Patients with non-insulin-dependent diabetes mellitus (NIDDM) usually exhibit a marked disturbance of lipid metabolism which is reflected in high levels of plasma total cholesterol, low-density lipoproteins (LDL), and triglycerides, along with low levels of high-density lipoproteins (HDL). Elevated triglycerides are the major contributor to diabetic hyperlipidemia. These plasma lipid concentrations and the fatty acid composition of these lipids are clearly influenced by the type of diet consumed along with the proportion of dietary fatty acids. Therefore, it was the purpose of this investigation to examine the relationships between glycemic control, serum lipid levels of total cholesterol, HDL, LDL and triglycerides to the amounts and types of fats in the typical diets of NIDDM patients as compared to non-diabetic individuals. The dietary fats were also compared with the distribution of fatty acids found in their total lipids and free (in vivo) fatty acids. The relationship between dietary fat intake and serum total lipid levels along with total and free fatty acid distributions was the primary focus.This investigation found that NIDDM subjects have significantly greater triglyceride levels (200 ± 18.4 mg/dL) than non-diabetic controls (93 ± 13.2 mg/dL). Total and LDL cholesterol levels of the NIDDM group were elevated from the control group while HDL levels were depressed, but these differences were of nonsignificant proportions. The NIDDM group typically consumed significantly lowered amounts of teal, saturated, and monounsaturated dietary fatty acids (46.7 ± 7.1 grams, 114.0 ± 2.9 grams, and 16.8 ± 2.5 grams, respectively) compared to the control group (80.0 ± 10.9 grams, 26.7 ± 4.5 grams, and 30.2 ± 4.5 grams, respectively). Even so, the percentage of kilocalories from total fat in the NIDDM vs. the control group diets was not statistically different which may explain the lack of significance between groups with regard to distribution of serum fatty acids. On an individual basis, the types of fat that predominated in the diet were also found in a large percentage in the serum lipid distributions. Positive correlations between saturated fat intake and the blood serum stearic free fatty acid along with polyunsaturated fat intake and linoleic free fatty acid supported this observation. Other investigators (6,62) have reported that dietary intake does indeed contribute to the percentage of fatty acids distributed in the plasma lipids. To determine if a particular dietary fatty acid contributes more significantly to hyperlipidemia, the diet needs to be controlled.On an individualized basis, it was also noted that the diabetics with the lowest amount and percentage of fat in their diets, also had the lowest serum lipid levels. Besides diet, other influential factors which may have contributed to the lipid levels of these NIDDM patients are genetic predisposition, environmental influences, and the stage and progression of each individual's disease. Thus, due to the underlying metabolic impairments which are exacerbated by genetic and/or environmental influences, it is of vital importance to recognize how essential diet manipulation is with regards to lipid control in the treatment of NIDDM patients. / Department of Biology

In type II diabetes, systemic metabolism is perturbed and on a cellular level the balance of fuel use is upset. More specifically, increased fatty acid use is seen alongside decreased glucose metabolism. This altered fuel use is mediated by changes in the activity and expression of multiple enzymes. One such enzyme within the glucose breakdown pathway is pyruvate dehydrogenase, whose activity is known to be reduced in the diabetic state. The field of real-time metabolic investigation has rapidly expanded over the past few years due to the invention of technology that has enabled the production of ¹³C labelled hyperpolarised compounds, which can generate high signal levels in magnetic resonance spectroscopy. This has provided the opportunity to measure real-time metabolism of injected hyperpolarised tracers both ex vivo and in vivo. This thesis aimed to develop the use of hyperpolarised compounds in vivo, to investigate the cardiac and hepatic metabolism of a diabetic rat model. We initially addressed the systemic nature of the disease by establishing a two-slice acquisition for obtaining cardiac and hepatic data during a single injection of hyperpolarised pyruvate. This was tested in the fed and fasted states before being used in the studies described in the subsequent chapters of this thesis. The value of hyperpolarised compounds in following metabolic modulation by drug treatment was explored in the next chapter. The effect on metabolism of two drugs targeted at pyruvate dehydrogenase, which differed in their isoform specificity, was investigated first in the perfused heart and subsequently in vivo, both in control and diabetic animals. Hyperpolarised magnetic resonance spectroscopy was combined with other established techniques to help both our understanding of the systemic changes that had occurred following treatment, and provide links between cardiac metabolism and function. The final chapter of this thesis explored the use of hyperpolarised ¹³C pyruvate to understand the effect of hypoxia on pyruvate dehydrogenase, firstly in healthy animals and subsequently in the diabetic, metabolically altered state. Understanding the combination of diabetes and hypoxia was interesting given the existence of several opposing metabolic effects seen in the two states. Overall this thesis has demonstrated developments in the use of hyperpolarised pyruvate that, when appropriately combined with other techniques, can yield valuable metabolic information, in terms of following disease progression, drug development, and understanding basic metabolism.