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1
Wu, Di. "Discovery of glyco-biomarkers for diabetes and complications in diabetes." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/e2eee4c8-c74c-4fc6-8658-ab51ecd793de.
Full textAbstract:
Diabetes mellitus is a group of metabolic diseases characterized in disordered blood glucose levels with many altered genes, proteins and metabolites. The chronic hyperglycemia in diabetes damages organ systems and makes the diabetic patients vulnerable to one or more complications. The onset of diabetes and complications in diabetes are estimated to occur 5 to 10 years before the clinical diagnosis. The early diagnosis of diabetes prevents the damage and pathological progress of diabetes and complications in diabetes. The central hypothesis of this study was that the protein N-glycosylation pathway in diabetes might be influenced by elevated hexosamine flux in diabetes elevating sugar nucleotide levels. This, in turn, might affect the N-glycan branching pathway and result in detectable changes in plasma glycoprotein glycoforms. The aim of the study was to discover potential glyco-biomarkers for diabetes and complication in diabetes. Mass spectrometry based glycomic quantification was performed to look for alterations in N-glycan profiles between normal and diabetic plasma samples. Fucosylated N-glycans and intersected N-glycans were found to be up-regulated in diabetes with statistical significance. The elevated fucosylation in diabetes was verified at the glycosylation site level by quantitative Aleuria aurantia lectin (AAL) pull-down experiments. Fucosylated fetuin-A and α-1-acid glycoprotein were selected as candidate glyco-biomarkers. A lectin ELISA using F(abʹ)2 fragments as capture antibody was developed to validate the fucosylation changes by screening 20 normal and 20 diabetic patient plasma samples. We conclude that the fucosylation level of fetuin-A is a potential glyco-biomarker for diabetes. Additional work is necessary to see whether this glyco-biomarker correlates with any pathological complications of diabetes.
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Dias, Stephanie Charmaine. "Investigating Molecular Biomarkers During Gestational Diabetes Mellitus." Thesis, University of Pretoria, 2019. http://hdl.handle.net/2263/73566.
Full textAbstract:
Introduction:
Gestational diabetes mellitus (GDM) is a significant public health concern, due to its association with short- and long-term complications in both mothers and offspring. DNA methylation and single nucleotide polymorphisms (SNPs) offer potential to serve as molecular biomarkers, which may lead to improved detection of GDM with positive effects on health outcomes.
Aim:
The aim of this study was to investigate whether DNA methylation and SNPs are associated with GDM and may offer potential as molecular biomarkers for GDM in South Africa (SA).
Methods:
This study followed a two-pronged approach. Firstly, literature searches were conducted to collate and synthesise all published articles reporting on the prevalence of GDM in SA, the screening and diagnostic strategies used, and the current status of DNA methylation and SNPs as biomarkers for GDM. Secondly, we conducted experiments to investigate global (n=201), genome-wide (n=24) and gene-specific DNA methylation (n=286) of the adiponectin gene (ADIPOQ) in whole blood of women with and without GDM, using an Enzyme-Linked Immunosorbent Assay, a methylationEPIC BeadChip Array and pyrosequencing, respectively. In addition, genotype and allele frequencies of ADIPOQ rs266729 and rs17300539, and methylenetetrahydrofolate reductase (MTHFR) rs1801133 were determined, using quantitative real-time PCR (n=449) and DNA sequencing for validation.
Results:
The literature search showed that the prevalence of GDM in SA has increased over the years. Furthermore, it showed that the lack of uniformity in screening and diagnosis between and within countries hamper the accurate detection of GDM. Lastly, the literature search identified several studies that support the use of DNA methylation and SNPs as potential biomarkers for GDM. Experimentally, we showed no differences in global DNA methylation between GDM and non-GDM groups. Interestingly, global DNA methylation levels were 18% (p=0.012) higher in obese compared to non-obese pregnant women. Genome-wide methylation analysis identified 1046 differentially methylated CpG sites (associated with 939 genes) (Cut-off threshold: M>0.06 and p<0.01). Among the top five CpG sites identified, one CpG mapped to the calmodulin-binding transcription activator 1 (CAMTA1) gene, which has been shown to regulate insulin production and secretion. Two CpG sites (-3410: p=0.048 and -3400: p=0.004) in the ADIPOQ promoter were hypomethylated during GDM in HIV negative, but not in HIV positive women. Lastly, no association between the ADIPOQ and MTHFR polymorphisms and GDM was observed in our population.
Conclusion:
To our knowledge, this is the first study to investigate the association between DNA methylation or ADIPOQ (rs266729 and rs17300539) and MTHFR (rs1801133) polymorphisms and GDM in SA. Findings suggest that gene-specific, but not global methylation nor SNPs rs266729, rs17300539 and rs1801133, may offer potential as molecular biomarkers of GDM in this population. Future longitudinal studies in larger samples that include both HIV negative and positive pregnant women are warranted to explore the candidacy of DNA methylation as molecular biomarkers for GDM.Thesis (PhD)--University of Pretoria, 2019.
National Research Foundation (NRF) of South Africa, Thuthuka Grant (unique grant no. 99391).
South African Medical Research Council (SAMRC)
Obstetrics and Gynaecology
PhD
Unrestricted
3
Wang, Yudong, and 汪玉東. "Neutrophil serine proteases as novel biomarkers for autoimmune diabetes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208026.
Full textAbstract:
Background and Objectives:
Type 1 diabetes (T1D) is an autoimmune disease that results from the immune-mediated destruction of insulin-producing β cells in the islets of Langerhans within the pancreas. A combination of genetic and environmental triggers has been acknowledged to contribute to the development of T1D. However, the detailed mechanisms underlying the initiation and progression of autoimmune diabetes still remain poorly understood. Recent studies have found that the reduction of circulating neutrophils is accompanied by neutrophil infiltration in the pancreas at the onset of T1D, suggesting that neutrophils may be causally involved in the pathogenesis of this disorder. However, further investigations are needed to clarify the precise roles of neutrophils and their cellular components in autoimmune destruction of pancreatic β cells.
The objective of this study was to investigate whether neutrophil elastase (NE) and proteinase 3 (PR3), both neutrophil serine proteases stored in neutrophil primary granules, and NETosis, a unique form of cell death of neutrophils characterized by the release of decondensed chromatin and granular contents to the extracellular space, were involved in the pathogenesis of T1D.
Key findings:
1) We developed several in-house immunoassays for the measurement of circulating levels of NE, PR3 and their endogenous inhibitor alpha-1 antitrypsin (A1AT), and validated the specificity, precision and sensitivity of these assays in clinical samples;
2) We provided the first clinical evidence demonstrating that both circulating protein levels and enzymatic activities of NE and PR3 were dramatically increased in patients with T1D, especially in those with disease duration less than one year. On the contrary, circulating concentrations of A1AT were significantly decreased in these patients;
3) By measuring circulating levels of myeloperoxidase (MPO)-DNA complexes, we demonstrated that NETosis was evidently increased in T1D patients, and positively correlated with the circulating protein levels as well as enzymatic activities of NE and PR3, suggesting that increased circulating NE and PR3 at least in part attributed to augmented NETosis;
4) Circulating NE and PR3 levels increased progressively with the increase in the positive numbers and titers of autoantibodies against pancreatic β cell antigens, but no significant correlation of NE or PR3 with fasting blood glucose levels was observed, suggesting that elevated NE and PR3 might be causally associated with β-cell autoimmunity, but not glycaemic status, in T1D patients. Furthermore, an obvious elevation of NE and PR3 was detected even in those autoantibody-negative patients, suggesting that circulating NE and PR3 may serve as a novel class of biomarkers for the early diagnosis of T1D.
Conclusions:
Our present study demonstrated that the drastic elevation of NE and PR3, accompanied by a decrease in the endogenous inhibitor A1AT and the enhancement of NETosis, are closely associated with the β-cell autoimmunity in patients with T1D. Measurement of circulating protein levels of neutrophil serine proteases and/or their enzymatic activities can be used to assist the differential diagnosis of autoimmune diabetes.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
4
Azmi, Shazli. "Longitudinal studies in metabolic neuropathies : development of imaging biomarkers." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/longitudinal-studies-in-metabolic-neuropathies-development-of-imaging-biomarkers(6913e957-0e81-4af8-a544-f943f0105b8c).html.
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Corneal Confocal Microscopy (CCM) is a non-invasive imaging technique to quantify small nerve fibre structure in patients with diabetic somatic and autonomic neuropathy and increasingly other metabolic, hereditary, toxic and inflammatory peripheral neuropathies. This thesis establishes that CCM is indeed a powerful imaging technique which can identify early small fibre degeneration and regeneration in relation to the clinical phenotype of subjects with obesity, impaired glucose tolerance and Type1/2 diabetes. We demonstrate a precise relationship between small fibre neuropathy and erectile dysfunction in subjects with Type 1 diabetes. We also demonstrate the utility of CCM in demonstrating relative protection from small fibre damage in Type 1 patients with extreme duration diabetes (medallists) at baseline and over 3 years and repair in patients undergoing simultaneous pancreas and kidney transplantation. This thesis provides further evidence for the utility of CCM as a marker of early small fibre neuropathy by demonstrating nerve damage in subjects with morbid obesity with and without diabetes and explore the mechanisms underlying nerve damage at baseline and repair following bariatric surgery. We also show that CCM can track dynamic changes in small fibre degeneration and regeneration in subjects with impaired glucose tolerance in relation to change in glucose tolerance status and following continuous subcutaneous insulin infusion in subjects with Type 1 diabetes.
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Anthony, Yancke. "Identification and validation of micrornas for diagnosing type 2 diabetes : an in silico and molecular approach." University of the Western Cape, 2015. http://hdl.handle.net/11394/4713.
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>Magister Scientiae - MScType 2 diabetes mellitus (T2DM), a metabolic disease characterized by chronic hyperglycemia, is the most prevalent form of diabetes globally, affecting approximately 95 % of the total number of people with diabetes i.e. approximately 366 million. Furthermore, it is also the most prevalent form in South Africa (SA), affecting approximately 3.5 million individuals. This disease and its adverse complications can be delayed or prevented if detected early. Standardized diagnostic tests for T2DM have a few limitations which include the inability to predict the future risk of normal glucose tolerance individuals developing T2DM, they are dependent on blood glucose concentration, its invasiveness, and they cannot specify between T1DM and T2DM. Therefore, there is a need for biomarkers which could be used as a tool for the early and specific detection of T2DM. MicroRNAs are small non-coding RNA molecules which play a key role in controlling gene expression and certain biological processes. Studies show that dysregulation of microRNAs may lead to various diseases including T2DM, and thus, may be useful biomarkers for disease detection. Therefore, identifying biomarkers like microRNAs as a tool for the early and specific detection of T2DM, have great potential for diagnostic purposes. The main focus of this investigation, therefore, is the early detection of T2DM by the identification and validation of novel biomarkers. Furthermore, based on previous studies, the aim of the investigation was to identify differentially expressed miRNAs as well as identify their potential target genes associated with the onset and progression of T2DM. An in silico approach was used to identify miRNAs found to be differentially expressed in the serum/plasma of T2DM individuals. Three publically available target prediction software were used for target gene prediction of the identified miRNA. The target genes were subjected to functional analysis using a web-based software, namely DAVID. Functions which were clustered with an enrichment score > 1.3 were considered significant. The ranked target genes mostly had gene ontologies linked with “transcription regulation”, “neuron signalling, and “metal ion binding”. The ranked target genes were then split into two lists – an up-regulated (ur) miRNA targeted gene list and a down-regulated (dr) miRNA targeted gene list. The in silico method used in this investigation produced a final total of 4 miRNAs: miR-dr-1, miR-ur-1, miR-ur-2, and miR-ur-3. Based on the bioinformatics results, miR-dr-1 and its target genes LDLR, PPARA and CAMTA1, seemed the most promising miRNA for biomarker validation, due to the function of the target genes being associated with T2DM onset and progression. The expression levels of the miRNAs were then profiled in kidney tissue of male Wistar rats that were on a high fat diet (HFD), streptozotocin (STZ)-induced T1DM, and non-diabetic control rats via qRT-PCR analysis. The hypothesis was that similar miRNA expression would be found in the HFD kidney samples compared to serum expression levels of the miRNA obtained from the two databases, since kidneys are involved in cleansing the blood from impurities. This hypothesis proved to be true for all miRNAs except for miR-ur-2. Additionally, miR-ur-1 seemed the most significant miRNA due to it having different expression ratios for T1DM and T2DM (i.e. -7.65 and 4.2 fold, respectively). Future work, therefore, include validation of the predicted target genes to the miRNAs of interest i.e. miR-dr-1: PPARA and LDLR and miR-ur-1: CACNB2, using molecular approaches such as the luciferase assays and western blots.
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McDonald, Timothy James. "Identification of monogenic diabetes utilising biomarkers clinical criteria, and molecular genetics." Thesis, Exeter and Plymouth Peninsula Medical School, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553697.
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Maturity-onset diabetes of the young (MODY) is caused by highly penetrant, mutations in a single gene that result in non-insulin dependent diabetes typically presenting in lean young adults. MODY accounts for approximately 1 % of diabetes and is often misdiagnosed as Type 1 diabetes or Type 2 diabetes. Over 80% of MODY patients in the UK remain unidentified. The aim of this thesis was to develop, characterise and determine the diagnostic accuracy of existing and novel biomarkers that could be used to identify patients with a monogenic form of diabetes. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. In chapters 1 and 2 the measurement of C-peptide in urine is explored. We find Urinary C-peptide creatinine ratio is a stable and reproducible measure of endogenous insulin secretion, which correlates strongly with 24 hour urine C-peptide and, both fasting and stimulated, blood C-peptide in non- diabetic controls and patients with Type 2 diabetes. In chapter 3 we assess assay specific stability of C-peptide and insulin in blood on a number of analytical platforms and storage conditions. In contrast to many published reports we find C-peptide is stable in K +-EDTA whole blood for at least 24 hours at ambient room temperature. The aim of chapter 4 was to determine the prevalence of GADA and IA-2 autoantibodies in a large cohort (n=508) of patients with a confirmed genetic diagnosis of MODY. Less than 1 % of MODY patients had islet autoantibodies and a combination of GADA and IA-2A testing gave the best discrimination between Type 1 diabetes and MODY (sensitivity of 99% and specificity of 82%). A pilot study previously showed hsCRP is lower in HNF1A-MODY than in other forms of diabetes. In chapter 5 we confirm that plasma hsCRP levels are lower in HNF1A-MODY than Type 2 diabetes, Type 1 diabetes, GCK-, HNF4A- and HNF1 B-MODY. In addition, an hsCRP level of <0.75 mg/L discriminates HNF1A-MODY from Type 2 diabetes with a sensitivity of 79% and specificity of 70%. In chapter 6 we investigate the lipid profiles in HNF1A-MODY. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non- diabetic controls. HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY (sensitivity of 75% and specificity of 63%). In the final chapter we determine the diagnostic accuracy of the biomarkers studied in this thesis (C-peptide, islet antibodies, HDL-cholesterol and hsCRP) within a single test set of patients. We determine that all the biomarkers with the exception of hsCRP add discriminative value to a clinical prediction model for MODY compared to using clinical criteria alone. An overview of the major findings of each chapter, the clinical implications and areas of future research are discussed in chapter 8.
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Price, Anna Helen. "Biomarkers for cardiovascular risk prediction in people with type 2 diabetes." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28785.
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Introduction: Type 2 diabetes continues to be one of the most common non-communicable diseases worldwide and complications due to type 2 diabetes, such as cardiovascular disease (CVD) can cause severe disability and even death. Despite advances in the development and validation of cardiovascular risk scores, those used in clinical practice perform inadequately for people with type 2 diabetes. Research has suggested that particular non-traditional biomarkers and novel omics data may provide additional value to risk scores over-and-above traditional predictors. Aims: To determine whether a small panel of non-traditional biomarkers improve prediction models based on a current cardiovascular risk score (QRISK2), either individually or in combination, in people with type 2 diabetes. Furthermore, to investigate a set of 228 metabolites and their associations with CVD, independent of well-established cardiovascular risk factors, in order to identify potential new predictors of CVD for future research. Methods: Analyses used the Edinburgh Type 2 Diabetes Study (ET2DS), a prospective cohort of 1066 men and women with type 2 diabetes aged 60-75 years at baseline. Participants were followed for eight years, during which time 205 had a cardiovascular event. Additionally, for omics analyses, four cohorts from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium were combined with the ET2DS. Across all studies, 1005 (44.73%) participants had CVD at baseline or experienced a cardiovascular event during follow-up. Results: In the ET2DS, higher levels of high sensitivity cardiac troponin (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) and lower levels of ankle brachial pressure index (ABI) were associated with incident cardiovascular events, independent of QRISK2 and pre-existing cardiovascular disease (odds ratios per one SD increase in biomarker 1.35 (95% CI: 1.13, 1.61), 1.23 (1.02, 1.49) and 0.86 (0.73, 1.00) respectively). The addition of each biomarker to a model including just QRISK2 variables improved the c-statistic, with the biggest increase for hs-cTnT (from 0.722 (0.681, 0.763) to 0.732 (0.690, 0.774)). When multiple biomarkers were considered in combination, the greatest c-statistic was found for a model which included ABI, hs-cTnT and gamma-glutamyl transpeptidase (0.740 (0.699, 0.781)). In the combined cohorts from the UCLEB consortium, a small number of high-density lipoprotein (HDL) particles were found to be significantly associated with CVD: concentration of medium HDL particles, total lipids in medium HDL, phospholipids in medium HDL and phospholipids in small HDL. These associations persisted after adjustment for a range of traditional cardiovascular risk factors including age, sex, blood pressure, smoking and HDL to total cholesterol ratio. Conclusions: In older people with type 2 diabetes, a range of non-traditional biomarkers increased predictive ability for cardiovascular events over-and-above the commonly used QRISK2 score, and a combination of biomarkers may provide the best improvement. Furthermore, a small number of novel omics biomarkers were identified which may further improve risk scores or provide better prediction than traditional lipid measurements such as HDL cholesterol.
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Maneerattanasuporn, Tiwaporn. "Maternal Diabetes, Related Biomarkers and Genes, and Risk of Orofacial Clefts." DigitalCommons@USU, 2017. https://digitalcommons.usu.edu/etd/6215.
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Orofacial clefts (OFCs) are among the most common congenital birth defects and are characterized by incomplete development of the lip or the palate or both. The lip and palate develop separately at different times during the first trimester of pregnancy. The etiology of OFCs is multifactorial and includes a combination of genetic and environmental factors. This project aims to examine role of maternal diabetes mellitus in orofacial clefts through studies of medical histories, biomarkers, and genes.
In a study of Utah birth certificates, mothers with pre-existing diabetes and gestational diabetes mellitus (GDM) had an increased risk of OFCs, and obese mothers also had an increased risk. Mothers of children with OFCs were more likely than mothers of unaffected children to develop obesity, metabolic syndrome and gestational diabetes mellitus later in life. These result were more strongly related to cleft palate than cleft lip. Many genes related to GDM were associated with OFCs through genetic effects alone and gene-environment interaction effects with periconceptional maternal multivitamin use, maternal smoking, and environmental tobacco smoke. These results support the hypothesis that GDM may be causally related to OFCs via multiple GDM susceptibility genes and interactions with environmental factors.
Individuals with OFCs face both physical and mental health problem, which require multi-specialty team care. OFC prevention and prediction are important to public health. This dissertation reported that maternal diabetes mellitus, maternal pre-pregnancy weight and genes related to GDM had an association with the risk of OFCs. Mothers having an OFC child had an increased risk of developing metabolic abnormalities later in life. Potential risk factors were reported in this dissertation that may be useful for OFC prevention. This dissertation also reported potential biomarkers for predicting OFCs. Moreover, mothers having an OFC child may require regular monitoring of metabolic abnormalities later in life.
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Wotherspoon, Amy Christine. "Biomarkers and outcomes of the diabetes and pre-eclampsia intervention trial (DAPIT)." Thesis, Queen's University Belfast, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728831.
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Pre-eclampsia is a serious condition that occurs during pregnancy, which can lead to significant maternal and neonatal morbidity and mortality. Women with type 1 diabetes are at high risk of developing pre-eclampsia. The aim of this thesis was to explicate the acceptability of a screening test for pre-eclampsia and to identify potential biomarkers for predicting pre-eclampsia in women with type 1 diabetes. A number of approaches were used. Firstly, a qualitative study, consisting of interviews and questionnaires, was conducted to gain insight into women’s views on the potential introduction of a pre-eclampsia screening test. Secondly, statistical analysis was conducted on the Diabetes and Pre-eclampsia Intervention Trial (DAPIT) cohort to assess the impact that pregnancy intention has on a number of pregnancy outcomes, including pre-eclampsia. Thirdly, a systematic review was conducted to identify biomarkers that may be of benefit to measure in the DAPIT cohort to predict pre-eclampsia. Finally, two biomarkers were measured in the cohort to assess their potential. Qualitative findings indicated that women wanted to know their risk of developing pre-eclampsia and were generally accepting of the introduction of screening test for the disease. There was no significant association between pregnancy intention and risk of pre-eclampsia. However, women with unplanned pregnancies were more likely to have a baby who needed to be admitted to the neonatal intensive care unit, a baby with a birth weight <5th centile, and to have a longer stay in hospital. The systematic review identified no potentially useful biomarkers suitable for measurement in DAPIT. After consulting existing literature, Fatty Acid Binding Protein 4 (FABP4) and vitamin D (25OHD) were identified to be measured. FABP4 was significantly associated with the development of pre-eclampsia when measured in the first and second trimester. FABP4 also demonstrated some promise as a predictor of pre-eclampsia. Vitamin D was not associated with pre-eclampsia, but was associated with a number of other adverse pregnancy outcomes, including neonatal respiratory problems and small for gestational age (SGA). In conclusion, women should be encouraged to plan their pregnancies to minimise the risk of adverse outcomes. While a screening test for pre-eclampsia would be acceptable to women, further research is needed to identify the optimal screening tool for the prediction in women with type 1 diabetes.
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Norberg, Margareta. "Identifying risk of type 2 diabetes : epidemiologic perspectives from biomarkers to lifestyle." Doctoral thesis, Umeå : Umeå universitet, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-953.
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Sukumar, Nithya. "Novel biomarkers associated with gestational diabetes mellitus and metabolic outcomes of pregnancy." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/90895/.
Full textAbstract:
Gestational diabetes mellitus (GDM), defined as glucose intolerance first identified during pregnancy, is an escalating problem worldwide which affects 5-20% of all pregnant women. It is associated with long-term consequences such as obesity, metabolic syndrome and type 2 diabetes in both the mother and affected offspring, the latter mediated in part by birthweight (“diabetes begets diabetes”). However, selective screening strategies based on established risk factors for GDM, accurately identify only around 60% of cases suggesting that there are other mechanisms involved. The aim of my thesis was to investigate the role of 2 novel biomarkers, vitamin B12 (B12) and glucagon-like peptide (GLP-1) in the development of GDM and related metabolic outcomes. A systematic review and meta-analysis showed that B12 insufficiency in pregnancy was in the order of 20-30% across the world and was associated with marginally higher, but significant, odds of low birthweight babies but these findings may be isolated to high-risk countries. In a local UK population, B12 insufficiency was independently associated with obesity, 2.6-fold higher risk of GDM and fetal macrosomia. A nationwide survey of women of child-bearing age confirmed that 12% were B12 insufficient with associated hyperhomocysteinaemia, despite apparently adequate dietary intakes of B12. This warrants urgent review of the recommended nutrient intake guidelines to optimise B12 status prior to conception. In the second part of my thesis, it was shown that overall GLP-1 response during a diagnostic glucose tolerance test is reduced in GDM women compared to controls, with a decrease in the early phase particularly predictive of post-prandial glucose levels. This potentially provides a novel mechanism to explain the delayed first phase insulin response which has been noted in GDM and T2D. Finally, to better understand how GLP-1 may exert a protective effect on the vascular complications of hyperglycaemia, a basic science project was carried out which demonstrated that liraglutide, a GLP-1 receptor agonist, enhanced the AMPK and phospho-AKT signaling pathways thereby contributing to the reduction of oxidative cell damage. In summary, this thesis supports the hypothesis there are multiple mechanisms which give rise to GDM (e.g. predominant insulin resistance or insulin secretion or combination of factors) and biomarkers such as B12 and GLP-1 can be clinically useful in identification of high-risk women. If proven in larger prospective studies, with measurements of the biomarkers from early pregnancy, these markers may be used to risk-stratify these women with the ultimate goal of reducing the transgenerational perpetuation of diabetes.
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Nowak, Christoph. "Insulin Resistance : Causes, biomarkers and consequences." Doctoral thesis, Uppsala universitet, Molekylär epidemiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-316891.
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The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors. The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality. In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk. In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.
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Ge, Siqi. "Screening of multi-omics biomarkers for Type 2 Diabetes Mellitus among Chinese population." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2019. https://ro.ecu.edu.au/theses/2293.
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Type 2 diabetes mellitus (T2DM) is a major international health challenge which has a great worldwide impact on morbidity. Increased fasting plasma glucose (FPG) level is characterised as an independent risk factors for T2DM development and the development of predictive biomarkers for increased FPG level are crucial in Predictive, Preventive and Personalised medicine (PPPM) of T2DM. Established diagnostic tools for T2DM includes the oral glucose tolerance test (OGTT), fasting blood glucose (FBG) and glycated haemoglobin (HbA1c). These tests, however, provide “retrospective” markers for the diagnosis and prognosis of the disease, and therefore cannot be applied as predictive markers for from the perspectives of PPPM. A deeper understanding of the disease pathogenesis is urgently needed. Since blood is in direct contact with all tissues, pathological changes of T2DM are likely to be reflected in the genomic, proteomic and glycomic profiles of serum.
With a multi-omics design, Study I combined genomics and glycomics factors to investigate the candidate genes and the glycosylation patterns of IgG that lead to increased FPG level among Chinese populations. Study I identified 9 new SNPs located in 5 genetic loci (RPL7AP27, SNX30, SLC39A12, BACE2 and IGFL2), which considerably affect the increase of FPG level. Moreover, out of 24 glycan peaks (GPs), GPs 2, 8 and 11 were found present positive trends with increased FPG level, while GPs 4 and 14 presented negative trends. Study I implied the feasibility of our current multi-omics study design for T2DM and potential application of multi-omics approaches T2DM biomarkers screening at DNA and glycan levels, which led to Study II, the serumbased proteomic biomarkers research for T2DM at protein level.
In Study II, we analysed differences in serum peptide between T2DM patients and healthy controls, using magnetic bead-based fractionation, coupled with MALDI-TOF MS. Diagnostic models for T2DM based on a set of potential specific serum peptide biomarkers generated from a training cohort were further tested using an independent validation set of samples. Study II have found 6 peptides (peaks m/z 1452.9, 1692.8, 1946, 2115.1, 2211.0 and 4053.6) to be novel candidate biomarkers for T2DM diagnosis. The diagnostic performance of this peptide model indicated a high discriminatory power for T2DM, with an accuracy of 82.20%, sensitivity 82.50%, specificity 77.80% and an AUC value of 0.864. By combining Study I and Study II, we identified multiple biomarkers for T2DM across genomic, glycomic and proteomic level. Hence, it was necessary to complement it with robust subjective markers, and this led to Study III and Study IV.
Study III is a community-based, real-life environment, prospective study to investigate whether suboptimal health status (SHS), along with life-style and other socio-economic factors, contributes to the incidence of chronic disease in Chinese adults. Furthermore, Study III affords the opportunity to longitudinally analyse the genetic, lifestyle and environmental factors that may determine onset and etiology of targeted chronic disease.
Based on Study III, we further investigated the relationship between SHS and the onset of T2DM during the follow-up in Study IV. The main result of Study IV was that participants with higher levels of SHS had a considerably higher risk of T2DM. This finding in Study IV indicated that the risk will increase with the increasing SHS performance of an individual. These results provide the potential application of SHS as dynamic monitoring index for the development of T2DM.
In conclusion,
1) We found significant associations of 9 genetic loci located in 5 genes (RPL7AP27, SNX30, SLC39A12, BACE2 and IGFL2) with increased FPG level. We also found that IgG GPs 3, 8 and 11 presented positive trends with increased FPG level, whereas GPs 4 and 14 showed negative trends with increased FPG level.
2) We have characterised 6 peptides (peaks m/z 1452.9, 1692.8, 1946, 2115.1, 2211.0 and 4053.6) to be novel candidate biomarkers for T2DM diagnosis.
3) SHS is a novel predictive factor for T2DM onset, and a higher SHS score is associated with a higher incidence of T2DM. The evaluation of SHS combined with the analysis of modifiable risk factors for SHS allows the risk stratification of T2DM, which might consequently contribute to the prevention of T2DM.
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Sharma, Masti Venugopal Srihari. "Identification of diagnostic biomarkers to improve the management of diabetes-related foot ulcers." Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/116374/1/Masti%20Venugopal%20Srihari_Sharma_Thesis.pdf.
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The project aimed to investigate biomarkers of therapeutic importance in diabetic foot ulcer samples. The thesis hypothesised that proteins and peptides are altered as diabetic foot ulcers transition from a non-healing to a healing state. The project profiled these biomolecules from diabetic wound fluid samples using MS approaches and identified biomarkers whose appearance or levels would correlate to the healing status of the wound.
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Donovan, Brittney Marie. "Early risk prediction tools for gestational diabetes mellitus." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6408.
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Gestational diabetes mellitus (GDM) is the most common metabolic complication in pregnancy and is associated with substantial maternal and neonatal morbidity. The standard of care for GDM in most developed countries is universal mid- to late- pregnancy (24-28 weeks gestation) glucose testing. While earlier diagnosis and treatment could improve pregnancy outcomes, tools for early identification of risk for GDM are not commonly used in practice. Existing models for predicting GDM risk within the first trimester of pregnancy based on maternal risk factors perform only modestly in the clinical setting. Heavy reliance on history of GDM to predict GDM development in the current pregnancy prevents these tools from being applicable to nulliparous women (i.e., women who have never given birth). In order to offer timely preventive intervention and enhanced antenatal care to nulliparous women, we need to be able to accurately identify those at high risk for GDM early in pregnancy.
Data from the California Office of Statewide Health Planning and Development Linked Birth File was used to address three aims: 1) improve early pregnancy prediction of GDM risk in nulliparous women through development of a risk factor-based model, 2) conduct a systematic review and meta-analysis assessing the relationship between first trimester prenatal screening biomarker levels and development of GDM, and 3) determine if the addition of first and second trimester prenatal screening biomarkers to risk factor-based models will improve early prediction of GDM in nulliparous women.
We developed a clinical prediction model including five well-established risk factors for GDM (race/ethnicity, age at delivery, pre-pregnancy body mass index, family history of diabetes, and pre-existing hypertension). Our model had moderate predictive performance among all nulliparous women, and performed particularly well among Hispanic and Black women when assessed within specific racial/ethnic groups. Our risk prediction model also showed superior performance over the commonly used American College of Obstetricians and Gynecologists (ACOG) screening guidelines, encouraging the prompt incorporation of this tool into preconception and prenatal care.
Biomarkers commonly assessed in prenatal screening have been associated with a number of adverse perinatal and birth outcomes. However, reports on the relationship between first trimester measurements of prenatal screening biomarkers and GDM development are inconsistent. Our meta-analysis demonstrated that women who are diagnosed with GDM have lower first trimester multiple of the median (MoM) levels of both pregnancy associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (free β-hCG) than women who remain normoglycemic throughout pregnancy.
Findings from our meta-analysis suggested that incorporation of prenatal screening biomarkers in clinical risk prediction models could aid in earlier identification of women at risk of developing GDM. Upon linkage of California Office of Statewide Health Planning and Development Linked Birth File and California Prenatal Screening Program records, we found that decreased levels of first trimester PAPP-A, increased second trimester unconjugated estriol, and increased second trimester dimeric inhibin A were associated with GDM development in nulliparous women. However, the addition of these biomarkers in clinical models did not offer improvements to the clinical utility (i.e., risk stratification) of models including maternal risk factors alone.
Our findings demonstrate that incorporation of maternal risk factors in a clinical risk prediction model can more accurately identify nulliparous women at high risk for GDM early in pregnancy compared to current standard practice. The maternal characteristics model we developed is based on clinical history and demographic variables that are already routinely collected by clinicians in the United States so that it may be easily adapted into existing prenatal care practice and screening programs. Future work should focus on evaluating the clinical impact of model implementation on maternal and infant outcomes as well as financial costs to the health care system.
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Robertson, Christine Mary. "Cardiovascular disease, type 2 diabetes and carotid ultrasound." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/21087.
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Cardiovascular disease contributes significantly to global morbidity and mortality and is particularly prevalent among individuals with Type 2 diabetes, which is thought to in part be due to the association between diabetes and the metabolic syndrome. Traditional cardiovascular risk prediction scores perform well in the general population but their use in people with Type 2 diabetes is limited as they are thought to underperform in high risk groups. Indeed, the use of any risk prediction in people with Type 2 diabetes is a point of discussion among clinicians as people with diabetes are thought by some to be at immediate high risk of CVD, whereas others view them as having a degree of modifiable risk which can be addressed using risk prediction. In the general population, novel markers such as cIMT and carotid plaque, as well as other potential biomarkers of cardiovascular risk, have been explored as possible adjuncts to risk scores in the prediction of cardiovascular disease. The evidence for their use in general populations has been established, although there have been no firm conclusions with regard to recommendations for their use, which is partly due to the high degree of variability in cIMT measurement. However, the evidence for their use in people with Type 2 diabetes is sparse, despite the use of such markers as surrogate CV endpoints in clinical trials. This thesis aimed to describe the frequency, distribution and change of cIMT and carotid plaque, as well as to explore the relationship of cIMT and carotid plaque with cardiovascular risk factors, prevalent cardiovascular disease and future cardiovascular events in older people with Type 2 diabetes. The association between cIMT, carotid plaque and other novel risk markers was also explored. The analysis was performed using data from the Edinburgh Type 2 Diabetes Study (ET2DS). This study is a large, prospective cohort study of 1066 men and women with Type 2 diabetes, aged 60-75 years at recruitment, living in Edinburgh and the Lothians. cIMT and carotid plaque were measured at year 1 follow up of the study. Variables concerning cardiovascular risk factors used in this thesis were obtained from the data collection performed at baseline and year 1. A mean of 3.5 years of follow up was available for analysis and is complete for the baseline cohort as data linkage was performed. Mean values of cIMT in the ET2DS were comparable with other studies of cIMT in people with Type 2 diabetes and may indeed be higher than cIMT in the general population. Measurement of cIMT by the sonographer was comparable with computer aided measurements. Increasing cIMT was independently associated (although only modestly) with increasing age, male sex and raised systolic blood pressure. Mean cIMT was associated with prevalent vascular disease and was predictive of incident global cardiovascular events and coronary artery events (but not stroke) over and above UKPDS risk factors, although the clinical impact of this on the reclassification of vascular risk (as demonstrated by net reclassification index (NRI)) was limited. There was a high prevalence of carotid plaque, and in particular “high risk” plaque, in the ET2DS. Different measures of carotid plaque were independently associated with several cardiovascular risk factors. Carotid plaque thickness was independently associated, albeit modestly, with increasing age, male sex, duration of diabetes and hypertension, plaque score with increasing age, hypertension, smoking and low BMI, and high risk plaque with hypertension and low BMI. All measures of carotid plaque were associated with prevalent vascular disease. However, despite these associations, carotid plaque did not have any additional predictive value for incident cardiovascular events over and above UKPDS risk factors. Finally, measures of cIMT and carotid plaque in the ET2DS were associated with the biomarkers ankle brachial index (ABI) and NTproBNP. In addition these markers were significantly higher in those individuals with prevalent vascular disease, suggesting a more extensive exploration of the association of these markers in relation to cardiovascular disease in the ET2DS may be warranted. cIMT and carotid plaque are modestly associated with traditional cardiovascular risk factors and prevalent cardiovascular disease in older adults with Type 2 diabetes. cIMT has been shown to be predictive of incident events while carotid plaque was not, in people with Type 2 diabetes, over and above traditional cardiovascular risk factors, although its impact on risk reclassification may only be small. Further evidence is required from the longer follow up of the ET2DS before firm conclusions can be drawn on the usefulness of cIMT and carotid plaque as risk markers in people with Type 2 diabetes. In addition, large collaborative studies could be used to further explore the relationship of carotid plaque, and change in cIMT with incident cardiovascular events, as well as exploring the additive effect of cIMT and plaque on risk prediction.
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Costa, Priscila Paganini. "Biomarcadores salivares de pacientes periodontais com diabetes mellitus tipo 2." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/58/58132/tde-30062008-154755/.
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A associação entre o diabetes e a periodontite produz uma descarga de proteínas inflamatórias que pode ser refletida na saliva. Com base nisso, o objetivo desse estudo foi mensurar as concentrações salivares de interleucina-6 (IL-6), metaloproteinase da matriz-8 (MMP-8) e osteoprotegerina (OPG) em pacientes com periodontite crônica associada ou não ao diabetes mellitus tipo 2. Um total de 90 indivíduos foi dividido em quatro grupos: saudáveis (Controle, n=22), pacientes com doença periodontal (DP, n=24), apenas com diabetes mellitus (DM, n=20) e com doença periodontal e diabetes mellitus (DP+DM, n=24). Dados clínicos e metabólicos foram registrados. Amostras de saliva não-estimulada foram analisadas pelo ensaio imunoenzimático (ELISA). Diferenças estatisticamente significantes foram detectadas entre os grupos para todos marcadores (p<0,05). Em relação à IL-6, diferenças estatisticamente significantes foram encontradas comparando os grupos Controle com DP e com DP+DM, e entre os grupos DP+DM com DM (p<0,005). Para MMP-8, a média das concentrações do grupo Controle foi significativamente menor que em todos os grupos doentes (p<0,01) e nenhuma diferença entre os grupos doentes foi detectada. Para OPG, diferenças estatisticamente significantes foram encontradas entre os grupos Controle com DP e entre Controle com DM (p<0,05). Todos os parâmetros clínicos foram estatisticamente significantes entre os grupos (p<0,001), exceto supuração. No grupo DP, SS (sangramento à sondagem) mostrou uma correlação positiva com as concentrações de IL-6 (r=0,48; p<0,05), PS>=7 (profundidade de sondagem>=7mm) correlacionou-se positivamente com as concentrações de MMP-8 (r=0,46; p<0,05), e os níveis de HbA1c também correlacionaram-se positivamente com as concentrações de IL-6 (r=0,54; p<0,000). Concluindo, a saliva é um adequado substrato para identificação de biomarcadores inflamatórios em pacientes periodontais com ou sem diabetes. A IL-6 é um biomarcador candidato para periodontite e periodontite associada ao diabetes na saliva. Além disso, conclui-se que a super-expressão de MMP-8 e OPG pode acionar o aumento do colapso periodontal observado em indivíduos com diabetes tipo 2.Background: Association of diabetes and periodontitis produces an inflammatory proteins discharge that can be reflected in saliva. The aim of this study was to measure salivary concentrations of interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and osteoprotegerin (OPG) in patients with chronic periodontitis associated or not to type 2 diabetes mellitus. Methods: A total of 90 subjects was divided in four groups: healthy (Control, n=22), patients with Periodontal Disease (PD, n=24), Diabetes Mellitus only (DM, n=20), Periodontal Disease and Diabetes Mellitus (PD+DM, n=24). Clinical and metabolic data were recorded. Non-stimulated saliva samples were analyzed by enzyme-linked immunosorbent assay (ELISA). Results: Significant differences were detected between groups for the biomarkers (p<0.05). Regarding IL-6, significant differences were found comparing Control with PD and with PD+DM, and comparing PD+DM with DM groups (p<0.005). For MMP- 8, the concentrations mean of the Control group was significantly lower than all the diseased groups (p<0.01), and no differences between diseased groups were detected. For OPG, significant differences were found between Control and PD, and between Control and DM groups (p<0.05). All clinical parameters were significant between groups (p<0.001), except suppuration. In PD group, BOP (bleeding on probing) showed positive correlation with IL-6 concentrations (r=0.48; p<0.05), PPD>=7 (pocket depth>=7mm) correlated positively with MMP-8 concentrations (r=0.46; p<0.05), also HbA1c levels correlated positively with IL-6 concentrations (r=0.54; p<0.000). Conclusion: Saliva is an adequate substrate for inflammatory biomarkers identification in periodontal patients. IL-6 is a candidate biomarker for periodontitis and periodontitis associated to diabetes in the saliva.
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Costa, Priscila Paganini. "Biomarcadores diagnósticos relacionados à atividade da doença periodontal em diabéticos." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/58/58132/tde-23052012-161622/.
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O objetivo geral deste estudo foi monitorar a atividade da doença periodontal e sugerir potenciais biomarcadores salivares relacionados a esta atividade em pacientes com periodontite crônica associada ou não Diabetes mellitus tipo 2, a partir da avaliação do perfil da expressão gênica de sítios periodontais progressivos e de proteínas inflamatórias salivares. Foram incluídos 56 pacientes, sendo 21 com periodontite crônica (DP), 20 com periodontite crônica associada ao Diabetes mellitus tipo 2 (DP+DM) e 15 periodontal e sistemicamente saudáveis (controle). Foi realizado exame radiográfico antes e dois meses após a terapia periodontal básica, e posteriormente foi feita a subtração radiográfica a partir dos pares das radiografias. As medidas das áreas com perda de densidade foram registradas. Coleta de saliva não estimulada, verificação da hemoglobina glicada (HbA1c) e exame clínico periodontal profundidade de sondagem (PS), nível clínico de inserção relativo (NCIR), sangramento à sondagem (SS) e índice de placa (IP) também foram realizados antes e dois meses após a terapia periodontal básica. Os sítios periodontais com perda de inserção progressiva 1 mm na reavaliação foram considerados ativos de acordo com uma adaptação do método de tolerância. Biópsias de tecido gengival de sítios ativos e inativos com parâmetros clínicos semelhantes foram analisadas com real time PCR Array para análise do perfil de expressão gênica da resposta imune-inflamatória. As amostras de saliva foram submetidas ao imunoensaio Multiplex Cytokine Profiling para análise de expressão de proteínas. No grupo DP, 9% dos sítios foram classificados como ativos e no grupo DP+DM, 12% (p > 0,05). A média de perda de inserção clínica foi maior no grupo DP+DM (1,34 mm) em relação ao grupo DP (1,21 mm) (p < 0,05). Houve correlação entre a perda de inserção clínica e a área da perda de densidade radiográfica tanto nos sítios ativos do grupo DP (R = 0,79; p = 0,001), quanto do grupo DP+DM (R = 0,86; p < 0,001). Ambos os grupos DP e DP+DM apresentaram um perfil down-regulated em relação aos pacientes saudáveis (grupo controle). Quando comparado o grupo DP+DM ao grupo DP, pacientes diabéticos apresentaram um perfil up-regulated. Sítios ativos do grupo DP mostraram nove genes (ABCF1, CD40LG, IL10, IL5, CCR2, CCR4, CCR7, CCL18 e CXCL1) diferencialmente expressos (p < 0,05) com um perfil up-regulated. Sítios ativos do grupo DP+DM mostraram seis genes (LTA, CXCR1, CCL19, CCL8, CCL17 e CXCL12) diferencialmente expressos (p < 0,05) com um perfil up-regulated. Após a terapia periodontal básica, houve uma significante redução de algumas proteínas salivares (IL1b, IL1ra, IL10, IL17, TGFb, IL8, eotaxin e MCP-3) nos grupos DP e DP+DM, mas sem diferença estatisticamente significante (p > 0,05). Concluindo, este estudo foi capaz de monitorar a atividade da doença periodontal em pacientes com e sem diabetes após a terapia periodontal básica; foi possível identificar genes diferencialmente expressos em sítios ativos de ambos os grupos, que podem ser úteis na indicação de potenciais biomarcadores para diagnóstico da doença periodontal na fase ativa; as proteínas salivares analisadas mostram uma tendência em diferenciar o padrão de saúde e de doença, podendo ser futuramente utilizadas como potenciais biomarcadores de periodontite associada ou não ao diabetes.The overall aim of this study was to monitor the periodontal disease activity and suggest potential salivary biomarkers related to this activity in chronic periodontitis patients with or without type 2 Diabetes mellitus (DM), based on the evaluation of gene expression profile of progressive periodontal sites and salivary inflammatory proteins. Fifty-six patients were enrolled, 21 with chronic periodontitis (PD group), 20 with chronic periodontitis and DM (PD+DM group) and 15 periodontal- and systemically healthy (control). Radiographs were taken before and two months after non-surgical periodontal therapy, and radiographic subtraction was performed from pairs of these radiographs. Measurements of the areas with density loss were recorded. Unstimulated saliva collection, glycated hemoglobin (HbA1c) measurement and periodontal examination probing pocket depth (PPD), relative clinical attachment level (rCAL), bleeding on probing (BOP) and plaque index (PI) were also conducted before and two months after non-surgical periodontal therapy. The periodontal sites with progressive attachment loss 1 mm at the recall visit were considered active sites according to the adapted method of tolerance. Gingival biopsies of active and non-active sites with similar clinical parameters were harvested for gene expression analysis of the immune-inflammatory response with Real Time PCR Array. Saliva samples were analyzed by Multiplex Cytokine Profiling Immunoassay for analysis of protein expression profile. In PD group, 9% of the sites were classified as active and in PD+DM group, 12% (p > 0.05). The clinical attachment loss mean was higher in the PD+DM group (1.34±0.23 mm) compared to the PD group (1.21±0.16 mm) (p < 0.05). There was a correlation between clinical attachment loss and darkened radiographic areas in active sites of the PD group (R = 0.79, p = 0.001) and PD+DM group (R = 0.86, p < 0.001). Both PD and PD+DM groups showed a down-regulated profile compared to healthy subjects (control group). When compared PD group to PD+DM, patients with diabetes had an upregulated profile. Active sites of the PD group showed nine genes (ABCF1, CD40LG, IL10, IL5, CCR2, CCR4, CCR7, CCL18 and CXCL1) differentially expressed (p < 0.05) with an up-regulated profile. Active sites of the PD+DM group showed six genes (LTA, CXCR1, CCL19, CCL8, CCL17 and CXCL12) differentially expressed (p < 0.05) with an up-regulated profile. After non-surgical periodontal therapy, there was a significant reduction of clinical parameters and HbA1c levels (p < 0.05), accompanied by a reduction of some salivary proteins (IL1b, IL1ra, IL10, IL17, TGFb, IL8, eotaxin and MCP-3) in groups PD and PD+DM, but without statistically significant difference (p > 0.05). In conclusion, this study was able to monitor the periodontal disease activity in periodontal patients with or without diabetes after the non-surgical periodontal therapy; it was possible to identify genes differentially expressed in active sites from both groups, which may be considered useful in indicating potential biomarkers for the diagnosis of active periodontal disease; salivary proteins show a trend in distinguishing the standard of health and disease and may be used in the future as potential biomarkers of periodontitis with or without diabetes.
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Sharma, G. "Methods for the measurement of urinary biomarkers of oxidative stress application to type 1 diabetes mellitus." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1344091/.
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The principal aim of the study was to develop methods for the measurement of potential urinary biomarkers of oxidative stress using liquid chromatography/tandem mass spectrometry with minimum sample preparation to avoid artefact formation. Initially the development of an assay to measure the urinary concentrations of isoprostanes (8- isoPGF2α) was attempted but this did not prove to be sufficiently sensitive and gave nonreproducible results. An assay to measure the intact sulphate and glucuronide conjugates of urinary metabolites of vitamin E [α-tocopheronolactone (α-TLHQ) and α-carboxy-ethylhydroxychroman (α-CEHC)] was then developed, as it has been suggested that α-TLHQ with an oxidised chroman ring might be an indicator of oxidative stress. A novel method was also developed to quantitate urinary amino acids associated with NO• metabolism (Larginine - precursor, L-citrulline - product, L-ADMA –inhibitor of nitric oxide synthase and L-homocysteine – reduces bioavailability of nitric oxide). This method was extended to quantitate seven additional amino acids. The latter two methods were applied to 32 children with type 1 diabetes and compared with age and sex matched controls. The mean concentrations of all the α-THLQ conjugates were highly significantly increased in the diabetic subjects (p<0.002). The concentrations of the α-CEHC conjugates were also increased but not to the same degree of significance (p<0.05). When the diabetic children were divided into those who were poorly (n=24) and adequately (n=8) controlled, the α- THLQ conjugates remained highly significantly increased (p<0.002) in the poorly controlled group compared to controls. However, the concentrations of the α-CEHC conjugates were not significantly different. The diabetic subjects had a highly significantly increased concentration (p<0.0001) of all the urinary amino acids studied compared to controls. These results suggest that the measurement of urinary α-TLHQ conjugates may provide a useful biomarker of oxidative stress. The clinical relevance of the increased concentrations of urinary amino acids in children with type 1 diabetes requires further investigation.
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Barbosa, Sara Castanho. "Avaliação da função renal em cães diabéticos : análise de indicadores." Master's thesis, Universidade de Lisboa, Faculdade de Medicina Veterinárias, 2020. http://hdl.handle.net/10400.5/19846.
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Dissertação de Mestrado Integrado em Medicina VeterináriaA diabetes mellitus (DM) é a doença mais comum do pâncreas endócrino no cão. É uma síndrome caracterizada por hiperglicemia crónica, glicosúria, polifagia, poliúria/polidipsia e perda de peso. A nefropatia diabética (ND) corresponde a uma possível complicação da DM que, no caso dos humanos, corresponde à principal causa de doença renal crónica nos países ocidentais. A ND é caracterizada por microalbuminúria, proteinúria, hipertensão arterial sistémica e perda de função renal. Os estudos realizados no âmbito da ND canina são escassos e, apesar da sua existência estar documentada, a sua expressão na prática clínica é baixa, o que a torna um tópico pouco discutido. Este estudo teve como principal objetivo avaliar a função renal em cães com diagnóstico de DM, assim como a ocorrência de proteinúria, de modo a identificar a presença, ou não, de ND. Foi também avaliada a correlação entre estas variáveis e o tempo desde o diagnóstico de DM e a dose de insulina instituída. O estudo incluiu 18 cães diabéticos e 17 cães saudáveis de idades e pesos idênticos. Nos cães diabéticos, 38,9% apresentaram um RPCU superior a 0,5. Este grupo apresentou ainda uma razão de possibilidades (odds ratio) de 10,87 (95% IC, 1,71-127,08, p <0,05) de desenvolver proteinúria em relação aos saudáveis. Apesar de os níveis de ureia não diferirem significativamente entre os dois grupos, o grupo diabético apresentou concentrações de creatinina e DMAS inferiores às encontradas no grupo saudável (p<0,05). Não foi encontrada uma correlação significativa entre as concentrações de ureia, creatinina, DMAS ou o RPCU e a duração do diagnóstico de DM, ou com a dose de insulina em curso. Apesar de a ND clínica ser improvável em cães, os resultados obtidos evidenciam o possível efeito da DM a nível renal. Os níveis inferiores de creatinina e DMAS nos cães diabéticos sugerem a ocorrência de hiperfiltração glomerular, o que pode indicar a presença de alterações hemodinâmicas renais. Além disto, estes cães apresentam uma maior possibilidade de desenvolver proteinúria, o que reforça a importância da monitorização do RPCU nestes animais. Este é o primeiro estudo de que temos conhecimento que não só avalia os valores de DMAS em cães diabéticos, como também os compara com os encontrados em cães saudáveis. Dos resultados obtidos poderemos inferir que os animais do nosso estudo com DM se possam encontrar numa fase de pré-nefropatia diabética, numa fase silenciosa, ou numa fase de nefropatia diabética incipiente. Continuam a ser necessários mais estudos que elucidem o impacto da DM sobre os biomarcadores de função e lesão renal de modo a melhor esclarecer a sua relevância na prática clínica veterinária.
ABSTRACT - Diabetes mellitus (DM) is the most common disease of the endocrine pancreas in dogs. It’s a syndrome characterized by chronic hyperglycaemia, glycosuria, polyphagia, polyuria/polydipsia and weight loss. Diabetic nephropathy (DN) is a possible complication of DM that, in humans, is the main cause of chronic kidney disease in western countries. DN includes microalbuminuria, proteinuria, systemic hypertension and impaired kidney function. There are only a few studies regarding canine DN and, even though there are some reports of its occurrence in dogs, it isn’t a popular topic because of how rare it is in clinical practice. The aim of this study was to evaluate the renal function of dogs diagnosed with DM, as well as the occurrence of proteinuria, in order to identify the presence or absence of DN. We also tested if there was a correlation between these biomarkers and the time of diagnosis of DM and the insulin dosage they were being treated with. The study included 18 diabetic dogs and 17 healthy dogs with similar ages and weights. 38,9% of the diabetic dogs had an UPC ratio higher than 0,5. This group had an odds ratio of 10,87 (95% IC, 1,71-127,08, p<0,05) of developing proteinuria when compared to healthy ones. Even though the serum urea concentration didn’t differ between the two groups, diabetic dogs had significatively lower serum concentrations of creatinine and SDMA (p<0,05). There was no significant correlation between serum urea, creatinine or SDMA and UPC ratio and the time of diagnosis. We also didn’t find an association between any of these variables and insulin dosage. Even though the occurrence of clinical DN is unlikely in dogs, our results show the possible impact of DM on the kidney. The lower levels of serum creatinine and SDMA seen in diabetic dogs when compared to healthy ones suggest that glomerular hyperfiltration is present, which may be related with hemodynamic changes in the kidney. Besides, these dogs showed a higher chance of developing proteinuria, which reinforces the importance of UPC ratio assessment when monitoring these patients. To our knowledge, this is the first study that not only evaluates SDMA levels in diabetic dogs, but also compares them to those found in healthy ones. Our results suggest that the diabetic dogs in our study can be in a pre-diabetic nephropathy phase, in a silent phase or in an incipient diabetic nephropathy phase. More studies are needed in order to better understand how DM impacts kidney’s function and injury biomarkers and their relevance in veterinary practice.
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Walter, Debra L. "Renal Consequences of Coxsackievirus Infection and Type 1 Diabetes in Non-obese Diabetic Mice." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1526020616767063.
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Browning, Geoffrey Robinson. "Salivary Biomarkers of Acute Stress and Insulin Sensitivity in Nonhuman Primates." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1354912347.
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Gutta, Sridevi. "Increased Urinary Angiotensin Converting Enzyme 2 (ACE2) and Neprilysin (NEP) in Type 2 Diabetic Patients." Wright State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=wright1420732616.
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Franken, Holger [Verfasser]. "Machine Learning and Computational Mass Spectrometry for the Discovery of Metabolite Biomarkers Involved in Type 2 Diabetes / Holger Franken." München : Verlag Dr. Hut, 2013. http://d-nb.info/1033041831/34.
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Juszczak, Agata. "Assessment and translation of novel biomarkers for diagnosis of maturity onset diabetes of the young due to HNF1A variants." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:e5dcd952-f092-4269-bb9b-35bfd577a031.
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HNF1A-MODY is the most common form of monogenic diabetes, but due to low awareness among clinicians and limited availability of genetic testing in many countries, the majority of cases are misdiagnosed as type 1 or type 2 diabetes. In clinical practice, it is apparent that some young adults with non-autoimmune diabetes share several features of MODY and type 2 diabetes. Hence, I aimed to understand the range of genetic variation in HNF1A in this group and whether we could use biomarkers to help identify those with HNF1A alleles likely to be influencing their diabetes status. I performed HNF1A sequencing in 1058 subjects with non-autoimmune diabetes diagnosed below 45 years of age and identified 26 rare non-synonymous HNF1A alleles in 30 probands and 8 relatives. A systematic assessment assigned a likely damaging functional effect to 50% of these HNF1A alleles. The assessment of HNF1A alleles and their experimental characterisation unveiled the complexity of the genotype-phenotype relationship and continuity of the functional spectrum of HNF1A alleles from benign through likely benign, likely damaging to damaging effect. To clarify the performance of C-reactive protein (CRP) and N-glycan profile as biomarkers of HNF1A-MODY, I evaluated them in the above unselected sample of individuals who also underwent HNF1A sequencing. I have shown that 3-antennary fucosylated N-glycans and CRP were significantly lower in subjects with likely damaging HNF1A alleles in this group when compared to participants without HNF1A variants. Both biomarkers distinguished individuals with likely damaging HNF1A alleles from those without HNF1A variants with a C-statistic of 0.82-0.92. Plasma levels of these biomarkers negatively correlated with the predicted pathogenicity of HNF1A alleles. The expression of several steroidogenesis enzymes had been reported to be reduced in the liver cells of Hnf1a knock-out mice. Hence, I assessed the urinary steroid profile in individuals with HNF1A-MODY and age- and BMI-matched non-diabetic subjects and those with type 2 diabetes. The activity of 11β-hydroxysteroid dehydrogenase type 2 was reduced and the activity of 5β-steroid reductase increased in individuals with HNF1A-MODY. Their performance in selecting subjects with HNF1A-MODY was inferior to that of CRP and 3-antenary fucosylated glycans. In summary, my thesis has shown the complexity of the interpretation of genetic variation which is crucial for an accurate diagnosis and the assessment of potential biomarkers for genetic disease. Careful evaluation of the functional effect of HNF1A alleles identified on sequencing informs diagnosis in individuals with early-onset diabetes. Furthermore, the combination of functional assessment and clinical phenotype can guide management in those without canonical monogenic phenotypes found to have variant HNF1A alleles.
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Sharpe, Chantelle. "Sex after Gray Hair? Association between Sexual Activity, Hugging, and Health among older Adults?" Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6951.
Full textAbstract:
Research on sexual behavior in late life is limited but is growing. Despite ageist stereotypes associating old age with asexuality, older adults continue to desire and engage in sexual behavior. Previous studies have examined the relationship between health and the ability to engage in sexual behavior, sexual satisfaction, desire, or interest in sex. Research has yet to examine the potential reverse of this relationship, where sexual behavior may serve as a protective factor against health outcomes.
This dissertation examined three research questions to test the relationship between sexual activity or hugging and self-reported health outcomes (e.g., arthritis and diabetes) and biomarkers (e.g., C-reactive protein (CRP) and hemoglobin (HbA1c)). The first question explored whether sexual activity or hugging is associated health outcomes. The second question explored whether social support modifies the relationship between sexual activity or hugging and health outcomes. The final question explored whether sexual activity or hugging and demographic or health variables interact as moderators to health outcomes.
This study examined data of older adults between 57 and 85 years, from two waves of the National Social Life, Health, and Aging Project (NSHAP). The subjective health outcomes were self-reported arthritis and self-reported diabetes diagnoses. Objective health measures were analyzed using biomarkers. Both C-reactive protein and HbA1c were collected from dried blood spots. The main independent variables of interest were sexual activity and hugging. Sexual activity was assessed by combining participant responses to frequency of intercourse, foreplay and masturbation in the last 12 months. Hugging was assessed by participant responses to frequency of close physical contact over the last 12 months.
Results from question one indicated at wave 1, engaging in hugging was associated with higher likelihood of self-reported arthritis (OR = 1.23, p = 0.029), while sexual activity was associated with decreased likelihood of diabetes (OR = 0.61, p < 0.001). Examining objective markers of health, sexual activity was associated with 0.25 points lower HbA1c level (p < 0.001). Although some significant results were found at wave 1, none of the associations remained significant when examining change in health at wave 2.
The findings from question two examined the interaction of social support and sexual activity or hugging on health outcomes. The interactions between social support and sexual activity or social support and hugging did not significantly influence health at wave 1 or change in health at 2.
Question three examined potential moderators of the relationship between sexual activity or hugging and health, including age, race, education, income, gender, and hours of sleep. At wave 1, the findings showed a significant interaction between race and sexual activity associated with a decreased likelihood of reporting arthritis (OR = 0.79, p = 0.021). A significant interaction of age and sexual activity was associated with an increased likelihood of diabetes (OR = 1.04, p = 0.008). At wave 2, a significant interaction between age and hugging was associated with decreased likelihood of arthritis (OR = 0.97, p = 0.006), while the interaction term of sleep and hugging was associated with increased likelihood of diabetes (OR = 1.19, p = 0.015).
The results from this study show some support for the exploration of a potential bi-directional pathway between sexual activity or hugging and health. This study provides some evidence indicating the importance of understanding the role of sexual activity or hugging in the lives of older adults, and the possible influence on physical health. Future studies should continue exploring this pathway indicating possible benefits of engaging in sexual activity or hugging on health, and a larger impact on quality of life for older adults who desire to maintain intimate relationships in late life.
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Evans, Jonathan. "APOE, PCSK9, and CETP genetic variants as potential biomarkers of dyslipidaemia in black South Africans with Type 2 Diabetes Mellitus." Master's thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29630.
Full textAbstract:
Dyslipidaemia is a commonly encountered clinical condition and is a major risk factor for cardiovascular diseases. Although there are many factors associated with dyslipidaemia, a strong genetic component is evident. Apolipoprotein E (APOE), proprotein convertase subtilisin/kexin type 9 (PCSK9), and cholesteryl ester transfer protein (CETP) are key regulators of plasma cholesterol levels. Thus, genetic variation in the genes coding for these proteins contributes to dyslipidaemia. In this study, a cohort of black South African Type 2 Diabetes Mellitus (T2DM) patients was characterized for mutations in genes coding for APOE, PCSK9, and CETP, and the possible effects of these variants on their lipid profiles was evaluated. Participants (n=417) were recruited from the Chris Hani Baragwaneth Hospital Diabetes Clinic, Johannesburg from whom blood samples were obtained for DNA extraction. The cohort was further stratified into two groups; individuals on statin treatment (Sim+, n=291), and the second that was not on treatment (Sim-, n=87). Lipid profiles were determined by enzymatic methods. DNA was genotyped for APOE, PCSK9, and CETP variants using PCRRFLP and Sanger sequencing. Analysis of the effects of the genetic variants was carried out in two ways. Firstly, for all the participants combined, and then by separating those on statin treatment from those without (Sim+ vs. Sim-). Genotype and allele frequencies were calculated followed by genotype-phenotype correlations with lipid profiles. Univariate analysis showed a significant association between the APOE4 isoform and lower HDL-c levels in the combined cohort (p=0.034). The effects were more pronounced in the Sim- group (p=0.004) but were absent in the Sim+ group. Contrary to above, APOE2 was significantly associated with lower total cholesterol (TC) (p< 0.001) and lower LDL-c (p< 0.001) when compared to APOE3 in the combined cohort. Upon analysing treatment groups, the correlations were observed in the Sim+ group (p=0.027 and p=0.003, respectively), while there were no observed correlations in the Sim- group. The CETP rs34065661C/G and G/G genotypes were significantly associated with increased HDL-c levels (p=0.017; when applying a dominant genetic model) in the combined cohort, as well as in the Sim+ group (p=0.026). Multivariate analysis, using a generalized linear model, confirmed associations between APOE rs429358C and lower HDL-c (OR=0.881, p=1.64e04), and APOE rs7412T and decreased LDL-c (OR=0.759, p=0.012). No significant associations were observed for PCSK9 polymorphisms. We report significant associations between APOE and CETP genetic variations and altered lipid levels in this black South African T2DM population. These genetic variants could be biomarkers for dyslipidaemia among Africans. However, it is imperative that the APOE, PCSK9, and CETP genes are fully characterized for additional polymorphisms in order to come up with a better genetic profile that explains the variance in lipid levels observed in the black South African population. The impact of these genetic variants could be relevant to other black African populations as well.
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Jagannathan, Ram. "Identification of biomarkers for type 2 diabetes : analysis of a primary prevention study among Asian Indians with impaired glucose tolerance." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/32118.
Full textAbstract:
Primary prevention of type 2 diabetes (T2DM) is an important strategy for curbing its rising global burden. Though lifestyle modification has provided an effective method of preventing/delaying incidence of diabetes in high-risk individuals, it has not been widely implemented even in developed countries due to its high-cost, need for expertise and difficulties in translating the benefits of lifestyle intervention to the community at large. Hence, there is an urgent need to identify an alternate mode of delivery to transmit healthy lifestyle information to high-risk individuals. In this trial, we sought to determine whether lifestyle advice through mobile phone text messaging could reduce incident diabetes compared to standard lifestyle advice in Asian Indian men with prediabetes. The study showed for the first time that mobile phone messaging is an effective and acceptable method to deliver advice and support towards lifestyle modification to prevent T2DM in men at high risk. The identification of novel predictors for T2DM is an arduous task. The glycaemic markers of diabetes (fasting plasma glucose, 2hr post glucose load and HbA1c) are, in fact, risk factors for microvascular complications of diabetes and it was on this basis that diagnostic cut-offs for diabetes were arrived at. Nevertheless, elevated levels of glycaemic markers in the sub-clinical, or pre-diabetic, range are associated with increased risk of progression to diabetes. However, there is already considerable deterioration of beta cell function by the time diabetic dysglycaemia occurs. The way forward is clearly to identify biomarkers that serve as reliable predictors of progression to diabetes rather than simply reflecting accompanying levels of glycaemia. In this thesis using the database of the above mentioned trial it was aimed to identify the predictors of T2DM in Asian Indian cohort with prediabetes at baseline. The classical risk factors studied here are: 1) increased prevalence of the hypertriglyceridemic waist phenotype, 2) a combination of HbA1c and gamma glutamyl transferase and 3) a measure of beta cell compensation (disposition index) predicted incident diabetes. Among these, the disposition index was the most powerful predictor in the cohort. In addition to these classical risk factors mentioned above, in a small nested-case control, cross sectional study, the association of adipokines (adiponectin, leptin, interleukin-6 (IL-6), retinol-binding protein4 (RBP4)) and vitamin D3 were assessed to study the mechanistic link of novel biomarkers with diabetes. In this cohort, lower levels of baseline adiponectin, and higher IL-6 and RBP4 were associated with diabetes. Though, many of these provided a novel mechanistic pathogenic link with diabetes they did not improve prediction over and above that of glycaemic measures in identifying individuals with diabetes. However, the non-glycaemic biomarkers appear to have a role in the underlying pathogenesis of diabetes.
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Ajabshir, Sahar. "The Effect of Vitamin D3 Supplementation of Biomarkers of Oxidative Stress and Glycemic Status in Adults with Type 2 Diabetes." FIU Digital Commons, 2018. https://digitalcommons.fiu.edu/etd/3649.
Full textAbstract:
The aim of the present study was to assess the effect of 4000 IU and 6000 IU of daily vitamin D3 supplementation for 3 months and 6 months on 8-hydroxy-2`-deoxyguanosine (8-OHdG) and glycated albumin (GA%) among a group of individuals with T2D and hypovitaminosis D. Furthermore, this study investigated the association between dietary inflammatory index (DII), C-reactive protein (CRP), 8-OHdG, hemoglobin A1C (HbA1c), GA% and insulin. Ninety participants were recruited by community outreach and were screened. Sixty-eight participants met the inclusion criteria were enrolled and completed the study. DII for each individuals was calculated based on the values obtained from a validated food frequency questionnaire. Measurements of variables were conducted at baseline, after 3 months and after 6 months of supplementation. Serum CRP, 8-OHdg, GA%, HbA1c and insulin were measured by enzymatic immunoassay methods. Mixed model was used to compare treatment groups. Covariates in the adjusted model included age, gender, body mass index (BMI), insulin, HbA1c, years with type 2 diabetes, perceived stress, physical activity, and sun exposure. Mean age was 54.94± 7.93 years.A multivariable linear regression model adjusted for age, gender, waist circumference, and fasting plasma glucose was used to test for the linear trend between DII and CRP, 8-OHdG, GA% and insulin.The unadjusted model showed no significant associations between quartiles of DII, CRP, HbA1c and GA%. A significant inverse association was observed between the fourth DII quartile and insulin level (p=0.030). There was a significant association between SBP and DII in Q4 (p=0.029).The unadjusted mean ± SD for 8-OHdG levels at baseline, after 3 and 6 months were 8068.94 ± 2158.13 pg/mL, 9462.22 ± 2403.89 pg/mL, and 7412.69 ± 2031.68 pg/mL, respectively. The unadjusted mixed model showed no difference between the 4000 and 6000 IU groups regarding the oxidative stress and GA%. Interactions between time and treatment were not significant. The model showed a statistically significant difference in 8-OHdG level between baseline and 3 months (PP=0.015), and from 3 months to 6 months (P=0.039), but not from baseline to 6 months (P= 0.488). The results of the present study showed daily oral supplementation with higher doses of vitamin D for 6 months may have beneficial effects on oxidative stress and glycemic status among a group of individuals with type 2 diabetes and vitamin D deficiency/insufficiency. Furthermore, pro-inflammatory dietary patterns may be associated with increased risk of hyperinsulinemia and hypertension among individuals with T2D and hypovitaminosis D.
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Santos, Aritania Sousa. "Expressão de microRNAs circulantes relacionados ao diabetes tipo 1 autoimune." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-14082018-124100/.
Full textAbstract:
INTRODUÇÃO: O diabetes tipo 1 autoimune (DM1A) está associado a alterações na imunidade inata e adaptativa. A agressão autoimune, órgão específica, determina a destruição das células beta do pâncreas e a deficiência da produção de insulina. O infiltrado inflamatório do tipo linfomononuclear, configurando a insulite, e a escassez ou a ausência das células ?, definem o quadro histológico do DM1A. Os autoanticorpos contra antígenos das células beta, que geralmente se desenvolvem na fase pré-clínica, conferem predisposição para DM1A. No entanto, é difícil definir quando e quais indivíduos progredirão para o diabetes manifesto, justificando a busca de outros biomarcadores que auxiliem nas indicações de tratamentos preventivos. Nesse contexto, sabe-se que os microRNAs (miRNAs), pequenos RNAs que atuam pós transcrição, desempenham papel crucial na regulação de genes, integrando fatores genéticos e ambientais e influenciando o funcionamento de órgãos e tecidos de maneira pontual ou sistêmica. OBJETIVOS: avaliar o envolvimento biológico e a relevância da expressão de miRNAs na resposta imunológica e na função das células ? na patogênese do DM1A. MÉTODOS: analisamos o perfil dos miRNAs séricos em 4 grupos, a saber: pacientes portadores de DM1A, até 6 meses do diagnóstico (DM1A recente), (n=30); pacientes portadores de DM1A com duração de 2-5 anos (DM1A 2-5)(n=26) e indivíduos com autoanticorpos pancreáticos positivos sem diabetes (AcP) (n=25), os quais foram comparados aos indivíduos controles saudáveis(n= 29). A expressão dos microRNAs foi obtida com ensaios individuais TaqMan® MicroRNA Assays 5x primers e TaqMan MicroRNA Human Array Card A, (Applied Biosystems- Forster City CA, USA) constituído por 377 alvos e 4 endógenos. Os dados de expressão foram analisados no Software Cloud, (Thermo Fisher Scientific) e no programa Limma (Linear Models for Microarray and RNA-Seq Data). RESULTADOS: Não houve diferença nas características demográficas, como idade, cor auto referida e sexo entre os grupos (p > 0,05). Pacientes portadores de DM1A (recente e com duração de 2-5 anos), diferiram do grupo controle pelos valores elevados de glicose, hemoglobina glicada, títulos de autoanticorpos pancreáticos, e menores de peptídeo C (p < 0,05) e foram semelhantes entre si. Os portadores de autoanticorpos (AcP) tinham características intermediárias entre os grupos: menores valores de HbA1c e de anticorpo anti-tirosina-fosfatase (anti-IA2) e maiores de peptídeo C em relação aos dois grupos com diabetes. Diferiram dos controles apenas pelos maiores títulos de anticorpo anti-insulina (IAA) e anti-descarboxilase do ácido glutâmico 65 (anti-GAD65). A frequência dos alelos HLA de risco para diabetes (-DR3 ou -DR4 e -DQ2 ou DQ-8) decresceu dos grupos DM1A recente e DM 2-5 para AcP e controles. Foram avaliados 135 miRNAs que estavam expressos em 20% ou mais das amostras dos quatro grupos analisados. Maior expressão foi observada em 13, 4 e 33 miRNAs dos grupos AcP, DM1A recente e DM1A 2-5 respectivamente e menor em 11, 7 e 31 miRNAs destes grupos. Destes, 4 miRNAs foram diferencialmente expressos nos grupos AcP, DM1A recente e DM1A 2-5 em relação ao grupo controle. Os miRNAs: miR -16, miR-195 e miR-454, relacionados com regeneração endócrina do pâncreas, efeito anti-inflamatório e resposta à injúria da célula ? estavam diminuídos nestes 3 grupos. O miR-200a, implicado em apoptose das células beta, estava aumentado nos grupos AcP e DM1A recente e diminuído nos pacientes com maior duração do diabetes (DM1A 2-5), possivelmente devido à escassez destas células. Outros 8 miRNAs apresentaram expressão diferente da do grupo controle em dois dos grupos avaliados, e tendência semelhante no terceiro grupo, sendo 4 deles elevados (miR-193a-5p, miR- 323-3p, miR-423-5p, e miR-92a) e 4, diminuídos (miR-191, miR-19a, miR- 376a, miR-590-5p) ou neutralidade no 3º grupo (miR-15b, miR-100, miR-181a e miR-483-5p) Resposta antagônica foi observada para o miR-25 e miR-485- 3p, diminuídos no grupo AcP e aumentados no DM1A 2- 5. Tais miRNAs estão relacionados com resposta imunológica, secreção de insulina, lesão de células ? e glicotoxicidade, à semelhança do observado para o miR-101-3p, validado por ensaios individuais numa casuística maior. CONCLUSÃO: nossos dados sugerem que miRNAs circulantes podem estar envolvidos na patogênese do DM1AINTRODUCTION: Autoimmune type 1 diabetes (T1D) is associated with changes in innate and adaptive immunity. The organ-specific autoimmune aggression determines the destruction of beta-cells in the pancreas and the deficient insulin production. The inflammatory infiltration of the lymphomononuclear type, configuring the insulite, and the scarcity or the absence of the beta cells, define the histological picture of T1D. Autoantibodies against beta-cell antigens, which usually develop in the preclinical phase, confer predisposition to T1D. However, it is difficult to define when and which individuals will progress to overt diabetes, justifying the search for other biomarkers that could be indicative of preventive treatments. In this context, it is known that the microRNAs (miRNAs) - small RNAs that act post transcription - play a crucial role in regulating genes and in integrating genetic and environmental factors, influencing the function of organs and tissues in a punctual or systemic way. OBJECTIVES: to evaluate the biological involvement and relevance of miRNA expression in the immune response and ?-cell function in the pathogenesis of T1D. METHODS: we analyzed the profile of serum miRNAs of 4 groups, namely: patients with T1D up to 6 months after diagnosis (recent T1D), (n = 30); patients with T1D lasting 2-5 years (T1D 2- 5) (n = 26) and individuals expressing pancreatic autoantibodies without diabetes (AbP) (n = 25), which were compared to healthy controls (n = 29). Expression of the microRNAs was obtained with individual assays TaqMan® MicroRNA Assays 5x primers and TaqMan MicroRNA Human Array Card A (Applied Biosystems-Forster City CA, USA), consisting of 377 targets and 4 endogenous. The expression data was analyzed in the Cloud Software (Thermo Fisher Scientific) and Limma (Linear Models for Microarray and RNASeq Data) program. RESULTS: There was no difference in demographic characteristics, such as age, self-reported color, and sex among groups (p > 0.05). Patients with T1D (both recent and 2-5 years), similar to each other, differed from the control group by high glucose, glycated hemoglobin levels, pancreatic autoantibody titers, and lower C peptide values (p < 0.05) . Pancreatic autoantibodies (AbP) carriers had intermediate characteristics among the groups: lower HbA1c and anti-tyrosine phosphatase antibody (anti- IA2) values and higher C-peptide levels than the two groups with diabetes. They differed from controls only by the higher titers of anti-insulin (IAA) and anti-decarboxylase of glutamic acid 65 (anti-GAD65) autoantibodies. The frequency of high risk HLA alleles for diabetes (-DR3 or -DR4 and -DQ2 or DQ- 8) decreased from the recent T1D and T1D 2-5 groups to the AbP and controls. We evaluated 135 miRNAs that were expressed in 20% or more of the samples from the four groups analyzed. Higher expression was observed in 13, 4 and 33 miRNAs of the Abp, recent T1D and T1D 2-5 groups respectively and lower in 11, 7 and 31 miRNAs of these groups. Of these, 4 miRNAs were differentially expressed in the AbP, recent T1D and T1D 2-5 groups in relation to the control group.The miRNAs: miR -16, miR-195 and miR-454, related to endocrine regeneration of the pancreas, anti-inflammatory effect and response to beta-cell injury were decreased in these 3 groups. miR-200a, implicated in beta-cell apoptosis, was increased in the recent and decreased AbP and T1D groups in patients with longer duration of diabetes (T1D 2-5y), possibly due to the shortage of these cells. Another eight miRNAs showed different expression of the control group in two of the evaluated groups, and a similar trend in the third group, four of them high (miR-193a-5p, miR-323-3p, miR-423-5p, and miR- 92a ) and four, decreased (miR-191, miR-19a, miR-376a, miR-590-5p) or neutrality in the 3rd group (miR-15b, miR-100, miR-181a and miR-483-5p) was observed for miR-25 and miR-485-3p, decreased in the AbP group and increased in T1D 2-5y. Such miRNAs are related to immune response, insulin secretion, ?-cell damage and glycotoxicity, similar to that observed for the miR- 101-3p, validated by individual trials in a larger cohort. CONCLUSION Our data suggests that circulating miRNAs may be involved in the pathogenesis of T1D
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Ribeiro, Gianine Lima. "EFEITOS DA N-ACETILCISTEÍNA SOBRE O DANO OXIDATIVO RENAL E HEPÁTICO DE RATOS DIABÉTICOS." Universidade Federal de Santa Maria, 2010. http://repositorio.ufsm.br/handle/1/8977.
Full textAbstract:
Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia, which is related to oxidative stress and plays an important role in the development of other diseases and tissue damage, such as liver and kidney damage. Thus, it is important for studies with potential antioxidant that may reduce the deleterious effects of oxidative stress due to diabetes. In this sense, N-acetylcysteine (NAC) is used as a hepatoprotective drug in the treatment of acute poisoning by paracetamol to reduce oxidative damage. Along these lines, the aims of this study were to evaluate biomarkers of oxidative stress such as reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), malondialdehyde (MDA) and delta aminolevulinate acid dehydratase (ALA-D) in liver and kidneys of controls and animals with diabetes induced after treatment with NAC. Treatments consisted of intraperitoneal administration of 25 mg / kg and 75 mg / kg N-acetylcysteine. In the liver, MDA levels were significantly increased in the diabetic group compared to controls, treatment with 75 mg / kg reduced the levels of MDA, being similar to the control group. GSH levels of the enzyme was found to be highest in kidney and liver of diabetic animals than controls, and treatment with NAC led to these reduced levels in the liver of diabetic animals, but in the kidney, no changes. The levels of SOD and GPx decreased in the liver of diabetic animals compared to control, and administration of NAC did not alter these indices. Diabetes also reduced the activity of ALA-D in the liver, and treatment with 25 mg/ kg NAC did with this activity increased significantly. In the kidney, both doses of NAC increased the levels of ALA-D in diabetic animals. The results suggest that NAC may be more effective in the liver, the organ that suffers most oxidative changes, and especially in groups of diabetic animals.O diabetes mellitus (DM) é uma doença crônica caracterizada pela hiperglicemia, que está relacionada Com o estresse oxidativo, o qual possui papel importante no desenvolvimento de outras patologias e danos teciduais, tais como dano hepático e renal. Dessa forma, faz-se importante à realização de estudos com possíveis antioxidantes, que possam diminuir os efeitos deletérios do estresse oxidativo decorrentes do diabetes. Neste sentido, a N-acetilcisteína (NAC) é um medicamento utilizado como hepatoprotetor por estimular a síntese de Glutationa Reduzida, diminuindo o dano oxidativo. Nesta linha, o objetivo deste trabalho foi avaliar o efeito antioxidante da NAC nos tecidos renal e hepático de ratos diabéticos através dos biomarcadores do estresse oxidativo como: glutationa reduzida (GSH), glutationa peroxidase (GPx), superóxido dismutase (SOD), malondialdeído (MDA) e ácido delta aminolevulinato desidratase (ALA-D) no fígado e rins de animais controles e com diabetes induzida, tratados e não tratados com NAC. Os tratamentos consistiram em administrações intraperitoneais de 25 mg/Kg e 75 mg/Kg de N-acetilcisteína. No fígado, os níveis de MDA foram significativamente aumentados no grupo diabético comparados ao grupo controle. O tratamento com 75 mg/Kg foi capaz de reduzir os níveis de MDA, ficando semelhantes ao grupo controle. Os níveis da GSH mostrou-se mais elevada no rim e no fígado dos animais diabéticos do que dos controles, e o tratamento com a NAC fez com que esses níveis fossem reduzidos no fígado dos animais diabéticos, entretanto no rim, não houve alterações. Os níveis de SOD e GPx diminuíram no fígado dos animais diabéticos quando comparados ao controle, e a administração de NAC não alterou esses índices. O diabetes também diminuiu a atividade da ALA-D no fígado, e o tratamento com a 25 mg/Kg NAC fez com essa atividade aumentasse significativamente. No tecido renal, ambas as doses de NAC elevaram os níveis de ALA-D nos animais diabéticos. Diante dos resultados encontrados, comparando-se os tecidos renal e hepático dos ratos controles com os diabéticos tratados com NAC, sugere-se que a NAC demonstrou diminuir o dano oxidativo mais no fígado do que no rim.
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Čukić, Iva. "Personality traits and health outcomes : an exploration into associations and potential mechanisms." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/16170.
Full textAbstract:
There were two main objectives of this thesis. First, given that personality traits have been linked to a number of diabetes risk factors and precursors such as lifestyle and the metabolic syndrome, our aim is to explore whether personality traits are associated with type 1 and type 2 diabetes mellitus. Second, we aim to investigate several potential mechanisms by which personality could influence diabetes, and other health outcomes such as cardiovascular disease and mortality. Chapter 1 provides an introductory overview of the history of personality-health research, and discusses strengths and limitations of different methodological frameworks. Chapters 2-4 focus on the associations between personality and diabetes. Two studies described in Chapter 2 examine cross-sectional and longitudinal associations between personality and type 1 and type 2 diabetes. We used a large national sample with ten years of follow-up. We detected positive associations between openness and neuroticism and type 1 diabetes prevalence, and negative associations between neuroticism and type 2 diabetes incidence. In Chapter 3, we examine relationships between personality and type 2 diabetes incidence using aggregated personality and diabetes data on a level of the U.S. counties and states. In a six-years follow-up study, we found no evidence that mean levels of personality traits were associated with diabetes incidence in the U.S. states. In the following chapter we explore whether a possible mechanism by which personality may influence diabetes is by moderating the expression of its genetic risk. The study described in Chapter 4 looks at interactions between personality domains and facets with polygenic risk score for type 2 diabetes in predicting glycated haemoglobin levels using a large community-dwelling sample. This study found a negative phenotypic correlation between openness and glycated haemoglobin levels, though this association was confounded by cognitive ability. Moreover, genetic risk for diabetes was more strongly associated with glycated haemoglobin levels in people with lower levels of either agreeableness or conscientiousness. In Chapter 5 we move away from diabetes to discuss previously reported contradictory results regarding the effects neuroticism has on mortality. Some of the previous studies reported higher neuroticism being associated with higher risk of mortality, whereas some reported that higher neuroticism was associated with lower risk of death. We tested whether the sign of the neuroticism effect was a function of the covariates included in the models. In a national sample with ten years of follow-up we found that neuroticism was a risk factor for death in the models that did not include objective and self-rated health variables. However, when these variables were included, neuroticism was related to lower risk of death. In the last empirical chapter, Chapter 6, we explore whether autonomic nervous system activity is a biomarker for personality traits. The first study tests whether openness is associated with measures of sympathetic and parasympathetic nervous system activation. We find that openness was associated with sympathetic nervous system activity under baseline but not in the stress conditions, and that it was not associated with measures of parasympathetic activation. The second study describes a model of associations between neuroticism and autonomic nervous system activation, while controlling for cardiovascular disease and depression and their mutual associations. We found that neuroticism has independent contributions to all measures of autonomic nervous system activity, and to heart disease, even when controlling for relevant clinical variables. Thus, autonomic nervous system activity may explain in part observed links between personality, and heart disease and mortality. Finally, in Chapter 7 we summarize the findings presented in the five empirical chapters, discuss the limitations of the current method, and offer suggestions for future research in the field.
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Schamarek, Imke [Verfasser]. "Association between biomarkers of subclinical inflammation and nerve conduction in individuals with recently diagnosed type 1 and type 2 diabetes / Imke Schamarek." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/117038899X/34.
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Pedersen, Henrik Bo. "The effect of time-restricted feeding on glycemic biomarkers : A literature study." Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-97732.
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Background: The prevalence of diabetes and obesity has been on the rise for many years and the search for new and effective dietetic solutions aiming at reducing calories, reducing body mass and improving diabetes has been ongoing. Currently, the intermittent fasting diet - the practice of alternating periods of eating and fasting - is gaining popularity. One of them is Time-restricted feeding (TRF), which time-limits energy intake within a defined window of time up to 10 hours per day without necessarily altering diet quality or quantity. A reduction in calorie intake, bodyweight, blood pressure, oxidative stress, inflammation biomarkers and triglycerides are evident with TRF studies conducted so far. Aim: The aim of the thesis is to investigate the effects of time-restricted feeding on glycemic biomarkers in human studies. Methods: A literature study is conducted with six chosen experimental studies which are primarily randomized controlled trials or randomized crossover trials with a TRF window of maximum 10 hours per day and predominantly with participants with overweight/obesity, prediabetes, type 2 diabetes and metabolic syndrome. Results: Compared to either baseline and/or control group, fasting glucose was reduced in 3 out of 6 TRF studies, while fasting insulin was reduced in 3 out of 5 TRF studies and HbA1C was decreased in 1 out of 2 TRF studies. For postprandial response, 1 out of 2 TRF studies found a reduction in glucose and likewise for insulin. Mean glucose levels were reduced in 1 out of 3 TRF studies. Insulin resistance was reduced in 3 out of 4 TRF studies while insulin sensitivity was reduced in the one study measuring this. Beta cell function improved in 2 out of 2 TRF studies compared to the control group or baseline. Conclusion: There are indications that TRF has an effect on glycemic biomarkers and thus potentially being able to reduce the risk and/or improve the treatment of type 2 diabetes. But in order to give a more definite answer more studies need to be conducted. In general, these studies should preferably have more participants and be methodologically stronger when it e.g. comes to the control of the dietary regimen.
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Martins, Emerson Renato. "Analise de componentes do metabolismo lipídico na resposta inflamatória induzida por ligadura e punção cecal em ratos diabéticos." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5164/tde-15122017-124007/.
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INTRODUÇÃO: A sepse permanece entre as principais causas de morte nos países desenvolvidos e subdesenvolvidos com uma incidência que aumenta a cada ano. O aumento no número de pacientes diabéticos internados em unidades de terapia intensiva (UTIs) também tem chamado a atenção pela complexidade das comorbidades e demais complicações metabólicas encontradas nesta população, contribuindo assim para a desregulação de vias imunológicas e falência de múltiplos órgãos. Diversos estudos sobre distúrbios lipídicos em pacientes diabéticos criticamente enfermos tem sido discutido amplamente na última década com o intuito de identificar características que possam fornecer uma visão mais abrangente das alterações metabólicas e da fisiopatologia desta doença. OBJETIVO: O objetivo deste estudo foi buscar através da análise do perfil lipídico, novos marcadores biológicos e compreender as variáveis da resposta imunoinflamatória encontrada em modelo experimental de sepse, comparando ratos sépticos com e sem diabetes mellitus. MÉTODOS: Utilizamos o modelo de ratos (Wistar) de 8 semanas, divididos em 4 grupos: controle, diabetes (DM), sepse (CLP) e sepse/diabetes (DM+CLP). Através do modelo de punção e ligadura cecal (CLP), induzimos sepse. Através do modelo de Alloxana, induzimos diabetes. Coletamos o plasma para teste de Ensaio Imunoenzimático (ELISA) e células para extração de Ácido Ribonucleico (RNA) que, em seguida, foi submetido a análise através da Reação em Cadeia da Polimerase (PCR). RESULTADOS: A nossa curva de mortalidade demonstrou diferenças significativas entre os grupos analisados (p=0,04). Descobrimos que os grupos CLP vs DM+CLP obtiveram alterações significativas para as expressões de RNAm das lipoproteinas, Fabp4 em adipócitos (p=0,0095) e miócitos (p=0,0152), Acat2 em miócitos (p=0,0303), Gk em leucócitos (p=0,0260) e por ELISA a isoforma Fabp7 (p=0,0152) demonstrou concentrações aumentadas no plasma dos animais diabéticos induzidos a sepse (DM+CLP). CONCLUSÃO: Concluímos que as alterações observadas nas expressões das lipoproteínas revelam um papel importante na patogênese da sepse em animais diabéticos. Acreditamos que através de estudos futuros poderemos complementar a efetividade desde mecanismo complexo e utilizá-lo de forma terapêuticaINTRODUCTION: Sepsis remains among the leading causes of death in developed and underdeveloped countries with an incidence that increases every year. The increased incidence of sepsis in diabetic patients admitted to intensive care units (ICUs) has also drawn attention due to the complexity of the disease and other metabolic complications, leading to immune deregulation, multiple organ failure and high mortality rates. Lipid metabolism in critically ill diabetic patients has been widely investigated in the last decades, since it is an important characteristic in the pathophysiology of this complex disease. OBJECTIVE: The aim of this study was to investigate the lipid profile of diabetic rats, submitted to cecal ligation and puncture. METHODS: Wistar rats 8-week were divided in the following groups: control, diabetes (DM), sepsis (CLP) and sepsis/diabetes (DM+CLP). Plasma was collected for the Enzyme Linked Immuno Sorbent Assay test (ELISA) and the cells were used for Ribonucleic Acid extraction (RNA) that was then analyzed through the Polymerase Chain Reaction (PCR-array). RESULTS: Our mortality curve showed significant differences among the study groups (p=0.04). We found that the CLP vs DM+CLP groups showed significant differences in the mRNA expression of the lipoproteins Fabp4 in adipocytes (p=0.0095) and myocytes (p=0.0152), Acat2 in myocytes (p=0.0303) and Gk in leukocytes (p=0.0260). The protein values of Fabp7 (p=0.0152) exhibited increased plasma concentrations in diabetic animals submitted to sepsis (DM+CLP). CONCLUSION: We conclude that our results of the lipoprotein expression values of several molecules reveal key findings in the pathogenesis of sepsis in diabetic animals and can be used as biomarkers of sepsis in this specific population
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Ricci, Pierbruno. "The Renal Cysts and Diabetes syndrome : from transcriptional profiling and functional analysis of a novel mouse model to biomarkers evaluation in human patients." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS111/document.
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Les mutations hétérozygotes du gène codant pour le facteur de transcription HNF1B sont à l'origine d'un syndrome multisystémique complexe connu sous le nom de « Renal Cysts and Diabetes » (RCAD). Un modèle de souris généré dans notre laboratoire s'est avéré reproduire plusieurs caractéristiques de la maladie humaine. Nous avons réalisé un séquençage ARNm-microARN à différents stades de développement (E14,5 ; E15,5 ; E17,5) de ce modèle. Nous avons montré que les gènes les plus dérégulés étaient impliqués dans les processus métaboliques de transport, de lipides et d’acides organiques et étaient exprimés dans les tubules proximaux et, dans une moindre mesure, dans l’anse de Henlé et les canaux collecteurs. Nous avons sélectionné quatre microARN (miR-802, 194-2, 192 et -30a), régulés à la baisse et potentiellement contrôlés par HNF1B. Des expériences de transactivation de gène rapporteur dans des cellules HEK-293 ont montré que HNF1B était capable de transactiver la transcription de ces microARN via des sites de liaison présents dans les séquences régulatrices de ces gènes. En utilisant des microARN MIMICS nous avons par la suite montré que mir-802, mir-194-2 et mir-192 étaient capables d'inhiber l’expression d’un gène rapporteur contenant la région 3'UTR de HNF1B. L'analyse d'échantillons d'urine de 22 patients RCAD et de 22 contrôles sains a permis d'identifier 146 peptides excrétés de manière différentielle et associés au syndrome. En utilisant ces résultats dans un modèle mathématique, classificateur prédit efficacement le syndrome RCAD avec une sensibilité de 91.7% et une spécificité de 91.1% sur une large population de patientsHeterozygous mutations in the gene encoding the transcription factor HNF1B are the cause of a complex multisystem syndrome known as Renal Cysts And Diabetes (RCAD). A mouse model generated in our laboratory was shown to reproduce several features of the human disease. We performed high-throughput mRNA-microRNA sequencing at different developmental stages (E14.5, E15.5, E17.5). We showed that the most down-regulated genes were involved in transport, lipid and organic acid metabolic processes and expressed in proximal tubules and to a lesser extent in the loop of Henle and collecting ducts. We then selected four microRNAs (mir-802, 194-2, 192 and -30a), which were down-regulated and potentially controlled by HNF1B. Luciferase assays in HEK-293 cells showed that HNF1B was able to specifically transactivate in a dose response mode these microRNAs through binding HNF1B-binding sites in their regulatory promoter/enhancer upstream sequences. We subsequently showed by luciferase assays using miRNA MIMICS that mir-802, mir-194-2 and mir-192 were able to inhibit luciferase vectors containing the 3’UTR of Hnf1b. Analysis of urine samples from 22 RCAD patients and 22 healthy controls led to the identification of 146 peptides differentially excreted and associated with RCAD including a similarity regarding collagen and uromodulin fragments with the RCAD mouse model. Combining the peptides into a mathematical model we used independent cohorts of patients to validate the prediction of the RCAD syndrome. Our classifier efficiently predicted RCAD syndrome with 91.7% sensitivity and 91.1% specificity on a wide population
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Köhler, Meike [Verfasser], and Sonja [Akademischer Betreuer] Greven. "Flexible Bayesian joint models for longitudinal biomarkers and time-to-event outcomes with applications to type 1 diabetes research / Meike Köhler ; Betreuer: Sonja Greven." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1142113728/34.
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Dib, João Mariana Ferreira 1987. "Relationship between the presence of periodontal pathogens and plasma biomarkers in development of periodontal disease in children with type I diabetes mellitus = Relação entre a presença de periodontopatógenos e os níveis de biomarcadores plasmáticos no desenvolvimento da doença periodontal em crianças portadoras de diabetes melito tipo I." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/290597.
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Orientadores: Cristiane Duque, Renata de Oliveira Mattos GranerDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
Made available in DSpace on 2018-08-23T19:41:09Z (GMT). No. of bitstreams: 1 DibJoao_MarianaFerreira_M.pdf: 1014789 bytes, checksum: 02391fe3292ee31afa12160829713a12 (MD5) Previous issue date: 2013
Resumo: A doença periodontal compreende um grupo de infecções inflamatórias que afeta os tecidos periodontais, podendo ser desencadeada por múltiplos fatores locais e sistêmicos. Indivíduos de todas as faixas etárias são susceptíveis ao desenvolvimento dessa doença e a gengivite, condição reversível limitada aos tecidos gengivais, é comumente vista em crianças e no início do período da adolescência. A presença de uma microbiota patogênica específica é um fator essencial para o desenvolvimento da doença periodontal (DP). Doenças sistêmicas tais como diabetes melito, podem contribuir para o desenvolvimento da doença, principalmente devido à resposta exacerbada do sistema imunológico e alterações em parâmetros fisiológicos que contribuem para a agressão tecidual. O objetivo deste estudo foi comparar os aspectos clínico, microbiológico e imunológico de crianças portadoras de diabetes melito tipo I (DM) com crianças não diabéticas (NDM). Vinte e quatro pacientes diabéticos e vinte e sete normoglicêmicos foram avaliados. As condições bucais foram avaliadas através dos índices de placa, gengival e profundidade de sondagem e o perfil de saúde geral dos pacientes foi avaliado através dos níveis de glicemia, HbA1c (hemoglobina glicosilada), triglicerídeos (TRG), colesterol total (CT), HDL, LDL, VLDL e lipídeos totais (LT), a partir de amostras sanguíneas. O método do PCR foi utilizado para identificação das seguintes bactérias: Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Treponema denticola (Td) (complexo vermelho), Prevotella intermedia (Pi) e Prevotella nigrescens (Pn), .Fusobacterium nucleatum (Fn), Campylobacter rectus (Cr) (complexo laranja), Capnocytophaga sputigena (Cs), Capnocytophaga ochracea (Co), Eikenella corrodens (Ec) (complexo verde) em amostras do sulco gengival de dentes decíduos e permanentes. A avaliação imunológica incluiu a detecção dos níveis dos biomarcadores inflamatórios IL- 1?, TNF-? e IL-6 através de ensaios de ELISA. Os dados foram submetidos à análise estatística considerando p? 0,05. Os resultados mostraram que a condição periodontal de pacientes diabéticos e não diabéticos foi similar. Quando considerados pacientes com gengivite (IG ? 2), todos os índices lipídicos avaliados foram maiores no grupo dos diabéticos, com diferença estatística para HDL, TRG e LT. A prevalência do "complexo verde", principalmente Cs e Co foi maior nos sítios periodontais de crianças diabéticas. Bactérias do "complexo vermelho" foram detectadas em poucos sítios dos grupos DM e NDM. Fn e Cr, do "complexo laranja", foram frequentemente encontrados em ambos os grupos. Níveis dos biomarcadores IL-1-?, TNF-? e IL-6 foram similares no soro de DM e NDM. Houve correlação positiva entre as variáveis lipídicas e imunológicas avaliadas somente para o grupo diabético. Conclui-se que os perfis periodontal, microbiológico e imunológico avaliados neste estudo foram similares entre as crianças diabéticas e não diabéticas. Os parâmetros glicêmicos e lipídicos foram maiores nos pacientes diabéticos, mas mantiveram-se dentro da normalidade, demonstrando que controle metabólico é essencial para a manutenção da saúde periodontal
Abstract: Periodontal disease (PD) comprises a group of inflammatory infections that affects the periodontal tissues and may be triggered by multiple local and systemic factors. Individuals of all age groups are susceptible to develop this disease and gingivitis, reversible condition limited to the gingival tissues, is commonly seen in children and in the early adolescence period. The presence of a specific pathogenic microbiota is an essential factor to PD development. Systemic diseases, such as diabetes mellitus, can increase the development and progression of the disease, mainly due to exacerbated immunological response and changes in physiological parameters that contribute to tissue injury. The aim of this study was to compare clinical, microbiological and immunological profiles of type 1 diabetes mellitus children (DM) to non-diabetic control group (NDM). A total of twenty four DM children and twenty seven NDM controls were evaluated. Periodontal status was assessed using plaque index, gingival index and probing depth and general health status were determined using glycemic levels, HBA1c (glycosylated haemoglobin), HDL, LDL, triglycerides (TRG), total cholesterol (TC), VLDL and total lipids (TL), from blood samples. Polymerase chain reaction (PCR) was used for identification of the following bacteria: Aggregatibacter actinomycetemcomitans (Aa), Campylobacter rectus (Cr), Capnocytophaga sputigena (Cs), Capnocytophaga ochracea (Co), Eikenella corrodens (Ec), Fusobacterium nucleatum (Fn), Tannerella forsythia (Tf), Treponema denticola (Td), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi) e Prevotella nigrescens (Pn) from gingival crevicular fluid of deciduous and permanent teeth. Immunological evaluation was determined by means of detection of inflammatory biomarkers -1?, TNF-? and IL-6 using ELISA assays. Data were submitted to statistical analysis, considering p? 0.05. The results showed that periodontal status of diabetic and non-diabetic patients was similar. Considering patients with gingivitis (GI ? 2), all lipid parameters evaluated were highest in DM group, however, statistical difference was observed only for HDL, TRG and TL. The prevalence of "green complex", mainly Cs and Co, was definitely more prevalent in periodontal sites of DM children. Bacteria from "red complex" were detected in few sites of DM and NDM groups. From the "orange complex", Fn and Cr were frequently found in both groups. Similar levels of the serum biomarkers, IL-1-?, TNF-? and IL-6, were detected in the serum of DM and NDM children. In conclusion, clinical, microbiological and immunological profiles evaluated in this study were similar between diabetic and nondiabetic children. Glycemic and lipid parameters were higher in diabetic patients, but remained within normal values, demonstrating that metabolic control is essential for maintaining periodontal health
Mestrado
Microbiologia e Imunologia
Mestra em Biologia Buco-Dental
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Ayepola, Omolola Rebecca. "Effects of kolaviron–a Garcinia kola biflavonoid on biochemical and histological parameters in streptozotocin - induced diabetes and diabetic complications (nephrotoxicity and hepatotoxicity) in male Wistar rats." Thesis, Cape Peninsula University of Technology, 2014. http://hdl.handle.net/20.500.11838/1512.
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Thesis submitted in fulfillment of the requirements for the
Doctor of Technology: Biomedical Technology
In the Faculty of Health and Wellness
At the
CAPE PENINSULA UNIVERSITY OF TECHNOLOGY
2014Diabetes mellitus (DM) results in severe metabolic imbalances and pathological changes in many tissues. Chronic inflammation and oxidative stress have been implicated in the pathophysiology of diabetes mellitus. Garcinia kola (Family: Guttiferae) is a plant well known for its ample medicinal values. The seed of the plant also known as ‘bitter kola’ due to its bitter taste is used as a masticatory agent in traditional hospitality, cultural and social ceremonies in Africa. Kolaviron (KV) is a defatted ethanol extract from the seeds of Garcinia kola (GK). Kolaviron has been shown in experimental models of diseases to have numerous beneficial effects due to the presence of flavonoids (mainly Garcinia biflavonoid (GB)-1, GB-2 and kolaflavanone). However, there is paucity of information regarding the possible effect of kolaviron on inflammatory mediators and oxidative stress in diabetes mellitus. Therefore, this study was carried out to investigate the potential beneficial effects of kolaviron on antioxidant status, inflammatory mediators and apoptosis. Other biochemical and histological alterations in the blood, liver and kidney of streptozotocin-induced diabetic rats were also evaluated. A single intraperitoneal injection of freshly prepared solution of streptozotocin (50 mg/kg.b.wt.) in citrate buffer (0.1M, pH 4.5) was administered to overnight fasted rats for diabetes induction. Diabetes was confirmed by stable hyperglycemia (>18 mmol/l) in the tail blood glucose after 5 days of streptozotocin injection. Kolaviron (100 mg/kg b.wt.) was administered to diabetic rats (by gastric gavage) on the 6th day after the induction of diabetes and treatment continued for 6 weeks (5 times weekly). The effects on blood glucose, body weight, organ (liver and kidney) weight, serum biochemical parameters, oxidative status, inflammatory mediators and histology of the liver, kidney and pancreas were assessed. Kolaviron (KV) treatment lowered blood glucose in diabetic and normoglycemic rats and reduced glycated haemoglobin [HbA1C (%)]. Plasma insulin level was raised in diabetic rats treated with KV. Histomorphometric analysis of the pancreas revealed increased β-cell area of pancreatic islets of kolaviron-treated diabetic group. The indices of organ (liver and kidney) damage were increased in diabetic rats. However, KV treatment protected against liver and kidney damage. The characteristic features of diabetic dyslipidemia such as elevated serum triglyceride and cholesterol concentration which are major risk factors for cardiovascular disease were also significantly reduced in KV-treated diabetic rats. Alteration in antioxidant enzymes status was observed in the liver, kidney and blood (erythrocyte, plasma and serum) of diabetic rats. Lowered catalase (CAT) activity was observed in the liver and kidney of diabetic rats while KV treatment significantly (p < 0.05) elevated catalase activity in the liver and kidney. There was no significant change (p > 0.05) in erythrocyte catalase activity among all treatment groups. Erythrocyte of diabetic rats showed a marked reduction in the activity of superoxide dismutase (SOD) with no significant changes in liver and kidney SOD activity of diabetic rats compared to control whereas KV administration to rats markedly increased SOD activity. Glutathione peroxidase (GPX) activity was elevated in the erythrocyte and kidney of STZ-induced diabetic rats with no significant effect on liver GPX activity. KV treatment reversed the alteration in GPX activity in the kidney and erythrocyte. Level of reduced glutathione (GSH), a non-enzymatic antioxidant was decreased in the both liver and kidney of diabetic rats and treatment of diabetic rats with KV elevated GSH concentration in both tissues. Also, malondialdehyde (MDA), a marker of lipid peroxidation was elevated in the liver, kidney and plasma of diabetic rats and significantly (p < 0.05) lowered following KV treatment. Diabetes induction reduced the capacity of liver and kidney to absorb oxygen radicals as demonstrated by lowered oxygen radical absorbance capacity (ORAC) values. KV administration to normal and diabetic rats significantly increased ORAC values. Increased rate of apoptosis, a major cellular response to high glucose induced stress was observed in the renal and hepatic tissues of diabetic control rats. Kolaviron treatment of diabetic rats protected the liver and kidney against hyperglycemia-induced apoptosis and decreased the number of TUNEL positive cells A significant (p < 0.05) elevation of pro-inflammatory cytokines; monocyte chemoattractant protein (MCP-1), Interleukin-1β (IL-1β), IL-6 and tumor necrosis factor (TNF)-𝛂 was observed in the liver of diabetes rats. KV treatment lowered these inflammatory biomarkers. On the other hand, the kidney of diabetic rats showed elevated concentration of pro-inflammatory IL-1β with no significant effect on kidney TNF-𝛂. An increase in the serum concentration of MCP-1 and IL-1β was observed in the untreated diabetic rats while kolaviron treatment normalized the alteration in serum concentration of MCP-1, IL-1β and vascular endothelial growth factor (VEGF). In conclusion, persistent and chronic hyperglycemia promotes the generation of free radicals and inflammatory molecules which contributes to progressive development of micro- and macro vascular complications and multi-organ damage. Kolaviron demonstrated beneficial effects on markers of oxidative stress and inflammation in the diabetic rats and also promoted the survival and functional integrity of the liver and kidney.
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Chiyoda, Alberto. "Programa de exercícios físicos : análise dos fatores de risco cardiovaculares e biomarcadores de inflamação e estresse oxidativo em diabéticas exercitadas e não exercitadas /." Rio Claro : [s.n.], 2011. http://hdl.handle.net/11449/87367.
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Orientador: Eliete LucianoBanca: Eduardo Kokubun
Banca: Fúlvia de Barros Manchado Gobatto
Resumo: As doenças cardiovasculares (DC) são a principal causa de morte e inabilidade em diabéticos, o que gera enormes custos em saúde pública. Os problemas cardiovasculares afetam mulheres diabéticas de forma ainda mais pronunciada que em homens. Por outro lado, crescentes evidências reafirmam a importância da atividade física (AF) no tratamento do DM e para a saúde cardiovascular. Assim, objetivo do trabalho foi comparar diabéticas exercitadas e não exercitadas em relação aos fatores de risco cardiovasculares e biomarcadores de inflamação e estresse oxidativo. A amostra foi composta por mulheres diabéticas do tipo 2 com idade acima de 40 anos divididas em dois grupos: exercitadas (E) (n=21) e nãoexercitadas (N) (n= 16). O grupo E participou do programa de exercícios físicos de intensidade moderada por mais de seis meses, duas vezes por semana com duração de uma hora por sessão. Para o tratamento estatístico foi aplicado o teste de Shapiro-Wilk e Kolmogorov Smirnov para verificar a normalidade dos dados. As variáveis que não apresentaram dados normais foi utilizado o teste de Mann Whitney e para as variáveis que apresentaram dados normais foi utilizado o Teste t para amostras independentes. Em relação às variáveis, estatura (E: 1,53 ± 0,06 m; N: 1,58 ± 0,07 m), peso (E: 74,6 ± 14,4 kg; N: 71,4 ± 14,6 kg), IMC (E: 30,8 ± 5,8 kg/m²; N: 28,6 ±4 ,8 kg/m²), circunferência de cintura (E: 97,5 ± 12,4 cm ; N: 97,2 ± 10,9), relação cintura/quadril (E: 0,9 ± 0,1; N: 0,9 ± 0,08), pressão arterial sistólica (E: 131,9 ± 19,4 mmHg; N: 126,9 ± 15,8 mmHg) e pressão arterial diastólica (E: 79,7 ± 11,9 ; N: 79,4 ± 12,4) os grupos estudados foram semelhantes estatisticamente. Para as variáveis metabólicas, glicemia (E: 157,4 ± 75,6 mg/dl; N: 139,1 ± 69,5 mg/dl ), HDL (E: 54,4 ± 19,4 mg/dl ; N: 56,3 ± 25,7 mg/dl ), TG ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Cardiovascular diseases are the main cause of death and inability in diabetics, and it generates high costs in public health. The cardiovascular problems affect mostly women. Besides that, lately evidences confirms the importance of the physical activity in the treatment of diabetes and for the cardiovascular health in general. Thus, the purpose of the study was to compare exercised and not exercised diabetic women regarding cardiovascular risks factors and biomarkers of inflammation and oxidative stress. The sample was composed of type 2 diabetics women aging over 40 years old, separated by two groups: exercise (E) (n=21, age= 62,5 ± 11,9 years) and not exercised (N) (n= 16, age: 57,2 ± 7,2 years). Group E has participated of a moderated physical activities program over six months, on a one hour session, twice a week. For the statistics was applied the test of Shapiro-Wilk and Kolmogorov Smirnov in order to verify the accuracy of the data. For the ones that had not presented normal data was used the test of Mann Whitney and for ones that had presented normal data test t was applied for independent samples. In relation to the variables, stature (E: 1,53 ± 0,06 m; N: 1,58 ± 0,07 m), weight (E: 74,6 ± 14,4 kg; N: 71,4 ± 14,6 kg), BMI (E: 30,8 ± 5,8 kg/m²; N: 28,6 ±4 ,8 kg/m²), waist cincumference (E: 97,5 ± 12,4 cm ; N: 97,2 ± 10,9), waist/rip ratio (E: 0,9 ± 0,1; N: 0,9 ± 0,08), systolic blood pressure (E: 131,9 ± 19,4 mmHg; N: 126,9 ± 15,8 mmHg) and diastolic blood pressure (E: 79,7 ± 11,9 ; N: 79,4 ± 12,4) the studied groups had similar statistics.For the metabolics variables, glucose (E: 157,4 ± 75,6 mg/dl; N: 139,1 ± 69,5 mg/dl), HDL (E: 54,4 ± 19,4 mg/dl ; N: 56,3 ± 25,7 mg/dl ), TG (E: 137,0 ± 85,0 mg/dl ; N: 136,6 ± 65,3 mg/dl), TBARS (E: 24,3 ± 2,3 μmol/L; N: 22,7 ± 2,4 μmol/L) and C-reactive protein (E: 3,6 ± 0,6 log; N: 3,7 ± 0,6 log) no differences ... (Complete abstract click electronic access below)
Mestre
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Saldarriaga, Magda Elizabeth Graciano. "Pesquisa de miRNAs circulantes, potenciais biomarcadores de aterosclerose subclínica em indivíduos euglicêmicos e pré-diabéticos." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-24052017-161009/.
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As doenças cardiovasculares e o diabete melito fazem parte das DCNT prioritárias da OMS, devido às altas taxas de morbimortalidade e incapacidade que geram a cada ano. Estima-se que no mundo existam 387 milhões de diabéticos e outros 316 milhões de pessoas com características de risco, como pré-diabete. Cerca de 60% dos pacientes com DM2 desenvolvem doença cardiovascular, a qual inicia de forma concomitante aos distúrbios do metabolismo da glicose, podendo existir mecanismos fisiopatológicos comuns entre as doenças. Metade dos eventos coronarianos, inclusive a morte súbita, ocorrem em indivíduos assintomáticos, evidenciando a necessidade de novos marcadores precoces, já que em muitos deles a morte é a primeira manifestação. Recentemente, tem sido sugerido que os miRNAs envolvidos na regulação da expressão gênica podem ser caracterizados como biomarcadores em diversas doenças. Nosso objetivo é identificar alterações no perfil de miRNAs circulantes em indivíduos euglicêmicos e pré-diabéticos com e sem aterosclerose subclínica, utilizando a tecnologia de qPCR Arrays, com a finalidade de identificar candidatos a biomarcadores moleculares dessa condição. Encontrou-se que a aterosclerose subclínica esteve associada com o envelhecimento, a menopausa, etnia branca, dislipidemia, resistência à insulina, o aumento da adiposidade, leptina e do TNF-α. O aumento do miR98-5p e a diminuição dos miRNAs miR-212-3p, miR-145-5p, miR-93-5p, miR15a-5p, miR-19a-3p, miR32-5p levaram a ativação da via de sinalização da aterosclerose. Os resultados sugerem que a inflamação foi o principal mecanismo associado com o desenvolvimento de aterosclerose subclínica neste estudo.Cardiovascular Disease and Diabetes Mellitus are relevant NCDs for the WHO. It´s estimated that, worldwide, there are 387 millions of diabetics and 316 millions of people with risk characteristics like prediabetes. About 60% of patients with T2DM develops cardiovascular disease, which starts at the same time as disorders of glucose metabolism, there may be common pathophysiological mechanisms among diseases. Half of coronary events, including sudden death, occurs in asymptomatic individuals. This fact, highlights the need for new early markers of the disease, especially in asymptomatic patients, since in many of them, death is the first manifestation. It has been recently suggested that miRNAs involved in pos-transcriptional regulation of gene expression, could be characterized as biomarkers of diseases. Our goal is to identify changes in the profile of circulating microRNAs in euglycemic and prediabetic patients with or without subclinical atherosclerosis, by quantitative Polymerase Chain Reaction array (qPCR Array) in order to find molecular biomarkers of this condition. We found that subclinical atherosclerosis was associated with aging, menopause, white ethnicity, dyslipidemia, insulin resistance, increased adiposity, leptin and TNF-α. The up-regulation of miR98-5p and the down-regulation miR-212-3p, miR-145-5p, miR-93-5p, miR15a-5p, miR-19a-3p, miR32-5p led to activation of the signaling pathway of atherosclerosis. The results suggest that inflammation was the main mechanism associated with the development of subclinical atherosclerosis in this study.
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Chiyoda, Alberto [UNESP]. "Programa de exercícios físicos: análise dos fatores de risco cardiovaculares e biomarcadores de inflamação e estresse oxidativo em diabéticas exercitadas e não exercitadas." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/87367.
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As doenças cardiovasculares (DC) são a principal causa de morte e inabilidade em diabéticos, o que gera enormes custos em saúde pública. Os problemas cardiovasculares afetam mulheres diabéticas de forma ainda mais pronunciada que em homens. Por outro lado, crescentes evidências reafirmam a importância da atividade física (AF) no tratamento do DM e para a saúde cardiovascular. Assim, objetivo do trabalho foi comparar diabéticas exercitadas e não exercitadas em relação aos fatores de risco cardiovasculares e biomarcadores de inflamação e estresse oxidativo. A amostra foi composta por mulheres diabéticas do tipo 2 com idade acima de 40 anos divididas em dois grupos: exercitadas (E) (n=21) e nãoexercitadas (N) (n= 16). O grupo E participou do programa de exercícios físicos de intensidade moderada por mais de seis meses, duas vezes por semana com duração de uma hora por sessão. Para o tratamento estatístico foi aplicado o teste de Shapiro-Wilk e Kolmogorov Smirnov para verificar a normalidade dos dados. As variáveis que não apresentaram dados normais foi utilizado o teste de Mann Whitney e para as variáveis que apresentaram dados normais foi utilizado o Teste t para amostras independentes. Em relação às variáveis, estatura (E: 1,53 ± 0,06 m; N: 1,58 ± 0,07 m), peso (E: 74,6 ± 14,4 kg; N: 71,4 ± 14,6 kg), IMC (E: 30,8 ± 5,8 kg/m²; N: 28,6 ±4 ,8 kg/m²), circunferência de cintura (E: 97,5 ± 12,4 cm ; N: 97,2 ± 10,9), relação cintura/quadril (E: 0,9 ± 0,1; N: 0,9 ± 0,08), pressão arterial sistólica (E: 131,9 ± 19,4 mmHg; N: 126,9 ± 15,8 mmHg) e pressão arterial diastólica (E: 79,7 ± 11,9 ; N: 79,4 ± 12,4) os grupos estudados foram semelhantes estatisticamente. Para as variáveis metabólicas, glicemia (E: 157,4 ± 75,6 mg/dl; N: 139,1 ± 69,5 mg/dl ), HDL (E: 54,4 ± 19,4 mg/dl ; N: 56,3 ± 25,7 mg/dl ), TG...
Cardiovascular diseases are the main cause of death and inability in diabetics, and it generates high costs in public health. The cardiovascular problems affect mostly women. Besides that, lately evidences confirms the importance of the physical activity in the treatment of diabetes and for the cardiovascular health in general. Thus, the purpose of the study was to compare exercised and not exercised diabetic women regarding cardiovascular risks factors and biomarkers of inflammation and oxidative stress. The sample was composed of type 2 diabetics women aging over 40 years old, separated by two groups: exercise (E) (n=21, age= 62,5 ± 11,9 years) and not exercised (N) (n= 16, age: 57,2 ± 7,2 years). Group E has participated of a moderated physical activities program over six months, on a one hour session, twice a week. For the statistics was applied the test of Shapiro-Wilk and Kolmogorov Smirnov in order to verify the accuracy of the data. For the ones that had not presented normal data was used the test of Mann Whitney and for ones that had presented normal data test t was applied for independent samples. In relation to the variables, stature (E: 1,53 ± 0,06 m; N: 1,58 ± 0,07 m), weight (E: 74,6 ± 14,4 kg; N: 71,4 ± 14,6 kg), BMI (E: 30,8 ± 5,8 kg/m²; N: 28,6 ±4 ,8 kg/m²), waist cincumference (E: 97,5 ± 12,4 cm ; N: 97,2 ± 10,9), waist/rip ratio (E: 0,9 ± 0,1; N: 0,9 ± 0,08), systolic blood pressure (E: 131,9 ± 19,4 mmHg; N: 126,9 ± 15,8 mmHg) and diastolic blood pressure (E: 79,7 ± 11,9 ; N: 79,4 ± 12,4) the studied groups had similar statistics.For the metabolics variables, glucose (E: 157,4 ± 75,6 mg/dl; N: 139,1 ± 69,5 mg/dl), HDL (E: 54,4 ± 19,4 mg/dl ; N: 56,3 ± 25,7 mg/dl ), TG (E: 137,0 ± 85,0 mg/dl ; N: 136,6 ± 65,3 mg/dl), TBARS (E: 24,3 ± 2,3 μmol/L; N: 22,7 ± 2,4 μmol/L) and C-reactive protein (E: 3,6 ± 0,6 log; N: 3,7 ± 0,6 log) no differences ... (Complete abstract click electronic access below)
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Eendebak, Robert. "The potential relationships between hormone biomarkers and functional and health outcomes of ageing." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/the-potential-relationships-between-hormone-biomarkers-and-functional-and-health-outcomes-of-ageing(e28321cc-703c-44df-99b4-fb0d76f7f429).html.
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Although the female menopause has been extensively characterized as a well-defined symptomatic state of oestrogen deficiency, which responds relatively well to oestrogen replacement therapy, the symptomatic state of androgen deficiency in men is poorly defined and uncertainty exists whether it responds to testosterone replacement. It has been proposed that hypothalamic-pituitary-testicular (HPT)-axis function (responsible for the production of androgens) and regulation could be viewed as a âbarometerâ of health status in older men and that potential alterations in HPT-axis function and regulation reflect subclinical and clinical deficits in function and health, which may result in an aged phenotype of human health and disease in older men. The HPT-axis constitutes a well-defined, tractable, clinically-relevant, biological system, which may permit insight into the mechanisms underlying the expression of ageing-related phenotypes of human health and disease. By using a different lens â such as the genetic background; the compensatory responses within the HPT-axis; the syndromes of androgen deficiency; the ethnic background of an individual or the life course trajectory of function and health from conception into older age â to magnify potential dysregulation in the HPT-axis will it be possible to visualize and understand the phenotypic expression of human male ageing as a gradient of functional and health outcomes. This will allow for a better understanding of the physiological mechanics underlying symptomatic expression of dysregulation in the HPT-axis.
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Somineni, Hari Krishna. "Physical exercise training but not metformin attenuates albuminuria and shedding of ACE2 in type 2 diabetic db/db mice." Wright State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=wright1369704228.
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Vinagre, Torres Irene. "Biomarcadores de la inflamación en la diabetes mellitus tipo 2: Efecto del control glucémico y del fenotipo de las LDL." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/285417.
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Las enfermedades cardiovasculares constituyen las complicaciones más prevalentes en los pacientes con diabetes mellitus tipo 2 (DM2) y son las que se asocian con mayor morbi-mortalidad. Los mecanismos responsables del desarrollo acelerado de arteriosclerosis en los pacientes con DM2 no se conocen con precisión, pero tanto la dislipemia aterogénica y la inflamación de bajo grado características de esta población, están implicados. La información sobre la relación del grado de control glucémico con las características cualitativas de las lipoproteínas de baja densidad (LDL) y alta densidad (HDL) es insuficiente y se desconoce el efecto que puede tener la optimización del control glucémico sobre las características cualitativas de las partículas de LDL y HDL y la distribución de la fosfolipasa A2 asociada a las lipoproteínas (Lp-PLA2) entre ambas. Igualmente, los estudios que tratan de determinar la correlación entre los parámetros inflamatorios y el control glucémico no son del todo concluyentes, y la información existente acerca del efecto que tiene la mejoría del control glucémico sobre los parámetros inflamatorios es también escasa.
Así, nuestra hipótesis es que la intensificación del control glucémico aporta beneficios relacionados con la modificación de los parámetros inflamatorios y los cambios cualitativos en las lipoproteínas y de la distribución de Lp-PLA2, que podrían contribuir a disminuir el riesgo cardiovascular en los pacientes con DM2. Para ello se ha elaborado un estudio transversal de 122 pacientes con DM2 y mal control glucémico (hemoglobina glicosilada (HbA1c) > 8,5%) y 54 individuos control, y un estudio longitudinal con un subgrupo de 42 pacientes con DM2, a los que se les ha optimizado con distintas estrategias terapéuticas y seguido durante 3 meses. Se ha realizado una caracterización clínica de los sujetos (edad, sexo, peso, índice de masa corporal, tiempo de evolución de la DM2, medicación previa, complicaciones crónicas), determinación del perfil lipídico (colesterol total, fracciones lipoproteicas de colesterol, tamaño de LDL, características cualitativas de LDL y HDL, triglicéridos, Apolipoproteína A-I, Apolipoproteína B, ácidos grasos libres) y de marcadores de inflamación sistémica (proteína C reactiva, interleucina-6, interleucina-8, proteína quimiotáctica de monocitos 1, factor transformante del crecimiento β1 (TGF-β1), adiponectina, leptina). Se han comparado estos aspectos entre los diferentes grupos estudiados y, además, se ha valorado el efecto que tiene la mejora del control glucémico (HbA1c) sobre sobre el perfil lipídico, los parámetros inflamatorios y las características cualitativas de las lipoproteínas.
Los principales hallazgos de los trabajos desarrollados en esta tesis doctoral son: 1- Las pautas de insulina bolo-basal son factibles y permiten mejorar el control glucémico sin comprometer la seguridad y calidad de vida, en los pacientes con DM2 de larga evolución y mal control; 2- Los pacientes con DM2 tienen alteraciones en las características cualitativas y cuantitativas de las LDL y HDL y que muchas de ellas están relacionadas con el fenotipo B de las partículas LDL; 3- La mejoría del control glucémico promueve modificaciones menos aterogénicas en las partículas LDL y HDL; 4- Los marcadores inflamatorios se encuentran elevados en los sujetos DM2, sobretodo en aquellos con fenotipo B; 5- La optimización del control glucémico podría reducir los niveles de TGF-β1, en parte implicado en la patogenia de la nefropatía diabética. Por tanto, los sujetos con DM2, especialmente aquellos con fenotipo B de las LDL, tienen niveles elevados de marcadores inflamatorios y alteraciones cualitativas de las partículas LDL y HDL relacionadas con mayor aterogenicidad. La intensificación del control glucémico aportaría beneficios que podrían contribuir a disminuir el riesgo cardiovascular en los pacientes con DM2.Cardiovascular diseases are the most prevalent complications in patients with type 2 diabetes mellitus (T2DM) and are associated with increased morbidity and mortality. The mechanisms responsible for the accelerated development of atherosclerosis in patients with T2DM are not known with precision, but both atherogenic dyslipidemia and low-grade inflammation characteristics of this population, are involved. There is limited information on the relationship between the degree of glycemic control and quality characteristics of low-density lipoproteins (LDL) and high-density lipoproteins (HDL) and also the effect that the optimization of glycemic control could have on the quality characteristics of LDL and HDL particles and distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) is unknown. Similarly, studies that attempt to determine the correlation between inflammatory parameters and glycemic control are not entirely conclusive, and information on the effect of improved glycemic control on inflammatory parameters is also scarce. Thus, our hypothesis is that the intensification of glycemic control provides benefits due to inflammatory parameters modification and qualitative changes in lipoproteins and distribution of Lp-PLA2, which could help to reduce cardiovascular risk in patients with T2DM. We have developed a cross-sectional study of 122 patients with T2DM and poor glycemic control (glycosylated hemoglobin (HbA1c) > 8,5%) and 54 control subjects, and a longitudinal study with a subgroup of 42 patients, which were optimized with different therapeutic strategies and followed for 3 months. There has been a clinical characterization of the subjects (age, sex, weight, body mass index, duration of T2DM, previous medication, chronic complications), determination of the lipid profile (total cholesterol, lipoprotein cholesterol fractions, LDL size, qualitative characteristics of LDL and HDL, triglycerides, apolipoprotein AI, apolipoprotein B, free fatty acids) and inflammatory biomarkers (C-reactive protein, interleukin-6, interleukin-8, monocyte chemotactic protein 1, transforming growth factor β1 (TGF -β1), adiponectin, leptin). We compared these aspects between the different groups studied and we assessed the improvement of glycemic control (HbA1c) on the lipid profile, inflammatory parameters and qualitative characteristics of lipoproteins. The main findings of this thesis are: 1- Switching to basal-bolus insulin therapy is feasible, effective and safe in patients with long-standing T2DM and poor glycemic control, and does not impair their quality of life; 2- Patients with T2DM have alterations in the qualitative and quantitative characteristics of LDL and HDL and many of them are related to phenotype B of LDL particles; 3- Improvement of glycemic control promotes less atherogenic changes in LDL and HDL particles; 4- Inflammatory biomarkers are elevated in T2DM subjects, especially in those with phenotype B; 5- Optimization of glycemic control may reduce levels of TGF-β1 in part involved in the pathogenesis of diabetic nephropathy. Thus, subjects with T2DM, especially those with LDL phenotype B, have elevated levels of inflammatory biomarkers and qualitative changes in LDL and HDL particles associated with increased atherogenicity. The intensification of glycemic control brings benefits that could help to reduce cardiovascular risk in patients with T2DM.
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Tegg, Michelle. "Plasma insulin-degrading enzyme: Characterisation and evaluation as a potential biomarker for Alzheimer's disease." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2014. https://ro.ecu.edu.au/theses/1198.
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Alzheimer’s disease (AD) is increasing in prevalence due to increasing lifespan and altered lifestyle. It is the fourth major cause of death in Western countries, resulting in significant economic and social impact (Von Strauss, et al., 1999; Goate, 1997). There are no blood biomarkers currently accepted for the diagnosis of AD, and the identification of suitable biomarkers would eventually reduce the necessity for invasive, expensive and slow diagnostic procedures, as well as facilitate prognostic studies. An AD blood test would decrease the need for delaying diagnosis due to ambivalent presentation, and allow therapeutic intervention to commence at an earlier and more functional stage for the sufferer, thereby maximising the benefits of treatment. It is also feasible that a blood biomarker would be of use in the development of therapeutic treatments, which are currently inadequate.
Numerous studies have suggested that hyperinsulinemia and type II diabetes (DM2) significantly increase the risk of developing Alzheimer’s disease (AD). Therefore, much research interest has been aimed recently toward determining the putative common mechanisms of these conditions. One enzyme which has been implicated in both AD and DM2 is insulin degrading enzyme (IDE). This project focuses largely on the characterisation of plasma IDE expression and catalytic activity, to help determine potential role/s of IDE in the development of AD, and the suitability of IDE as an AD biomarker. Evidence is also provided to support the concept that IDE impairments may be the common factor that links AD, hyperinsulinemia and DM2.
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Banerjee, Srikanta. "Inflammatory Markers Associated With Disease Progression of Cardiorenal Syndrome." ScholarWorks, 2015. https://scholarworks.waldenu.edu/dissertations/1433.
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An increase in cellular inflammatory biomarkers directly increases the risk of cardiovascular disease (CVD). Using the social ecological and biomedical theories, the study examined quantitatively how specific inflammatory biomarkers are associated with cardiorenal syndrome (CRS), a potential complication of hypertension and diabetes, and how sociodemographic factors modify this association in the U.S. adult population. A retrospective secondary data analysis of the data collected from National Health and Nutrition Examination Survey (NHANES) 1999-2010 was utilized to evaluate these hypotheses. High sensitivity C-reactive protein, homocysteine (hcy), and fibrinogen had a modifying effect on Type 4 (chronic reno-cardiac etiology), Type 2 CRS (chronic cardio-renal etiology), and a significant additive effect on CRS even after controlling for known CVD and Chronic Kidney Disease (CKD) risk factors. For Type 4 CRS, the adjusted Odds Ratio of CVD in individuals with CKD was elevated, 2.29 (Confidence Interval [CI] 1.17-3.64, p < 0.05), among individuals with elevated hcy levels but close to 1.0 (0.65 CI 0.28-1.53, p > 0.05) among patients with normal hcy after the results were controlled for medical and demographic risk factors. Finally, race modified the effect of inflammatory markers on CRS. Out of all the biomarkers, income only modified the effect of hcy on CRS. Education level modified the effect of every inflammatory marker on CRS. While Ferritin-to-Transferrin ratio (F/T ratio) had a non-significant additive effect, due to the lack of adequate subjects, the modifying effect of F/T ratio could not be tested. This study can help initiate social change by urging healthcare professionals to monitor these biomarkers as a part of preventing hypertension, diabetes, and CRS.
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Lundin, Ulrika. "Biomarker Discovery in Diabetic Nephropathy by Targeted Metabolomics." Thesis, Linköping University, The Department of Physics, Chemistry and Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-15640.
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Diabetic nephropathy is a chronic kidney disease and one of the more severe complications from diabetes mellitus type 2. The glomerular and tubular dysfunctions usually lead to end stage renal disease and the treatments of these patients (dialysis, kidney transplants) are a huge economic burden for the society. Due to an epidemiologic increase of type 2 diabetes, conventional diagnostic markers like creatinine and albumin are not sufficient, since they are only able to identify already existing kidney damage. With targeted metabolomics, the analysis of small molecules produced from metabolism, this project aimed at finding novel and more sensitive metabolic biomarkers from several different classes of metabolites. The different assays were performed with flow injection analysis, high performance liquid chromatography, gas chromatography and mass spectrometry, and with principal component analysis and discriminant analysis, up-and down-regulated metabolites could be identified and their respective biochemical pathways, if possible, explained. In diabetics significantly elevated concentrations of very long chain fatty acids (impaired peroxisomal β-oxidation), urinary sugars and acylcarnitines in plasma could be recognized. Markers indicating kidney damage included significantly increased plasma concentrations of asymmetric dimethylarginine (inhibition of nitric oxide synthase resulting in decreased endothelial functionality) and histamine (indication of uremic pruritus). Oxidative stress was also found to be a potential prognostic marker as indicated by the raised methionine-sulfoxide to methionine ratio in nephrotic patients. To summarize, this project succeeded in identifying metabolic biomarkers both for diabetes type 2 and nephropathy, which in the future might become important tools in slowing down progression or diagnosing these diseases.
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Шандиба, Ірина Олександрівна, Ирина Александровна Шандыба, Iryna Olexandrivna Shandyba, Андрій Миколайович Лобода, Андрей Николаевич Лобода, and Andrii Mykolaiovych Loboda. "Early diagnosis of diabetic nephropathy in children with type 1 diabetes mellitus using the VCAM-1 biomarker." Thesis, Lithuanian University of Health Sciences, 2020. https://essuir.sumdu.edu.ua/handle/123456789/78327.
Full textAbstract:
Васкулярна молекула клітинної адгезії-1 (VCAM-1) - це 90 кДа глікопротеїн, який експресується в ендотеліальних клітинах і бере участь в міграції і рекрутуванні запальних клітин. Недавні дослідження показали, що рівні VCAM-1 в сечі були значно підвищені у пацієнтів із захворюванням нирок. Метою цього дослідження було вивчення особливостей рівнів VCAM-1 в сечі дітей залежно від тривалості діабету. У дослідження були включені 47 дітей з діабетом 1-го типу і 8 дітей без діабету. VCAM-1 в сечі збільшився на 24 відсотки у дітей з тривалістю діабету менше одного року в порівнянні з контрольною групою. Рівні VCAM-1 були підвищені на 33 відсотки у дітей з тривалістю діабету від одного до п'яти років. Цей показник збільшився на 54 відсотки у дітей, які жили з діабетом більше п'яти років. Висновки. Збільшення рівня VCAM-1 в сечі спостерігалося вже в перший рік маніфестації діабету у дітей. Вимірювання рівня VCAM-1 в сечі може бути корисним для ранньої діагностики діабетичної нефропатії.Васкулярная молекула клеточной адгезии-1 (VCAM-1) - это 90 кДа гликопротеин, который экспрессируется в эндотелиальных клетках и участвует в миграции и рекрутировании воспалительных клеток. Недавние исследования показали, что уровни VCAM-1 в моче были значительно повышены у пациентов с заболеванием почек. Целью настоящего исследования было изучение особенностей уровней VCAM-1 в моче детей в зависимости от продолжительности диабета. В исследование были включены 47 детей с диабетом 1-го типа и 8 детей без диабета. VCAM-1 в моче увеличился на 24 процента у детей с продолжительностью диабета менее одного года по сравнению с контрольной группой. Уровни VCAM-1 были повышены на 33 процента у детей с продолжительностью диабета от одного до пяти лет. Этот показатель увеличился на 54 процента у детей, которые жили с диабетом более пяти лет. Выводы. Увеличение уровня VCAM-1 в моче наблюдалось уже в первый год манифестации диабета у детей. Измерение уровня VCAM-1 в моче может быть полезно для ранней диагностики диабетической нефропатии.
Vascular cell adhesion molecule-1 (VCAM-1) – is a 90-kDa glycoprotein that is expressed in endothelial cells and is involved in the migration and recruitment of inflammatory cells. Recent studies have shown that urinary VCAM-1 levels were significantly increased in patients with kidney disease. The aim of the current study was to investigate the features VCAM-1 levels in urine of children depending on the diabetes duration. Study included 47 children with 1 type diabetes mellitus and 8 children without diabetes. VCAM-1 in urine increased by 24 percent in children with the duration of diabetes below one year compared to the control group. VCAM-1 levels were elevated by 33 percent in children with the duration of diabetes from one to five years. The marker increased by 54 percent in children who lived with diabetes for more than five years. Conclusions. Increase in urinary VCAM-1 was observed in the first year of diabetes in children. Measuring the level of VCAM-1 in urine may be useful for the early diagnosis of diabetic nephropathy.
Thanks for the research group of Thomas Boren (Department of Medical Biochemistry and Biophysics/MIMS, Umea University) for the opportunity to conduct research in framework of collaboration in Erasmus+ (KA1) programme, 2018/2019. The authors declare absence of potential conflicts of interest.
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Crawford, Michelle Anne. "Assessment of glycated insulin as a novel clinical biomarker for pre-diabetes and diabetes." Thesis, University of Ulster, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.588748.
Full textAbstract:
The glycaemic environment within the pancreatic beta cell is reflective of prevailing, circulating glucose conditions. Furthermore, within the pancreatic beta cell, glucose and glucose metabolites provide a suitable environment for non-enzymatic glycation to occur. Insulin which is produced and secreted from the beta cell has been shown to readily undergo glycation and is detectable within the beta cell. Under hyperglycaemic conditions, such as in diabetes, it has been proposed that the glycation of insulin is augmented and as such will provide a novel means of identifying diabetes. This thesis examines the secretion of glycated insulin from healthy and diabetic individuals, how secretion is modulated following treatment with anti-diabetic medication using a novel immunoassay and furthermore, proposes potential mechanistic routes through which glycated insulin affects insulin secretion. Pre-clinical studies in pancreatic BRIN-BDII cells and murine islets have demonstrated an autocrine inhibitory effect of insulin release. At physiologically relevant intra-islet concentrations, insulin suppressed the insulin-secretory responses of a range of secretagogues acting at different points in the beta cell stimulus-secretion coupling pathway including tolbutamide (43% inhibition), alanine (45% inhibition), IBMX (35% inhibition), forskolin (28% inhibition), and arginine (41 % inhibition). In addition, alanine and IBMX- up-regulation of insulin gene expression was decreased in the presence of insulin. Furthermore, insulin decreased gene expression of the potassium channel pore forming proteins, KIR6.2 and SUR-I, and also expression of the insulin receptor. A similar inhibitory effect on insulin release and through tolbutamide-mediated pathway was demonstrated with glycated insulin albeit to a lesser degree. Insulin (10 urnol/l) inhibited its pancreatic secretion by 65% at high glucose concentrations compared to glycated insulin which exhibited 77% inhibition at the same concentration. Importantly, glycated insulin also inhibited the autocrine release of insulin and had diminished action through the tolbutamide stimulated pathway, which may contribute to insulin resistance. Furthermore, these studies suggest inhibition by glycated insulin and insulin may be mediated through impaired membrane depolarisation. As part of this thesis, an ELISA was optimised for the quantification of circulating glycated insulin in a number of human clinical studies to assess glycated insulin as a novel biomarker for diabetes. Following optimisation, the assay was determined to be specific (spike recovery 90-97.5%, (ECso 0.37 nmol/l) and sensitive «19.1 pmol/l) for glycated insulin detection. The assay was found to be reproducible with intra and inter-assay variations of 7.9% and 8.9%, respectively. In vitro studies in pancreatic beta-cells demonstrated augmented insulin release and suppression of glycated insulin release following treatment with metformin at hyperglycaemic conditions. Furthermore, the combination of metformin with GLP-1, further augmented metformin induced insulin release while glycated insulin release remained suppressed. These findings highlight an important supplementary benefit of metformin. In clinical studies, this thesis has for the first time, demonstrated circulating glycated insulin release to be raised 3-fold in type 2 diabetic subjects and 2-fold in pre- diabetes confirming a role for glycated insulin in identifying asymptomatic diabetes and those with impaired glucose tolerance. Importantly, in studies of pregnant women, circulating concentrations of glycated insulin were found to be augmented lO-fold and may present a novel means of monitoring the beta-cell expansion during pregnancy. In type 2 diabetes, glycated insulin exhibited a rapid release from the beta-cell following a mixed meal. Circulating glycated insulin concentrations were found to be similar between fasting or non-fasting however post-prandial sampling should be carried out at least 30 min following meal ingestion to avoid any post-prandial spikes. To further examine the drug induced changes to glycated insulin secretion in a clinical setting, the effect of anti-diabetic drugs on post-prandial glycated insulin were assessed in pre-diabetic and type 2 diabetic subjects. Metformin reduced glycated insulin excursion by 48% in pre-diabetes and 60% in diabetes. Additionally, Nateglinide inhibited the glycated insulin excursion by 65% in type 2 diabetes. Studies herein have demonstrated that glycated insulin is dynamically secreted from the beta-cell in pre-diabetes, diabetes and gestational diabetes, and is affected by anti-diabetic therapeutic agents. Collectively these studies confirm a putative role for glycated insulin as a biomarker for diabetes however further work to investigate the natural history of glycated insulin secretion, in diabetes is required.