Masters Theses

Date of Award

8-2006

Degree Type

Thesis

Degree Name

Master of Science

Major

Nutrition

Major Professor

Jung Han Kim

Committee Members

James W. Bailey, Lisa Jahns

Abstract

Over the past 20 years, a major shift in the type 2 diabetes mellitus (T2DM) epidemic has occurred. Even though the etiology of T2DM has not yet been discovered, insulin resistance, associated with plasma lipid and lipoprotein abnormalities, has shed light to this chronic disease. According to the Centers for Disease Control and Prevention (CDC), 97% of individuals with diabetes have one or more plasma lipid abnormalities, including decreased high density lipoprotein (HDL) cholesterol, a predominance of small dense low density lipoprotein (LDL) particles and hypertriglyceridemia (HTG). Diabetic patients often develop hyperlipidemia at the early stage of the disease and often before the onset of overt hyperglycemia (diabetes). It is also well established that the prevalence of T2DM in theUnited Statesisassociated with increased prevalence of obesity. The therapeutic plan for T2DM begins with modifications of lifestyle, such as physical activity, changes in diet, weight loss, and smoking cessation (2005 American Diabetes Association clinical guidelines). This is often concomitant with pharmacological therapy. Statins, fibrates, niacin, and thiazolidinediones are commonly used to treat dyslipidemia associated with insulin resistance and T2DM.

The TALLYHO/Jng (TH) mouse strain is a newly established polygenic inbred model for T2DM that shows obesity, hyperinsulinemia, insulin resistance, hyperglycemia (males), and dyslipidemia with the early onset of HTG. Previous work in this laboratory has revealed that insulin resistance is profoundly associated with HTG in TH male mice. The aim of the present study was to characterize the pathogenesis of HTG in TH mice and test the hypothesis that lowering the plasma lipid levels will improve insulin resistance and glucose metabolism in this model.

In vivo studies indicated that the very low density lipoprotein-triglyceride (VLDL-TG) production from liver was not significantly altered in TH mice compared to control B6 mice. On the other hand, TH mice showed a significantly increased residual percentage of injected [3H] TG- labeled VLDL at all sampling times compared to B6 mice, indicating slower VLDL-TG clearance rate in TH mice. In support of the slowed VLDL-TG clearance rate in TH mice, we found evidence of hepatic over-expression of the Apo C-III gene in TH mice compared to the age- and sex-matched B6 mice. Finally, addition of a drug bezafibrate, known to selectively lower plasma lipid levels without changing plasma glucose levels, to the diet significantly reduced plasma TG concentrations in both B6 and TH mice. Despite the remarkable decrease in plasma TG levels, either glucose tolerance or uptake was not improved in TH mice.

In summary, the HTG appears to be due to a defect in triglyceride-rich lipoprotein clearance in TH mice, and overproduction of Apo C-III may be in part involved in the pathogenesis. Further, the HTG is not likely the primary defect for the impaired insulin action in TH mice. These results shed light on the mechanism underlying the HTG in obese type 2 diabetic TH mice, which may contribute to understanding the pathophysiology of diabetic HTG in humans and ultimately provide biochemical targets for the intervention.

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