<div> <div> <div> <p>Incidence rates of adolescents with type 2 diabetes are increasing rapidly; there was an increase of 30% between 2019 and 2009. Even more alarming is that studies show that the most effective treatment, metformin monotherapy, is only effective at maintaining glycemic control in approximately 50% of individuals. Additionally, adolescents with diabetes may experience serious microvascular and macrovascular complications sooner than adults, which can impact the quality of life of young adults across the globe. Therefore, diabetes in adolescents is a public health concern, and there is very little research to guide treatment and prevention. It is widely known that adolescents have a very poor dietary pattern, characterized by increased intakes of added sugars from refined grains, and minimal amounts of fruits, vegetables, and fiber. There is conflicting evidence in the literature connecting increased added sugar intake to insulin resistance and diabetes development. Considering the very poor diets consumed by adolescents, and that nutrition is a modifiable risk factor for diabetes, we aimed to examine the associations between added sugar consumption, glycemic values, and measures of insulin resistance and beta-cell function. This pilot study analyzed dietary and glycemic data from participants that were screened for an ongoing randomized control trial which is an adolescent diabetes prevention program that uses health coaching to improve diet and physical activity behaviors called the Dietary Intervention for Glucose Tolerance in Teens (Dig It) Study. Fasting blood glucose, glycated hemoglobin (HbA1c), and 2-hour glucose concentrations were collected during an oral glucose tolerance test that was used to screen adolescents with obesity for diabetes. Consumption of added sugar and other dietary intake data were collected from food records created by the Technology Assisted Dietary Assessment (TADA) application. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin concentrations in the fasting state (1) obtained from an oral glucose tolerance test (OGTT). Whole-body insulin sensitivity index (WBISI), and the oral disposition index (DI) were calculated from measures obtained during oral glucose tolerance testing(2, 3)</p></div></div></div><div><div><div><p> Statistical analysis was performed using SPSS software and included independent t-tests and Pearson correlations. Of the 48 participants included in this analysis, 59.2% were female, 32% were African American, 57% were white, and 8.2% were more than one race. The mean age was 16.20 ± 2.7 years, and 42% had prediabetes. Those with normoglycemia consumed 11.0 ± 5.1% of energy from added sugars, compared to 9.4±5.1% energy from added sugars for individuals with prediabetes. There was no significant correlation between HbA1c and percent calories coming from added sugar (R= -0.237, P=0.063), percent calories coming from added sugar and fasting blood glucose (R= 0.208, P= 0.090), or percent calories from added sugar and 2-hour glucose (R= 0.017, P= 0.457). There were no significant correlations found between percent calories from added sugar and HOMA-IR (R= 0.129, P= 0.234), percent calories from added sugar and WBISI (R= -0.069, P= 0.350), or percent calories from added sugar and DI (R= -0.118, P= 0.253). There were also no significant differences between the mean values of HbA1c, fasting glucose, or 2-hour glucose between individuals that consumed high vs. low amounts of added sugar, as measured by an independent t-test. The p-values were 0.634, 0.434, and 0.234 respectively. To examine the extent to which % calories from added sugar predicted variances in glycemic values, hierarchical multiple regression analyses were performed. Once energy, physical activity, BMI Z-Score, and age were entered into the model, % energy from added sugar accounted for an additional 9.6% variance in HbA1c. In conclusion, we did not find significant associations between consumption of added sugar and glycemic and insulin resistance or beta-cell function outcomes in adolescents who are obese, however our study lacked sufficient power. While our findings were not definitive, studies to identify dietary factors that promote or prevent hyperglycemia and insulin resistance are needed to inform dietary intervention strategies that may be effective at decreasing T2D in adolescents. </p> <p>12 </p> </div> </div> </div>

Type 2 diabetes (T2D) is a major public health issue worldwide and it currently affects nearly 26 million people in the United States. It is estimated that one third of Americans will have diabetes by 2050. T2D is a result of chronic insulin resistance and loss of beta-cell mass and function. Both in experimental animals and people, obesity is a leading pathogenic factor for developing insulin resistance, which is always associated with the impairment in energy metabolism, causing increased intracellular fat content in skeletal muscle, liver, fat, as well as pancreatic islets. Constant insulin resistance will progress to T2D when beta-cells are unable to secret adequate amount of insulin to compensate for decreased insulin sensitivity. In the present study, I investigated whether sulforaphane, a natural compound derived from cruciferous vegetables, can prevent high-fat (HF) diet-induced obesity and diabetes in C57BL/6 mice. Dietary intake of sulforaphane (250 mg/kg diet) prevented hyperglycemia and increased insulin sensitivity in HF diet-induced obese mice. Mice treated with sulforaphane had significant lower serum insulin levels (1.93±0.11 μg/dl) as compared to those without treatment (3.09±0.27 μg/dl, P<0.05). In second study, administration of sulforaphane (40 mg/kg body weight daily via gavage) in obese mice enhanced body weight loss and improved insulin sensitivity. Moreover, sulforaphane increased pyruvate oxidation by 28.85% (P<0.05) and enhanced fatty acid oxidation efficiency by 2.2 fold (P<0.05) in primary human muscle cells. These results suggest that sulforaphane may be a naturally occurring insulin-sensitizing agent that is capable of preventing T2D. / Master of Science

The striking similarity between Gestational Diabetes Mellitus (GDM) and Type 2 Diabetes (T2D) in terms of the pathophysiologies and the risk factors has led to the hypothesis that GDM is an early manifestation of T2D, expressed under the stress of pregnancy, and therefore both diseases should share similar susceptibility genes. GDM patients may provide a more homogeneous sample for the genetic causes of the disease than T2D, and therefore make a useful group for the identification of the genes involved. Over 200 GDM affected sib-pairs from 178 families were investigated, with parents available in 40% of cases. Genomic regions from 4 different chromosomes, 6, 8, 14 and 18 were chosen from regions that showed clustering for positive linkage scores in previous linkage studies on T2D and one control region on 13, where no previous positive linkage was reported. A total of 19 microsatellite markers were analysed for linkage to GDM using sib-pair analysis. Subset analyses were performed by ranking sib-pairs on GDM-related variables, e.g. mean BMI of sibs, age at GDM episode, etc. GENEHUNTER was run multiple times, each time including the next highest ranked family in the analysis. This gave a continuous range of scores where increasing or decreasing NPL scores indicated heterogeneity associated with different environmental factors such as age and weight. To evaluate the significance of the subset analyses, the results were compared to 10,000 permutations generated by randomly ranking the sib-pairs. Using the entire dataset, the analysis showed no significant linkage to a disease locus. Positive evidence for linkage was found with the subset analysis on chromosomes 8 and 14, suggesting heterogeneity between sib-pairs in the dataset. Marker D8S1742 on 8p23 showed an NPL score of 3.01 (p=0.001) when age at GDM diagnosis was used as a covariate. Using waist-to-hip ratio (WHR), marker D14S275 on 14q12 showed an NPL score of 2.474 (p=0.006). When adjusted for multiple testing, the results were not statistically significant for linkage to a diabetes disease locus, but gave evidence that GDM and T2D share similar genetic determinants, and defined groups of siblings for follow-up analysis of both types of diabetes.

No description available.

Current dogma suggests modulating or preventing amyloid assembly will prove critical to the armamentarium of therapeutic interventions that will likely be required to overcome the multifaceted pathology associated with amyloid diseases. The work described in this dissertation reveals substantial gains in understanding key aspects relating to the anti-amylin amyloid activities associated with both individual and broad groups of small molecule amyloid inhibitors. A main observation was the important role that the catechol functional group plays in modulating and preventing amyloid formation. In this context, each chapter provides unique yet complementary mechanistic insight that delineates a wide range of anti-amyloid activities associated with preventing amylin amyloid formation by mainly catechol-containing structural scaffolds. Structure activity studies show that the catechol moiety present within baicalein, oleuropein and rosmarinic acid are critical for their anti-amyloid functions, including exerting cell rescue effects against amylin induced cytotoxicity. We also demonstrate that in general, autoxidation enhances the anti-amyloid potency associated with many catechol containing amyloid inhibitors that may be mechanistically linked to a covalent mode of action. For example, we demonstrate that the O-quinone form of baicalein conjugates with amylin via a Schiff base mechanism. In contrast, we also show that catechol mediated formation of protein denaturant resistant aggregates, which requires autoxidation and that also stems from a predicted covalent mode of action, does not necessarily correlate with the enhanced anti-amyloid activities that occur upon catechol autoxidation. Regardless of the chemical mechanism(s) that drive catechol mediated anti-amyloid activity in vitro, the observed cell rescue effects exhibited by catechol containing molecules against amylin amyloid induced cytotoxicity is congruent with several recent in vivo studies that indicate polyphenols prevent toxic amyloid deposition as well as decades of population based studies that show regular consumption of diets rich in polyphenols are linked to a reduce incidence of age-related neurodegenerative amyloid disease. Indeed, advances in structure based drug discovery against amyloid formation may provide new avenues to optimize various catechol containing scaffolds that could be readily leveraged into improving diagnostic tools or perhaps accelerate the effort of discovering anti-amyloid therapeutics. / Ph. D.

Population health data suggests that the development of metabolic disease is influenced by early life events. Gestational diabetes (GDM) is a common complication of pregnancy, but its effects on the offspring are poorly understood. It is hypothesized that a diet high in fat and sucrose will cause excessive weight gain and obesity during pregnancy accompanied by hyperglycemia and hyperinsulinemia that are characteristic of GDM. It is also hypothesized that gestational exposure to GDM will cause obesity, hepatic steatosis and insulin resistance in the offspring when compared to the offspring from metabolically healthy, lean mothers.

It is estimated by the World Health Organization (WHO) that 422 million people had diabetes worldwide in 2014, including 30.3 million people in the US. The cost of treating the disease is has tripled from 2003-2013 due to the increased number of patients. One of the genes strongly associated with type 2 diabetes (T2D) is the transcription factor 7 like 2 (TCF7L2). A single nucleotide polymorphism (SNP) of the TCF7L2 results in increased expression of long chain acyl-CoA synthetase 5 (ACSL5) while deletion of this part of the TCF7L2 gene reduces ACSL5 mRNA level. The regulation of ACSL5 gene expression by the high risk TCF7L2 allele highlights the importance of investigating the role of ACSL5 in T2D. ACSL5 is one of a family of enzymes that activates FA to its CoA ester and is required for FA metabolism within cells. Mice lacking this protein have reduced fat mass and are more insulin sensitive. Chronic exposure of clonal pancreatic ß-cells to excess nutrients has been shown to result in increased intrinsic lipid droplets, reduced insulin content, a left-shift in glucose dose-dependent insulin secretion curve characterized by basal insulin hypersecretion (IH) and blunted glucose stimulated insulin secretion (GSIS). We tested the hypothesis that the use of a putative ACSL5 inhibitor (Adipo C) can reduce accumulated lipid droplets, rescue insulin content and reverse the left-shift in glucose dose-dependent insulin secretion curve. INS-1 (823/13) cells were cultured in either 4 mM or 11 mM glucose media representing physiological and excess nutrients environment. Adipo C (10-25 µM) was added to cells to both acutely (2 hrs) and chronically (72 hrs) inhibit ACSL5 activity. Thin layer chromatography with C11 Bodipy fatty acid (BFA) was used to detect acute fatty acid incorporation into neutral lipids. Nile red was used to visualize intrinsic lipid droplets inside cells. Intracellular Ca2+ activity was detected using fura 2. Insulin assay was measured by HTRF. Acute fatty acid incorporation and lipid accumulation were reduced in cells exposed to Adipo C. An Adipo C concentration dependent right shift of glucose dose-dependent insulin release and increased insulin content were observed. 11 mM glucose cells cultured in 25 µM Adipo C showed decreased intracellular Ca2+ activity at 3 mM glucose and increased Ca2+ activity at 12 mM glucose, which are characteristic of cells cultured in 4 mM glucose having reduced lipid stores. These results all indicate possible protective effects on -cells exposed to excess nutrients. Islets of T2D patients who have a physiologically elevated blood glucose level are exposed to a similar excess nutrient environment. Therefore, the results illustrated here warrant further research on Adipo C compound to explore its therapeutic potential on T2D.

Glycemic control in patients with type 2 diabetes (T2D) can be achieved through potentiation of the signalling by glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both incretin hormones have been traditionally characterized to be secreted by distinct enteroendocrine cells within the gut in response to nutrients. Signalling through the incretin receptors stimulates islet hormone release by potentiating glucose-stimulated insulin secretion from the β-cell and decreasing glucagon secretion from the α-cell. However, the bioactivity of GLP-1 and GIP is controlled by post-translational, N-terminal cleavage by the widely expressed serine protease dipeptidyl peptidase 4 (DPP4). As such, DPP4 inhibitors (DPP4i) have been successfully used to treat millions of patients with T2D. DPP4i target the catalytic active site of DPP4 and prevent the cleavage of the incretin hormones, thus prolonging their action. Recently, studies in genetically modified mice have demonstrated that GLP-1 is not solely an intestinally-derived peptide hormone and proposed that islet-derived GLP-1 is required for proper glucose homeostasis. Therefore, with the current study, we sought to assess whether β-cell-derived DPP4 is an important target for the regulation of glycemia. Treatment of Glp1r/Gipr^(β-cell-/-) mice with the DPP4 inhibitor sitagliptin demonstrated that β-cell incretin receptor signaling is required to mediate the beneficial effects of this class of drugs on glucose homeostasis. Additionally, Dpp4^(-/-) mice exhibited a significant reduction in hepatic glucose production during hyperinsulinemic-euglycemic clamps. Dpp4 mRNA, DPP4 protein and activity are present in isolated mouse islets, further supporting the islet as an important potential site of DPP4i action. In this study, we show that both DPP4i-treated wildtype islets and islets isolated from Dpp4^(β-cell-/-) mice exhibit increased glucose-stimulated insulin secretion (GSIS) during perifusion after a high-fat diet feeding. Genetic elimination of Dpp4 from islet β-cells also improved oral glucose tolerance and insulin sensitivity in female mice, but had no effects on circulating DPP4 or incretin levels. Finally, eliminating Dpp4 from β-cells or the whole pancreas did not improve whole-body glucose tolerance, response to DPP4i, insulin tolerance, or body weight in male mice fed chow or a high-fat diet. Therefore, we provide evidence for islet-derived DPP4 to have a role in local hormone responses to glucose; however, its role in systemic glucose metabolism is shown to be sex-dependent.

The prevalence of type 2 diabetes (T2D) continues to rise and is predicted to increase to 30 million people by 2030 in the United Sates alone. African Americans (AA) have one of the highest prevalence rates of T2D among all ethnic groups. African American Women (AAW) are 100% more likely to develop T2D compared with their white counterparts. The aim of this study was to quantitatively investigate the relationship of the perceptions of AAW not previously identified that could lead to a reduction in risk of T2D among AAW. A cross-sectional study of 183 AAW 20 to 65 years old was conducted to identify any correlation among the variables, using validated surveys. The participants were recruited via flyers and online. The health belief model and the theory of planned behavior served as the theoretical framework. Spearman's rho correlation was used to determine the strength of the correlations. The majority of respondents had moderate to high lifestyle and behavior changes relative to diet (59%) and blood sugar testing (93%), as well as low participation for exercise (62%). The majority of the AAW had low awareness of T2D severity (72%), low interference to daily activities (88%), and low social support for diabetes management (74%). A significant correlation was observed between healthy diet and severity, interference, outcome expectancies, and self-efficacy (p < .001). A significant relationship was found between exercise and severity, interference, outcome expectancies, and self-efficacy (p < .001). This study may inspire social change by creating awareness among healthcare workers regarding educational resources, environmental changes, and community interventions to reduce the economic burden associated with health care costs, to mitigate T2D, and to reduce health disparity.

Most research on human pancreatic islets is conducted on samples obtained from normoglycaemic or diseased brain-dead donors and thus cannot accurately describe the molecular changes of pancreatic islet beta cells as they progress towards a state of deficient insulin secretion in type 2 diabetes (T2D). Here, we conduct a comprehensive multi-omics analysis of pancreatic islets obtained from metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum, from normoglycemia to T2D. We find that islet pools isolated from surgical samples by laser-capture microdissection display remarkably more heterogeneous transcriptomic and proteomic profiles in patients with diabetes than in non-diabetic controls. The differential regulation of islet gene expression is already observed in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive, but disharmonic, remodelling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or transdifferentiation stages in T2D. Furthermore, through integration of islet transcriptomics with preoperative blood plasma lipidomics, we define the relative importance of gene coexpression modules and lipids that are positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.