The incidence of diabetes mellitus and cardiovascular diseases is increasing at a worrisome rate globally. Diabetes mellitus is known to occur due to high blood glucose levels, caused by defects in insulin levels. Adult on-set type II diabetes, which is closely associated with obesity, is reported to be 90-95% of all diabetic cases and linked to diet and lifestyle factors. A large population of the developed and developing countries is now being effected by this epidemic. Natural sources of phenolic antioxidants and inhibitors of digestive enzymes from food sources have potential for low cost dietary management of type II diabetes. Therefore, the main focus of this study was to evaluate, develop and design effective dietary strategies based on a combination of Chilean potatoes and herb synergies for the management of hyperglycemia and hypertension linked to type II diabetes. Antioxidant, antihypertensive and anti-hyperglycemic potentials of Chilean potato (Solanum tuberosum ssp. tuberosum L.), herbs from the Apiaceae (Dill, Ajowan, Fennel, Caraway, Coriander and Anise) and Lamiaceae (Sage and Marjoram) families were evaluated, with a goal to target a new dietary management strategy for early stages of type II diabetes through lowering of hyperglycemia and related complications of hypertension The results indicated a high correlation between total phenolic content and total antioxidant activity in several Chilean potato varieties evaluated, which indicates that certain phenolic compounds may be responsible for high antioxidant activity. Also, certain varieties of Chilean potato had antihypertensive potentials, with ACE inhibition upto 88%. The -glucosidase inhibition relevant for hyperglycemia management for Apiaceae family ranged upto 50% (Dill) for aqueous extracts. A high correlation (r = 0.86) was observed between -glucosidase inhibition and total phenolic content for aqueous extracts of all species investigated in the Apiaceae family. A high rosmarinic acid activity was observed in aqueous extracts of Lamiaceae family, which ranged upto 39.7 mg/g of sample dry weight (DW). This suggests that high phenolic content and associated antioxidant activity found in sage and marjoram is dominated by rosmarinic acid. High enzyme inhibitory activities, reflecting in vitro anti-hyperglycemic and anti-hypertensive potentials indicates that consumption of these food sources in our diet would prove to be beneficial towards our health. Further in vivo studies for type II diabetes-linked functionalities of these natural sources of antioxidants and inhibitors would confirm the human health benefits achieved through dietary intake.

Objective: Atherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s). Methods and Results: Wild-typemice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less a-SMA-positive area) and had more inflammation (increased plasma IL-1b level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemicmice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks. Conclusion: We established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.

Diabetes mellitus is the most well-known endocrine dilemma suffered by hundreds of million people globally, with an annual mortality of more than one million people. This high mortality rate highlights the need for in-depth study of anti-diabetic agents. This review explores the phytochemical contents and anti-diabetic mechanisms of (cucurbitaceae). Studies show that contains several phytochemicals that have hypoglycemic effects, thus, the plant may be effective in the treatment/management of diabetes mellitus. Also, the biochemical and physiological basis of anti-diabetic actions is explained. exhibits its anti-diabetic effects via the suppression of MAPKs and NF-κβin pancreatic cells, promoting glucose and fatty acids catabolism, stimulating fatty acids absorption, inducing insulin production, ameliorating insulin resistance, activating AMPK pathway, and inhibiting glucose metabolism enzymes (fructose-1,6-bisphosphate and glucose-6-phosphatase). Reviewed literature was obtained from credible sources such as PubMed, Scopus, and Web of Science.

Introduction: Diabetes Mellitus is a metabolic disorder that affects a person’s ability to either produce insulin (Type I diabetes mellitus) or properly use insulin (Type II diabetes mellitus) in order to maintain adequate blood glucose levels. The most severe diabetic complications arise due to hyperglycemia – a state of extremely high blood glucose levels – such as, coronary artery disease (CAD), in which coronary stent therapy is a popular method of treatment. However, research has shown a high rate of in-stent restenosis in diabetic patients with CAD, most likely due to activation of cellular adhesion molecules on endothelial cells exposed to the hyperglycemic environment. Blood vessel mimics (BVMs) have been researched as viable options for in vitro studies on vascular stents; thus, it would be beneficial to create an in vitro diabetic BVM for stent manufactures to evaluate and determine the root cause of the high failure rate of stents in the diabetic population. In addition, a diabetic BVM would help manufactures optimize coatings or stent configurations for diabetic patients. Methods: The purpose of this thesis was to take the initial steps towards the goal of a diabetic BVM. The first aim was to establish a procedure of developing glycemic cell media solutions of various glucose concentrations, and to establish a feasible method of monitoring the glucose concentration of the solutions. Glycemic cell media solutions were developed and their glucose concentrations were evaluated with a blood glucose meter (specifically, the Aviva Accu-Chek blood glucose meter) or visual blood glucose test strips (Glucoflex R visual blood glucose test strips). The second aim was to ensure that the developed glycemic cell media solutions could be monitored in a cell culture environment over time, and to determine if the hyperglycemic conditions induced any change to endothelial cells. Bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs) were used to evaluate glucose consumption and cell morphology. Glucose concentration of the cell media was recorded to evaluate glucose consumption, and the cells were evaluated under a microscope in order to determine cell morphology and an increase in cell death. Results & Conclusions: Data accumulated from the first set of experiments confirmed that glycemic cell media solutions can be developed by adding Sigma G6512 D-(+)-glucose to base cell media. Additionally, the Aviva Accu-Chek blood glucose meter recorded the most accurate and precise glucose concentrations of the various glycemic cell media solutions compared to the Glucoflex-R blood glucose visual test strips. Lastly, the series of experiments with BAECs and HUVECs confirmed that the glycemic cell media solutions could be effectively monitored over time, and that these conditions evoked higher glucose consumption by the endothelial cells compared to the normal glycemic cell media solutions. Additionally, neither glycemic environment evoked significant cell death. These results met the aims of this thesis, and therefore provide the foundation for further development of a diabetic BVM.

Consensus in scientific literature is that hyperglycemia, which is a condition that manifests in individuals with uncontrolled diabetes, causes compromised bone growth, but the exact mechanisms of are unknown. It has been estimated that 5% of dental implant failures that have previously been linked to unknown causes may be associated with undiagnosed diabetes. It is important to study the early stages of bone growth as it is accepted that they are critical in the long-term success rate of endosseous implants. This study aimed to investigate the bone healing seen in the hyperglycemic group compared to the normal (i.e. control) group, at an early time point, using high-resolution microscopy techniques. Ten young (200-250gram) male Wistar rats were used for this study with five rats assigned to the control group and the other five rats intravenously injected with 65 mg/kg of streptozotocin (STZ) to induce diabetes. An osteotomy model was used to make a 1.3mm defect in the diaphysis of the rat femurs. After five days, the femurs were removed, fixed in glutaraldehyde, dehydrated, and embedded in resin. Structural and chemical analyses were conducted on the samples using a variety of microscopy techniques to examine various factors of bone quality including: bone porosity, relative mineralization level, and the arrangement of collagen and mineral. When analyzing the micro-structure, the hyperglycemic group showed increased porosity in the newly formed bone as compared to the control group. However, no significant differences were found in the nano-structure when analyzing the arrangement of collagen and mineral.Therefore, the results in this thesis suggest that alterations in micro-architecture rather than nano-architecture may play a pivotal role in the compromised bone healing in uncontrolled diabetes at this five-day time point. Future work should investigate additional time points in the bone healing process. / Thesis / Master of Applied Science (MASc) / According to the International Diabetes Federation, 387 million people worldwide are living with diabetes of which 46.3% are undiagnosed. Uncontrolled diabetes results in hyperglycemia, which is a condition where there is an increased level of glucose in the blood. When diabetes is not regulated correctly with medication, it leads to problems in the long-term success rate of dental implants. The objective of this thesis was to investigate the early stages of bone formation, which are accepted to be critical in the long-term success rate of dental implants, in hyperglycemic animal models compared to control groups using various microscopy techniques. The different techniques used allowed for the structural and elemental compositions of bone to be studied on the micro-scale and nano-scale. It was shown that at the 5-day healing time point studied, the micro-structure, rather than the nano-structure, was negatively altered in the hyperglycemic group compared to the control group.

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This thesis intends to utilize biomechanics to study the endothelial biomechanical response in a static hyperglycemic microenvironment. Hyperglycemia is a diabetic condition with abnormally high levels of glucose in the bloodstream. The effects of hyperglycemia over time lead to vascular complications resulting in patients being more prone to cardiovascular diseases. Current studies have focused on the molecular mechanisms affected by hyperglycemia; however, the mechanical mechanisms by which hyperglycemia causes vascular structural and functional changes are understudied. Therefore, to study the effects of hyperglycemia in the endothelium, Human Umbilical Vein Endothelial Cells (HUVEC) were cultured under three glucose conditions: normal glucose (4 mmol/l D-glucose), high glucose (30 mmol/l D-glucose), and an osmotic control (4 mmol/l D-glucose + 26 mmol/l D-mannitol). To evaluate the biomechanical response, we used traction force microscopy and monolayer stress microscopy to measure the cell-substrate tractions and cell-cell intercellular stresses. For the RMS tractions, HUVEC monolayers exposed to high glucose decreased by 10%, while the osmotic control decreased by 17% compared to the normal glucose. HUVEC monolayers exposed to high glucose produced average normal stresses that were 53% lower than monolayers exposed to normal glucose, while the osmotic control decreased by 51% compared to the normal glucose. For the maximum shear stresses, HUVEC monolayers exposed to high glucose decreased by 20%, while the osmotic control decreased by 14% compared to the normal glucose. To conclude this study, we report that hyperglycemia lowers the biomechanical response in the endothelium compared to normal glucose conditions. These results will contribute to understanding the specific role hyperglycemia has on endothelial mechanics and its role in the progression and development of cardiovascular diseases in diabetic patients.

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<p>Please remove prior submission under the same title</p> / <p>Diabetes mellitus (DM) is associated with a significantly increased risk of microvascular complications, such as retinopathy, nephropathy, and neuropathy, as well as macrovascular disorders, including cerebro- and cardiovascular disease. Traditionally, the micro- and macro- vascular complications of DM have been considered distinct and independent disorders; however, data from several epidemiological and pathophysiological studies suggest they may be linked. It has been suggested that the <em>vasa vasorum</em>, a microvascular network which nourishes the walls of large muscular arteries, may play a role in macrovascular atherosclerosis. The effect of hyperglycemia on the microvessels of the vasa vasorum, and the potential impact of these effects on macrovascular atherosclerosis are not known.</p> <p>Here, we use a multiple-low-dose streptozotocin (STZ) injected apolipoprotein-E deficient mouse model to investigate the effects of hyperglycemia on the vasa vasorum, and to correlate such effects to atherosclerotic plaque progression. Hyperglycemia significantly increased plaque size and necrotic area (3- and 4-fold, respectively) relative to controls by 15 weeks of age. However, the density of vasa vasorum microvessels in the aortic wall of hyperglycemic mice was reduced at each time point examined. A similar vasa vasorum deficiency was also seen in STZ-induced hyperglycemic C57Bl/6J mice and hyperglycemic Ins2^Akita mice, and microvessel density could be corrected by insulin-mediated glucose normalization, suggesting a hyperglycema-specific effect. A localized deficiency in VEGF appears to be responsible for the reduced neovascularisation. Lastly, hyperglycemic mice fed standard chow supplemented with benfotiamine, a drug used to treat microvascular disorders in DM, appear to have reduced atherosclerosis.</p> <p>These findings provide the first indication that, in addition to retinal and glomerular capillary beds, hyperglycemia alters the microvessel structure of the vasa vasorum. Such microvascular changes directly correlate to the development and progression of atherosclerosis in hyperglycemic ApoE-deficient mice.</p> / Master of Science (MSc)