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Cardiovascular disease is the most common cause of morbidity and mortality in type 2 diabetes. Short-term studies of glucagon-like peptide-1 (GLP-1)-targeted therapies suggest potential beneficial effects on cardiovascular outcomes. The mechanism behind this unexpectedly rapid effect is not known. In this study, full-length human GLP-1 receptor (GLP-1R) mRNA was cloned and sequenced from a human megakaryocyte cell line. Quantitative RT-PCR results showed that expression levels were comparable to other GLP-1R expressing tissues. Furthermore, incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in these cells. As megakaryocytes are the cellular precursors of platelets, the effect of GLP-1 and exenatide were studied in gel-filtered human platelet aggregation, where they were both shown to have an inhibitory effect on thrombin-stimulated platelet aggregation. Platelet inhibition by GLP-1 and GLP-1R agonists presents a potential mechanism for the reduced incidence of atherothrombotic events thought to be associated with GLP-1-targeted therapies.

Emerging evidence has shown that an abnormal postprandial accumulation of dietary tat IS atherogenic. The aim of this study is to measure triacylglycerol (TAG) kinetics in endogenous and exogenous lipoproteins in both fed and fasted states using stable isotopes.

Loss of glucose-stimulated insulin secretion (GSIS) from the pancreatic beta-cells is one of the earliest detectable defects in the pathogenesis of type 2 diabetes. However, despite its relevance, the mechanisms that govern GSIS are still not completely understood. ARNT/HIF-1β is a member of the bHLH-PAS family of transcription factors, with a prominent role in the transcriptional regulation of enzymes required for the metabolism of xenobiotics as well as regulation of genes that are critical for cellular responses to hypoxia. Recent research has uncovered a previously unknown function for ARNT/HIF-1β in the pancreatic beta-cells, where the gene was found to be 90% down-regulated in human type 2 diabetic islets and loss of ARNT/HIF-1β protein leads to defective GSIS in pancreatic beta-cells of mice. The main focus of this thesis was to understand the mechanisms by which ARNT/HIF-1β maintains normal GSIS from pancreatic beta-cells and understand how loss of ARNT/HIF-1β leads to beta-cell dysfunction and type 2 diabetes in mice. ARNT/HIF-1β was found to positively regulate GSIS in both INS-1 derived 832/13 cell line and mice islets. In the 832/13 cells, loss of ARNT/HIF-1β leads to a reduction in glycolysis without affecting the glucose oxidation and the ATP/ADP ratio suggesting that the regulation of GSIS takes place in a manner that is independent of the KATP channels. In order to further assess the mechanism of lowered GSIS in the absence of ARNT/HIF-1β in the 832/13 cells, a metabolite profiling was performed which revealed a significant reduction in the metabolite levels of glycolysis and the TCA cycle intermediates and glucose-induced fatty acid production, suggesting the involvement of ARNT/HIF-1β in regulating glucose-stimulated anaplerosis, which is believed to play a key role in the regulation of GSIS from the pancreatic beta-cells. The changes in metabolite levels in the absence of ARNT/HIF-1β were associated with corresponding changes in the gene expression pattern of key enzymes regulating glycolysis, the TCA cycle and fatty acid synthesis in beta-cells. In an attempt to understand how loss of ARNT/HIF-1β leads to beta-cell dysfunction and type 2 diabetes in mice, a pancreatic beta-cell specific ARNT/HIF-1β knock out mouse (β-ARNT KO) was generated using the Cre-loxP technology. Functional characterization of islets from both male and female β-ARNT KO mice revealed a significant impairment in GSIS, which was attributed due to a small, but significant reduction in rise in intracellular calcium upon glucose stimulation. Further analysis revealed reduced secretory response to glucose in the presence of KCl and diazoxide indicating a defect in the amplifying pathway of GSIS in β-ARNT KO islets. Expression of pyruvate carboxylase (PC) was significantly reduced in β-ARNT KO islets suggesting possible impairments in anaplerosis and consistent with this, defect in GSIS in β-ARNT KO islets could be almost completely rescued by treatment with membrane permeable TCA intermediates. Surprisingly, both male and female β-ARNT KO mice have normal glucose homeostasis. In an attempt to assess how β-ARNT KO mice maintained normal blood glucose levels, indirect calorimetry was used to understand changes in whole-body energy expenditure. This investigation revealed that β-ARNT KO mice exhibited a small but significant increase in respiratory exchange ratio (RER), suggesting a preference in utilizing carbohydrates as a fuel source, possibly leading to improved glucose uptake from the blood stream. Response to exogenous insulin was completely normal in β-ARNT KO mice suggesting intact functioning of the skeletal muscles. To conclude, based on our in vitro data, we believe that ARNT/HIF-1β plays an indispensable role in maintaining normal beta-cell secretory function, however, results from β-ARNT KO mice indicates that these mice are protected from the adverse effects of hyperglycemia. Although loss of ARNT/HIF-1β alone is not sufficient for the genesis of type 2 diabetes, it creates a perfect storm in the pancreatic beta-cells that may eventually lead to an imbalance in the whole body glucose homeostasis. Our study provides significant information to the scientific community that engages in assessing the pharmacological potential of gene targets for the treatment of type 2 diabetes.

Both type 2 diabetes (T2D) and the the metabolic syndrome (MetS) have been shown to increase the risk of cardiovascular disease (CVD). Inflammation and insulin resistance have each been associated with the development of MetS and the onset of T2D as well as the risk of CVD. Inflammation and insulin resistance are therefore suitable targets for public health initiatives and interventions in persons at risk for or living with CVD. Physical inactivity is a major risk factor for CVD as well as MetS and T2D. Conversely, increased physical activity is associated with improved health outcomes for individuals with a high risk for developing CVD. Two possible mechanisms for the deleterious effects of inactivity on health are inflammation and insulin resistance. Researchers have hypothesized that increased adiposity and reduced fitness are partially responsible for the associations between inactivity, inflammation, and insulin resistance. However, these relationships have not been studied extensively in overweight/obese individuals, who are often unfit and sedentary. The purpose of this study was to further examine the relationship between baseline measures of walking activity and sedentary behavior, and inflammation and insulin resistance in a sample of adults with type 2 diabetes and/or metabolic syndrome. This thesis examined baseline data from participants enrolled in either of two studies of patients with T2D (n = 116) or MetS without T2D (n = 126). Participants included low income men and women (not pregnant or nursing) between the ages of 18 and 70 who either show depressed affect (BDI > 11), and were overweight (BMI ≥ 27 kg/m2) and had type 2 diabetes or had at least 3 components of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) classification of the metabolic syndrome (MetS). Structural equation modeling was used to determine if physical inactivity is associated with inflammation or insulin resistance in these conditions. Possible mediational roles of adiposity and low cardiorespiratory fitness were also examined. Additional analyses were conducted to determine if these relationships can be estimated equally in MetS and T2D conditions. Activity was indirectly related to abdominal adiposity via an indirect, positive association with cardiorespiratory fitness. Abdominal adiposity was positively related to both inflammation and insulin resistance. There were no direct associations between activity and inflammation or insulin resistance in this population. Therefore, walking may be negatively related to cardiovascular risk, insofar as it reduces abdominal adiposity.

Due to the increase in type 2 diabetes in the child and adolescent population, examining the lifestyle habits of youth has become important. The purpose of this research was to examine the presence of dietary and physical activity risk factors for type 2 diabetes among youth in Alberta and to evaluate their relationship with insulin sensitivity. Lifestyle habits of Alberta youth with type 2 diabetes (n = 28), and age, sex and BMI matched controls (n = 28) were assessed by a chart review method. Those with diabetes had a higher intake of several nutrients (i.e. protein intake) and were less likely to be physically active. Dietary and physical activity risk factors for diabetes of a large sample of Alberta youth (n = 4981) were also assessed using the Web Survey of Physical Activity and Nutrition (Web-SPAN) and insulin sensitivity was measured in a sub-group (n = 318) using a C-13 glucose breath test. High Glycemic Index (GI) and Glycemic Load (GL) diets were common among Alberta adolescents and dietary patterns associated with dietary GI and GL were assessed. Dietary and physical activity risk factors for type 2 diabetes, including overweight and obesity, high GI, high GL, low fibre, low magnesium, low vegetable and fruit intake, high fat intake and low physical activity levels, were commonly reported among Alberta teens; with some risk factors, such as low fibre intake and high GI being reported by over half of all participants. Youth reported having an average of 3 diabetes risk factors. Boys reported more risk factors than girls, older students reported more risk factors than younger students and students with a higher BMI reported more risk factors than students with a lower BMI. Age, sex, BMI and dietary GI were associated with Insulin Sensitivity Score as measured by a C-13 glucose breath test. In summary, this research has shown that the dietary and physical activity habits of Alberta adolescents are sub-optimal for type 2 diabetes prevention and the relationship between diabetes risk factors and insulin sensitivity in this group suggests that these behaviours are related to early changes in carbohydrate metabolism. / Nutrition and Metabolism

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abstract: This study examined the effect of consuming pinto, black, and dark red kidney beans with white rice in comparison to a white rice only control meal on the glycemic response of adults with type 2 diabetes (T2D). These bean and rice combinations are part of many traditional diets. Seventeen subjects with T2D treated by diet and/or metformin were randomly assigned to 4 treatments: white rice (control), pinto beans/rice, black beans/rice, and dark red kidney beans/rice. All treatments were portioned by weight and matched for available carbohydrate content of &sim; 50 grams. Capillary whole blood samples were collected at baseline and at 30, 60, 90, 120, 150 and 180 minutes posttreatment and assessed for glucose concentration using the YSI Stat Plus Analyzer. Net change glucose responses were significantly lower for the pinto, black, and dark red kidney bean and rice meals than control at 90, 120 and 150 minutes posttreatment (P < 0.05). Incremental area under the curve (iAUC) values were also significantly reduced for the bean/rice meals containing pinto (P < 0.01) and black beans (P < 0.05) in contrast to the rice control. Results suggest that the combination of whole beans and rice may be beneficial to those with T2D to assist with blood glucose management. / Dissertation/Thesis / M.S. Nutrition 2011