoins : la constante d'absorption (ka), le temps au pic plasmatique de lispro (T[indice inférieur max]) et l'aire totale sous la courbe (AUC[indice inférieur 0-[infini]]) sont semblables à ceux des témoins. Cependant, chez les sujets DT2, l'augmentation de la dose injectée couduit [i.e. conduit] à une réduction de la ka et un retard du T[indice inférieur max]. Dans les paramètres de glucodynamie, des différences très significatives se manifestent entre les 2 groupes, avec une réponse à l'insuline retardée et réduite chez les sujets DT2. Avec l'injection de 10 U, le taux d'infusion maximal de glucose (GIR[indice inférieur max]) est 15 fois plus petit et le temps correspondant (tGIR[indice inférieur max]) a presque doublé. Dans ce même groupe, on note un délai qui augmente avec de la dose injectée : le tGIR[indice inférieur max] a doublé entre les doses de 10 et 50 U et se chiffre à 4 heures pour l'injection de 50 U. Cette étude suggère que dans l'application clinique, la taille des doses injectées doit être considérée et que la synchronisation entre l'injection d'une IAUR et la prise du repas chez les patients DT2 obèses doit être étudiée. Afin d'améliorer l'absorption de l'insuline chez nos sujets obèses et DT2, nous avons testé deux méthodes : ajouter un agent activateur de flot (AVD) à la lispro ou bien augmenter la concentration de l'insuline pour diminuer le volume de la dose injectée. L'ajout d'AVD a mené à des résultats surprenants : l'AUC, le pic plasmatique de lispro (C[indice inférieur max]), le GIR[indice inférieur max] et l'infusion totale de glucose (GI[indice inférieur tot]) ont augmenté de 3 fois. Cependant, la diminution du volume de la dose injectée n'a eût [i.e. eu] aucun effet notoire sur l'absorption de la lispro. D'autres études seront donc faites pour mieux caractériser l'effet de lAVD sur l'absorption sous-cutanée de l'insuline.
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Glidden, Michael D. II. "Single-chain insulin analogs as ultra-stable therapeutics and as models of protein (mis)folding: stability, structure, dynamics, and function of novel analogs." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522270994798884.
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Dong, Siyuan. "A time dependent adaptive learning process for estimating drug exposure from register data - applied to insulin and its analogues." Thesis, KTH, Beräkningsbiologi, CB, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-128438.
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Hartmann, Thorsten [Verfasser], Jürgen [Akademischer Betreuer] Eckel, and Eckhard [Gutachter] Lammert. "Effect of long-acting insulin analogues on human cardiovascular cell models / Thorsten Hartmann ; Gutachter: Eckhard Lammert ; Betreuer: Jürgen Eckel." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2017. http://d-nb.info/1136421882/34.
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Marsh, Andrew. "Characterisation of the type I IGF receptor binding surfaces of insulin-like growth factor 1 using protein engineering." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245705.
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Gajanandana, Oraprapai. "Studies of complexes formed in blood in vivo between an insulin-like growth factor analog and binding proteins." Title page, contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phg145.pdf.
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Includes bibliographical references (43 leaves) This study shows that when LR3IGF-I is administered to animals in pharmacologically active doses, it may be present in either the free form or bound to IGF-binding protein(s) in the circulation. Age and nutrition which are factors that regulate synthesis of endogenous IGF-I and IGF-binding proteins, affect the in vivo formation of complexes between the analog and IGFBP(s). This study also suggests that IGFBP-1 inhibits the pharmacological activity of circulating LR3IGF-I on thymus whereas it appears to stimulate the pharmacological activity of LR3IGF-I in kidneys.
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Kornienko, Alexander. "Practical enantiospecific syntheses of differentially protected cyclitols and partial synthesis of a non-Hydrolyzable Phosphooligosaccharide analog related to insulin signal transduction /." Thesis, Connect to Dissertations & Theses @ Tufts University, 1999.
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Thesis (Ph.D.)--Tufts University, 1999.Adviser: Marc d'Alarcao. Submitted to the Dept. of Chemistry. Includes bibliographical references (leaves 123-128). Access restricted to members of the Tufts University community. Also available via the World Wide Web;
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Hall, Melanie J. "Pharmacology of the GLP-1 Analog Liraglutide in Healthy Cats." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405949641.
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Gleizes, Céline. "Mécanismes et contrôle de la réaction inflammatoire précoce au cours de la greffe d'îlots pancréatiques dans un modèle de lignée de cellules bêta de rat : rôle et modulation de la libération des microparticules." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ082/document.
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La greffe d’îlots pancréatiques est caractérisée par une réponse inflammatoire et procoagulante précoce, connue sous le nom d’IBMIR (Instant Blood Mediated Inflammatory Reaction). Les microparticules (MPs) porteuses de facteur tissulaire (TF) sont le témoin d’un important remodelage membranaire et constituent des acteurs centraux dans la dissémination du stress de l’IBMIR. Nous avons exploré l’effet d’un stress inflammatoire sur la survie et la fonction de la cellule β dans un modèle de communication cellulaire médiée par les MPs. La modulation pharmacologique par les analogues du GLP-1 a été évaluée, la par la mesure de la sécrétion d’insuline, de l’activité TF et l'analyse du remodelage de la membrane plasmique. Nos résultats décrivent les MPs comme des effecteurs autocrines et indiquent que les MPs sont des cibles potentielles pour les analogues du GLP-1 au cours de l'IBMIR. Les données apportent de nouvelles pistes sur les mécanismes cellulaires mis en jeu lors des phénomènes d’ischémie reperfusion durant l’IBMIRPancreatic islets graft is characterized by early inflammatory and procoagulant events known as Instant Blood Mediated Inflammatory Reaction (IBMIR). Tissue factor (TF) bearing microparticles (MPs) are surrogates of important membrane remodeling and key players in the systemic and local dissemination of such stress.We investigated the effect of inflammatory stress on β cell survival and function in a MP-mediated cell crosstalk model. Pharmacological modulation by GLP-1 analogues was evaluated by measurement of insulin secretion, TF activity and assessment of plasma membrane remodeling. Our data evidenced MPs as autocrine effectors and possible new target for GLP-1 analogues. They bring new hints on the cellular mechanisms prompted by ischemia reperfusion during IBMIR
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Duarte, Felipe Henning Gaia. "Síndrome da apnéia do sono na acromegalia: impacto do tratamento sobre o metabolismo dos carboidratos." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-19092011-152108/.
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Introdução: A acromegalia é uma doença rara, caracterizada pela produção aumentada de hormônio do crescimento, causada geralmente por um adenoma hipofisário, ocasionando uma série de comorbidades como apneia do sono e resistência insulínica que acarretam um aumento na mortalidade e redução da expectativa de vida. Objetivo: O objetivo deste estudo foi avaliar o impacto da terapêutica da apneia do sono com um dispositivo de pressão positiva contínuas nas vias aéreas (CPAP) e avaliar o impacto desta terapêutica na resistência insulínica pela realização do clamp euglicêmico hiperinsulinêmico (CEH). Pacientes: De 156 acromegálicos regularmente atendidos na unidade de Neuroendocrinologia do HC-FMUSP, foram selecionados 12 indivíduos com apneia do sono de moderada a grave em uso de análogos da somatostatina (AS). Método: Os pacientes foram randomizados em dois grupos com seis integrantes. O grupo A iniciou o tratamento com CPAP, e o grupo B, um adesivo dilatador nasal com efeito de placebo. A avaliação basal incluiu a polissonografia, determinação do GH, IGF-1, HbA1c, ácidos graxos livres, lípides, CEH, bem como os índices de resistência periférica à insulina (HOMA, HOMA2 e QUICKI). Após 3 meses de tratamento, os pacientes foram reavaliados pelos mesmos exames, sendo trocado o tratamento entre os grupos e feita nova avaliação, após mais 90 dias. Resultados: Analisando os resultados finais de todos os pacientes que fizeram uso do CPAP, foi observada uma redução significante na resistência periférica à insulina, verificada pelo índice de sensibilidade derivado do clamp (ISCLAMP, pré e pós- CPAP, 3,83 versus 6,11, p=0,032). Esta redução não foi observada no grupo que fez uso do adesivo nasal (ISCLAMP, pré e pós-adesivo, 5,53 versus 5,19, p=0,455). Não houve diferença significante nos níveis de lípides, HbA1c nem nos índices de resistência periférica à insulina. Conclusão: O tratamento da apneia do sono moderada a grave com CPAP, em pacientes acromegálicos em uso de AS, levou a uma redução da resistência periférica à insulina aferida pelo CEH, dado não observado por meio dos índices HOMA, HOMA2 e QUICKIIntroduction. Acromegaly is a rare disease, characterized by the production of high GH levels usually by pituitary adenoma leading to comorbidities as sleep apnea and insulin resistance, bringing increase of mortality and life span reduction. Objective: This study aims to assess the impact of treatment of sleep apnea with a continuous positive air pressure device (CPAP) on the insulin resistance by performing the hyperinsulinemic euglycemic clamp (HEC). Patients: From 156 acromegalic patients regularly attended on Neuroendocrine Unit of the Hospital das Clínicas, University of São Paulo Medical School, 12 subjects on somatostatin analogs (SA) harboring moderate to severe sleep apnea were selected. Methods: Patients were randomized in two groups of six subjects. Group A started treatment with CPAP while group B started treatment using a nasal dilator adhesive with placebo effect. Basal assessment included polysomnography, determination of GH, IGF-1, HbA1c, free fat acids, lipids assays, HEC as well as insulin resistance indexes (HOMA, HOMA2 and QUICKI). Patients were reevaluated after three months of treatment by the same tests and then the treatment was switched between groups with new assessment 90 days later. Results: A significant reduction on insulin resistance determined by the clamp derived sensibility index was observed after assessing the final data of all patients on CPAP (SICLAMP, pre and post CPAP, 3,83 versus 6,11, p=0,032). This reduction was not seen in the nasal dilator adhesive group (SICLAMP, pre and post adhesive, 5,53 versus 5,19, p=0,455). There was no significant difference on lipids, HbA1c or on peripheral insulin resistance indexes. Conclusion: CPAP treatment of acromegalic patients on AS with moderate to severe sleep apnea leaded to significant reduction on peripheral insulin resistance assessed by the HEC. HOMA, HOMA2 and QUICK did not detect this data
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Lord, Andrew P. D. "IGF transfer from blood to tissue: comparison of IGF-I with analogs that bind poorly to binding proteins, using a vascular perfusion model : a thesis submitted to the University of Adelaide, South Australia, for the degree of Doctor of Philosophy /." Title page, abstract and table of contents, 1993. http://web4.library.adelaide.edu.au/theses/09PH/09phl866.pdf.
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Jacob, Dolly. "Investigation into reliability and performance of an implantable closed-loop insulin delivery device." Thesis, De Montfort University, 2014. http://hdl.handle.net/2086/11126.
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An implantable closed-loop insulin delivery device (INsmart device) containing a glucose responsive gel has been developed within the INsmart research group, over a period of 10 years, to mimic pancreas. In this thesis, the reliability and performance capability of the INsmart device was studied for future clinical use. Investigations into the device material compatibility with insulin solution, assessed by monitoring insulin loss and degradant formation over a period of 31 days using RP-HPLC have shown that stainless steel and titanium are the most compatible materials. Polycarbonate contributes to insulin loss after 11 days, resin might not be the best material and polyurethane is the least compatible for future device designs. To study insulin delivery mechanism and kinetics from the device, fluorescently labelled human insulin (FITC-insulin) was synthesised and characterised using RP-HPLC and MS, to produce a product with predominantly di-labelled conjugate (>75%) with no unreacted FITC or native insulin. Clinically used insulin analogues were also fluorescently labelled to produce predominantly di-labelled FITC-insulin conjugate with potential future biological and in vitro applications. The drug release mechanism from the glucose sensitive gel held in the INsmart device, studied using fluorescein sodium was determined as a Fickian diffusion controlled release mechanism. The diffusion coefficient (D) for FITC-insulin in the non-polymerised dex2M-conA gel (NP gel) determined using mathematical models, QSS and TL slope methods was 1.05 ± 0.02 x 10-11 m2/s and in the cross-linked dex500MA-conAMA gel (CL gel) was 0.75 ± 0.06 x 10-11 m2/s. In response to physiologically relevant glucose triggers in the NP gel, the diffusivity of FITC-insulin increases with increasing glucose concentrations, showing a second order polynomial fit, device thus showing glucose sensitivity and graded response, mimicking pancreas. Rheological measurements further confirmed the gel glucose responsiveness demonstrated by a third order polynomial fit between FITC-insulin D and the NP complex viscosity in response to increasing glucose concentration. The knowledge of FITC-insulin diffusion kinetics in the gel has aided in making some theoretical predictions for the capability and performance of the INsmart device. Alternate device geometry and design optimisation is also explored.
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Blanchetier, Valérie. "Insulino-résistance et insuffisance rénale chronique : intérêt d'un régime restreint en protides et en phosphore et supplémenté en acides aminés essentiels et céto-analogues." Bordeaux 2, 1995. http://www.theses.fr/1995BOR23086.
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Lin, Jen-Chieh, and 林人傑. "Association of Insulin Analogue and Antihypertensive Drug Use with Sight-Threatening Diabetic Retinopathy in Type 2 Diabetes." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/11074019666950049637.
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博士國立臺灣大學
流行病學與預防醫學研究所
102
Objectives: The aims of the study are to estimate age- and sex-specific prevalence and incidence of sight-threatening diabetic retinopathy in Taiwan and evaluate the effect of systemic drugs on prevention of diabetic retinopathy progression, focusing on antihypertensive drugs and long-acting insulin analogues. Materials and Methods: Data was collected from a representative database, Longitudinal Health Insurance Database (LHID) 2005, during 2005, on a total of 222 incident cases of patients with sight-threatening diabetic retinopathy (STDR) among 29,165 type 2 diabetic patients. Sight-threatening diabetic retinopathy was defined as clinically significant macular edema or severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy according to the classification of the Early Treatment Diabetic Retinopathy Study Research Group. Gender-specific and age-adjusted incidence and prevalence rates of STDR were analyzed for the patients with type 2 diabetes and STDR identified using ICD-9-CM codes and procedure codes. Type 2 diabetic patients aged 20-100 years, with at least one prescription for antihypertensive drugs between 2000 and 2011 were identified from Longitudinal Health Insurance Database (LHID) 2005. The incidence rates of STDR were followed and Cox proportional hazards models were used to analyze the risk associated with antihypertensive drugs. A retrospective cohort consisting of patients with type 2 diabetes aged &;#8805; 20 years and newly initiated on long-acting insulin analogues (glargine and detemir) and intermediate-acting human insulin were identified from the National Health Insurance database between January 2004 and December 2006 and categorized into different cohorts. Risk of developing STDR was determined by Cox proportional hazards models and compared between different cohorts. Results: The number of incident cases of STDR increased in line with the increasing diabetic population during 2005-2011. During 2005, no gender differences in the age-adjusted incidence and prevalence rates were observed. The prevalence of sight-threatening DR was significantly higher when patients were aged 40-59 and 60-79. The crude incidence rates of STDR among patients received thiazide diuretics, alpha-blockers, beta-blockers, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and calcium channel blockers (CCB) were 16.45, 9.49, 12.81, 19.19, 17.63, and 18.15 per 1,000 person-years. Users of ACEI and ARB were associated with a significantly higher risk than CCB users, independent of baseline characteristics. After adjusting time-varying use of concomitant medications for propensity score (PS) matched or unmatched cohorts, the results showed that patients receiving ACEI, ARB and CCB were associated with a significantly greater risk compared with beta-blocker users. The hazard ratio varied from 1.18 to 1.55 with statistical significance. Of the 32,395 eligible patients, initiators of insulin glargine, insulin detemir and NPH insulin were identified for comparison through propensity score matching. Long-acting insulin analogue, glargine, was not associated with changed risk for STDR by intention-to-treat and time-varying use approaches between either matched or unmatched cohorts. However, patients treated with insulin detemir, were associated with significantly changed risk for sight-threatening DR while analyses were performed by different approach for matched and unmatched cohort. Conclusions: There was no significant difference in the incidence between genders. Our findings provide the evidence that the incident cases of STDR increased among identified type 2 diabetic patients, but the overall prevalence of STDR was in a declining trend in Taiwan, suggesting that decreased mortality rate, better diabetes management, and early detection of treatable DR might contribute to the prevalence patterns. Our study did not support a superiority of ACEI, ARB and CCB over beta-blockers for lowering the progression of DR over 11-year follow-up. While comparing long-acting insulin analogue, glargine, with NPH insulin, no significant difference in the risk of sight-threatening DR was found. However, significantly increased risk was detected in insulin detemir initiators compared with NPH insulin initiators. The strategies that aim at preventing DR by treating type 2 diabetic patients with long-acting insulin analogues remain further prospective studies with longer follow-up period to validate our observations within an appropriate dosage range and to further evaluate the safety of long-acting insulin analogues on reducing the progression of DR.
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Kuan-YingLi and 李寬穎. "Comparative effectiveness and safety of intermediate-acting human insulin versus long-acting insulin analogue in patients with type 2 diabetes: A prevalent new-user cohort study." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/4tkwkz.
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碩士國立成功大學
臨床藥學與藥物科技研究所
107
SUMMARY Basal insulin is recommended for the type 2 diabetes mellitus (T2DM) patients who need initial insulin therapy. However, there is not sufficient evidence about long-term vascular effects between basal insulin in T2DM population. This study was aimed to estimate the risks of macrovascular events, microvascular events, hospitalized hypoglycemia and all-cause mortality between intermediate-acting human insulin (IAHI) and long-acting insulin analogue (LAIA) users. Selection criteria of study population included newly diagnosed T2DM during 1999-2012 and stable basal insulin use during 2004-2012. Previous studies used incident new-user cohort design who never exposed to any kinds of basal insulin. A prevalent new-user cohort design was adopted to include all possible basal insulin users and generalizability to real-world clinical practice settings. Comparability between treatment groups was achieved by matching on (1) initiation time of study drugs, (2) prior exposure to glucose-lowering agents, and (3) diabetes severity and comorbidities (propensity score). Cox proportional hazard model was employed to assess the association between treatments and study outcomes. Study primary results revealed that IAHI users were associated with higher risks of macrovascular and hospitalized hypoglycemia, and lower risks of microvascular events compared to IAHI users. The higher risks of macrovascular events in IAHI users might be partly explained by hypoglycemia, glucose variability and medication adherence. Future research is needed to explore the association between hypoglycemia event and CVD event in insulin users.
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Chrudinová, Martina. "Studium interakce inzulinu, IGF-1/2 a analogu IGF-1 s receptory inzulinu a IGF-1." Master's thesis, 2014. http://www.nusl.cz/ntk/nusl-336909.
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Insulin-like growth factors 1 and 2 (IGF-1/2) are single-chain peptides exerting homology (in both amino-acid sequence and tertiary structure) to insulin. The main function of these peptides is promoting celular growth, proliferation and differentiation. Both insulin and insulin-like growth factors mediate their function through membrane receptors - insulin receptor (isoforms A and B) and IGF-1 receptor. All these receptors are members of the tyrosinkinase family of receptors and they exert the same subunit and domain composition. The activation of insulin and IGF-1 receptors is tightly associated with activation of two intracellular signaling pathways. The PI3-K/Akt pathway is involved in the glucose transport to the cell, induction of proliferation or inhibition of apoptosis, while the Ras/MAPK pathway is involved mainly in the induction of cell growth and differentiation. Due to the structure similarity in both the ligands and receptors, every ligand can activate different receptors (with different potency) and the signaling pathways associated with these receptors. Thus, the functions of IGFs and insulin, the same as their receptors, are overlapping. The distinct function of the concrete ligand can be distinguished by the different tissue distribution of both isoforms of insulin receptor and...
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Kaplan, Vojtěch. "Nové analogy lidského insulinu s kovalentně stabilizovanými cyklickými strukturami v C-konci B-řetězce." Master's thesis, 2011. http://www.nusl.cz/ntk/nusl-313005.
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Diabetes mellitus is considered as one of world's most common metabolic diseases. Complicated treatment and increasing number of newly diagnosed patients, suffering from diabetes every year, shows the importance and necessity of research in this area. Some of the major aims of this research are the development of new therapeutically utilized drugs and defining the problems of insulin acting in human body. Insulin is a peptide hormone whose main physiological function is to regulate blood glucose level in organism connected with large impact on whole metabolism. Insulin acts through binding of its monomeric form to the insulin receptor. Upon binding to the receptor molecule of insulin undergoes specific structural changes, which put the hormone into an active state. As of now, the structure of the insulin's active monomeric form is still unknown. By testing binding affinities of many modified insulin analogues there was discovered strong evidence between structural conformation of the C-terminus of the B-chain and binding affinity to the receptor. The most crucial data, necessary for this work, were observed from the structure of highly active insulin analogues that possessed unique B26 turn, recently prepared and described by team of Dr. J. Jiráček, IOCB AS CR. The aim of this work was synthesis of...
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Chrudinová, Martina. "Studium aktivačních vlastností analogů insulinu, IGF-1 a IGF-2 vůči receptorům pro insulin a IGF-1." Doctoral thesis, 2019. http://www.nusl.cz/ntk/nusl-397235.
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The insulin/insulin-like growth factor signaling axis is a complex system that is involved in the regulation of metabolism and body growth. It includes three related peptide hormones: insulin and two insulin-like growth factors (IGF-1 and IGF-2), and their receptors: two isoforms of insulin receptor (IR-A and IR-B), and IGF-1 receptor (IGF-1R). Whereas insulin is involved predominantly in regulation of the metabolism, IGFs participate mainly in the regulation of cell growth, proliferation and differentiation. Due to the similarities in the structures of both the hormones and the receptors, all the hormones can bind and activate all the receptors, although with different potencies. At which point and how are the "metabolic" and "mitogenic" functional outcomes of the system diversified, as well as the structural determinants responsible for the different affinities of the hormones to the individual receptors, is still not completely understood. Deregulation of the insulin/IGF system can result in many types of pathological states, mainly diabetes mellitus and cancer. Therefore, to deeply understand the functioning of the insulin/IGF system to the structural details is crucial for development of analogs with desirable properties, that are of great clinical interest. First of all, we developed a...
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Garnaut, Sonja Michelle. "The effect(s) of increasing intestinal mass with insulin-like growth factor-I peptides on nutrient absorption : a comparison of IGF-I and an analogue that binds poorly to binding proteins in normal rats using three methods to assess nutrient uptake / Sonja Michelle Garnaut." 2004. http://hdl.handle.net/2440/22233.
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Bibliography: leaves 193-236.244 leaves : ill. (s. col.) ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics and Women's and Childrens Hospital, 2005
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Křížková, Květoslava. "Příprava a charakterizace selektivních analogů insulinu a IGF-2 pro různé isoformy insulinového receptoru." Master's thesis, 2014. http://www.nusl.cz/ntk/nusl-337324.
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Modern lifestyle with its lack of exercise and healthy diet often leads to obesity which is accompanied by a decreasing biological effect of insulin and the onset of hyperinsulinemia, and consequently type 2 diabetes. Persistently high levels of insulin stimulate signalling pathways with growth effects; cells thus become more sensitive to mitogenic effects of all growth factors which may even lead to the loss of control over cell proliferation and the rise of various malignancies. Due to a high degree of structure homology of insulin, IGF-I/II as well as particular IR (existing in "mitogenic" IR-A isoform and "metabolic" IR-B isoform) and IGF-1R, there are a number of cross- interaction among hormones and receptors; nevertheless, the biological response may be different during the binding to a receptor. The determination of the crucial structural regions in insulin and IGF which are responsible for binding to the receptors could lead to the evolution of selective insulin analogues with strengthen metabolic effects, or could lead to the evolution of selective antagonism of IGF which would, in turn, suppress the mitogenic effect. The highest overlap is between insulin and IGF-II since both hormones are able to bind to the isoform A of an insulin receptor (IR-A) with a high affinity, and to activate...
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Kletvíková, Emília. "Syntéza a charakterizace nových analogů insulinu s cílem objasnit interakci insulinu s jeho receptorem." Doctoral thesis, 2013. http://www.nusl.cz/ntk/nusl-329261.
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The objective of this thesis is to characterize insulin analogues modified at the C-terminus of the B-chain with the aim to observe the impact of the inserted modifications on the insulin-insulin receptor (IR) interaction and the ability of the analogues to dimerize. Therefore, a series of analogues with modifications at B24-B26 positions was prepared. Using the synthetic and semisynthetic methods we inserted coded and non-coded amino acids to this part of B-chain. We studied full-length analogues and analogues truncated by three to four amino acids. Binding affinity of all analogues to the insulin receptor was determined by competition of analogue with radioactive (125I) human insulin. Dissociation constant in the dimer dissociation process of selected analogues (especially of those with N- methylation of B23-B24, B24-B25 and B25-B26 peptide bonds) was determined by isothermal titration microcalorimetry. The crystal structures of several analogues were resolved by X-ray crystallography and nuclear magnetic resonance. The structural results showed the consequences of inserted modifications to the insulin molecule. We characterized analogues with higher, equipotent and lower binding affinity to the IR. The results...
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Milner, Steven John. "The oxidative folding of insulin-like growth factor-I analogues / by Steven John Milner." Thesis, 1996. http://hdl.handle.net/2440/18702.
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Addendum pasted onto back end-paper.Bibliography: leaves 146-179.
Bibliography: leaves 146-179.
ix, 179, [66] leaves, [2] leaves of plates : ill. (some col.) ; 30 cm.
This thesis investigates the effect of mutations and an N-terminal extension on the oxidative folding pathway of IGF-I, analyses the structure of the stable mis-folded molecule in terms of its biological interactions, examines the kinetics of the late stages of oxidative folding and finally attempts to dissect the folding pathway of a mutant of IGF-I.
Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1996?
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Laajoki, Leanne G. "Nuclear magnetic resonance studies of insulin-like growth factor-I analogues displaying enhanced biological activity." Phd thesis, 2000. http://hdl.handle.net/1885/148063.
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Mlčochová, Květoslava. "Příprava a charakterizace selektivních analogů insulinu a IGF-2 pro obě isoformy insulinového receptoru a IGF-1 receptoru." Doctoral thesis, 2019. http://www.nusl.cz/ntk/nusl-411971.
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Insulin and insulin-like growth factor 1 (IGF-1) and 2 (IGF-2) are related protein hormones with different but overlapping biological functions. All the hormones interact with a receptor within the insulin-IGF system (insulin receptor A and B, IGF-1 receptor), however with different affinity. The different interaction with individual receptors is just one of the main tools for regulation of the system that is essential for the proper functioning of the organism. Although the residues directly interacting with receptors are mainly located in A and B domains, the C and D domains probably play a role in receptor specificity. Here, we firstly focused on the impact of D domains of IGF-1 and 2 (D1 and D2 domains) and C domain of IGF- 2 (C2 domain). To probe the impact of C and D domains, we prepared insulin analogues containing a part of or an entire domain following a pattern seen in IGFs. The receptor-binding affinities of these analogues and their receptor autophosphorylation potentials were characterised. Our results revealed that the initial part of D1 domain has a detrimental effect on IR affinity that is only slightly enhanced by the rest of the D1 domain. D2 domain has rather neutral effect on IR affinity. We further showed that the addition of amino acids derived from the C2 domain to the...
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Lieblich, Seth Aharon. "Non-Canonical Amino Acid Mutagenesis of Position B28 In Insulin with Proline Analogs." Thesis, 2017. https://thesis.library.caltech.edu/10166/7/Thesisv5.pdf.
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Insulin is a protein hormone that is crucial for maintaining the concentration of blood glucose in vivo and is used clinically as a drug for the treatment of diabetes.
Chapter I provides for an overview and background on the state of the art in insulin treatment of diabetes and the many attempts, over 95 years, to improve the pharmaceutically relevant properties of insulin and improve our understanding of the model globular protein.
Chapter II demonstrates the incorporation of hydroxyproline analogs into insulin and shares the discovery of insulin with enhanced stability and an accelerated kinetic rate of dissociation. We also provide the highest resolution structure deposited in the PDB of insulin in the T2 state and the 3rd highest of any insulin to date.
Chapter III extends the incorporation of proline analogs in insulin to include fluorinated insulins. We also provide, for the first time, high-resolution structures of a single globular protein systematically mutated with all possible stereoisomers of fluorination at the 4-position on a single proline residue (4S, 4R, di-substituted).
Chapter IV extends the incorporation of proline analogs in insulin to include ring variant analogs. We also provide, for the first time, high-resolution structures of globular proteins containing pipecolic acid, azetidine-2-carboxylic acid and 3,4 dehydroproline in the polypeptide chain.
Chapter V discusses the significance of the findings described herein and discusses future directions to undertake in further engineering insulin for improved characteristics.
This thesis describes a systematic approach, akin to medicinal chemistry, of altering a particular protein side chain by atomistic changes. I hope that the breadth of different amino acids incorporated into a single globular protein combined with the structural, functional, thermodynamic and kinetic information contained within this set of mutants will provide future protein engineers, computational protein designers and proline enthusiasts with a wealth of new information to be used to improve our understanding of proteins and predictive power.
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Povalová, Anna. "Analogy insulinu s řetězcem A prodlouženým o doménu D proteinů IGF-1 a IGF-2." Master's thesis, 2015. http://www.nusl.cz/ntk/nusl-331976.
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Insulin and insulin-like growth factors (IGF-1 and -2) together with their receptors take part in a complex system, which affects both basal metabolism of carbohydrates, lipids and proteins as well as cell growth, proliferation, differentiation and apoptosis. Defects in action of insulin or IGFs can lead to serious diseases such as diabetes or cancer. Both of these disorders represent nowadays one of the biggest health threats to the world's population. Insulin and IGFs induce different biological effects through their cognate receptors; two isoforms of the insulin receptor (IR-A and IR-B) and the receptor for IGF-1 (IGF-1R). These receptors bind insulin and IGFs with different affinities and induce different but partially overlapping signalling events leading towards metabolic (especially insulin) or mitogenic responses (IGFs and insulin). To understand the mechanism of action of insulin and IGFs it is important to specify which structural domains of these hormones are responsible for binding to the receptors and exerting specific effects. One region that is missing in insulin is the D-domain of IGF-1 and -2. For this reason, we decided to prepare insulin analogues with the A-chain extended by either the whole D-domain of IGF-1 or IGF-2, or by fragments of the IGF-1 D-domain in order to define the...
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Bryant, Katherine J. (Katherine Jane) 1962. "Design, production and characterisation of IGF-I analogues with increased gastric stability / by Katherine J. Bryant." 1995. http://hdl.handle.net/2440/19074.
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Bibliography: leaves 112-140.xi, 141, [39] leaves, [8] leaves of plates : ill. ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
The aims of this thesis are to determine the initial cleavage sites of purified pepsin in long-R3-IGF-I and assess whether the resulting cleavages affect biological activity, to design and produce analogues of long-R3-IGF-I which contain amino acid substitutions, to characterise the resulting analogues for pepsin resistance and retention of biological activity and to assess the stability of the long-R3-IGF-I analogues under in vivo conditions using luminal stomach flushings.
Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1996
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Bryant, Katherine J. (Katherine Jane) 1962. "Design, production and characterisation of IGF-I analogues with increased gastric stability / by Katherine J. Bryant." Thesis, 1995. http://hdl.handle.net/2440/19074.
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Bibliography: leaves 112-140.xi, 141, [39] leaves, [8] leaves of plates : ill. ; 30 cm.
The aims of this thesis are to determine the initial cleavage sites of purified pepsin in long-R3-IGF-I and assess whether the resulting cleavages affect biological activity, to design and produce analogues of long-R3-IGF-I which contain amino acid substitutions, to characterise the resulting analogues for pepsin resistance and retention of biological activity and to assess the stability of the long-R3-IGF-I analogues under in vivo conditions using luminal stomach flushings.
Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1996
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Hančlová, Ivona. "Nové zkrácené a nezkrácené analogy insulinu s modifikacemi v poloze B26." Master's thesis, 2007. http://www.nusl.cz/ntk/nusl-370258.
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Marshall, Nicholas John. "The influence of insulin-like growth factor 1 and its analogues on fibroblasts and dermal wound healing." Thesis, 1998. http://hdl.handle.net/2440/38369.
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Includes bibliography (leaves 191-219).x, 219 leaves
Examines the levels of insulin-like growth factor and the presence of IGF binding proteins in human wound fluid. Tests the potency of IGF-1 and 2 analogues in in vitro models of fibroblast activity and their effect on healing in normal and diabetic rodent wounds. Shows that IGF-1, IGF-2 and their binding proteins are present in fluid from a partial thickness cutaneous wound; that the binding proteins negatively modulate the activity of insulin-like growth factors in vitro, but that the IGFs do not necessarily show enhanced activity in vivo at the wound site if binding protein affinity is decreased. Discusses possible roles of these binding proteins in wound repair.
Thesis (M.D.) -- University of Adelaide, Dept. of Surgery, 2001?
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Cottam, Jade Misty. "A study on the interactions of synthetic IGF-II analogues with the type 1 IGF and insulin receptors." Thesis, 2014. http://hdl.handle.net/2440/92810.
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Insulin-like growth factor II (IGF-II) is a unique regulatory peptide containing 67 residues and three disulfide bonds. It binds with high affinity to three receptors, the insulin receptor (IR), the type 1 insulin-like growth factor receptor (IGF-1R) and the We 2 insulin-like growth factor receptor (IGF-2R). Binding of IGF-II to these receptors signals mitogenic responses, such as cell proliferation, differentiation and migration. The interactions of IGF-II with the IR and IGF-1R have recently been identified as potential therapeutic targets for the treatment of cancer. Thus, an increased understanding of the interactions of IGF-II with the IGF-1R and the IR-A is required for the improved design and development of potential anticancer therapeutics. A crystal structure of IGF-II bound to either the IGF-1R or the IR-A has not been reported. Thus, the precise location of IGF-II within the receptor binding pocket remains undefined. A fluorescence resonance energy transfer (FRET) approach was proposed to investigate the binding location and orientation of IGF-II within the IGF-1R. Two fluorescent IGF-II analogues, the Fl9Cou IGF-II and F28Cou IGF-II proteins, were synthesised for use in the desired FRET studies. These FRET experiments first required the synthesis of an appropriate coumarin-based probe for incorporation into IGF-II. The synthesis of a range of fluorescent coumaryl amino acids is described in Chapter 2, and an analysis of the spectroscopic properties of these coumaryl amino acids is also detailed. Site-specific incorporation of the coumarin-based probe into IGF-II was then undertaken. Three complementary methods were used for the preparation of the desired fluorescent IGFII analogues. Chapter 3 describes the use of the nonsense suppression methodology for the expression of the novel Fl9Cou IGF-II protein. This was followed by an improved chemical synthesis of the Fl9Cou IGF-II protein using a linear solid phase peptide synthesis (SPPS) approach and is detailed in Chapter 4. A robust native chemical ligation approach was developed in Chapter 5, which allowed for the facile incorporation of the coumarin-based probe at various locations within the IGF-II protein. Chapter 5 also details the synthesis of the native IGF-II, Fl9Cou IGF-II and F28Cou IGF-II proteins. The biological activity of the resultant IGF-II analogues was evaluated by competition binding assays. The fluorescent IGFII analogues bind with low nanomolar affinity to the IR and IGF-1R, and as such were deemed suitable for use in the desired FRET-based experiments. The FRET-based investigation into the binding interactions of the native IGF-II, Fl9Cou IGFII and F28Cou IGF-II proteins to the IGF-1R is described in Chapter 6. FRET interactions were observed for both the Fl9Cou IGF-II and F28Cou IGF-II proteins. The results show the fluorophore binds in close proximity to Trp residues within the IGF-1R receptor and suggest the location of IGF-II binding within the IGF-1R is consistent with what is proposed in the literature. These experiments provide a basis for further investigations for determining the precise binding location and orientation of IGF-II within the IGF-1R.Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2014
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Macháčková, Kateřina. "Analogy IGF-1 pro studium interakce tohoto hormonu s receptory pro IGF-1 a insulin." Doctoral thesis, 2018. http://www.nusl.cz/ntk/nusl-389624.
Full textAbstract:
Insulin/IGF system is a complex network of three similar hormones (insulin, IGF-1 and IGF-2) and their three similar receptors (IR-A, IR-B and IGF-1R,), which play important roles in maintaining basal energy homeostasis of the organism, in growth, development, life-span but also in development of diseases such as diabetes mellitus, cancer, acromegaly or Laron dwarfism. Despite structural similarities between family members, each member have its unique role in the system. Identification of structural determinants in insulin and IGFs that trigger their specific signalling pathways is important for rational drug design for safer treatment of diabetes or for more efficient combating of cancer or growth-related disorders. In this thesis, we focused on identification of such structural determinants in IGF-1. Comparison of our data with parallel studies with IGF-2 and insulin could give a more complex picture of the problem. First of all, we developed necessary methodologies for the preparation of IGF-1 analogues. We developed a new methodology for the total chemical synthesis of IGF-1 analogues based on the solid-phase synthesis of fragments and their ligation by a CuI -catalyzed cycloaddition of azides and alkynes. In parallel, we developed a procedure for a recombinant production of IGF- 1 and its...
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DONG, SIYUAN. "A time dependent adaptive learning process for estimating drug exposure from register data - applied to insulin and its analogues." Thesis, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-124386.
Full text
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Gajanandana, Oraprapai. "Studies of complexes formed in blood in vivo between an insulin-like growth factor analog and binding proteins / by Oraprapai Gajanandana." Thesis, 1997. http://hdl.handle.net/2440/19153.
Full textAbstract:
Includes bibliographical references (43 leaves)xxiii, [216] leaves : ill. ; 30 cm.
This study shows that when LR3IGF-I is administered to animals in pharmacologically active doses, it may be present in either the free form or bound to IGF-binding protein(s) in the circulation. Age and nutrition which are factors that regulate synthesis of endogenous IGF-I and IGF-binding proteins, affect the in vivo formation of complexes between the analog and IGFBP(s). This study also suggests that IGFBP-1 inhibits the pharmacological activity of circulating LR3IGF-I on thymus whereas it appears to stimulate the pharmacological activity of LR3IGF-I in kidneys.
Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1998?
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Lord, Andrew P. D. (Andrew Peter Duncan). "IGF transfer from blood to tissue: comparison of IGF-I with analogs that bind poorly to binding proteins, using a vascular perfusion model / by Andrew Peter Duncan Lord." Thesis, 1993. http://hdl.handle.net/2440/21662.
Full textAbstract:
xxiii, 222 leaves : ill. ; 30 cm.Insulin-like growth factor-I circulates at high concentrations in blood, mainly complexed with IGF-binding proteins. The main objective of the thesis is to determine the general role played by plasma IGF-binding proteins in the regulation of IGF transfer from blood to tissues.
Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Science, 1994