This research proposal has three major aims. The first is to define the relationship between resistance to insulin-stimulated glucose uptake, hyperinsulinemia, and the presence of small, dense low density lipoprotein (LDL). There is reason to believe that the latter change, which has been associated with increased risk of coronary heart disease (CHD) is a consequence of insulin resistance and hyperinsulinemia, and an effort will be made to demonstrate this relationship in family studies of healthy individuals, patients with various dyslipidemic syndromes, and patients with non-insulin- dependent diabetes mellitus (NIDDM). The second major aim of this proposal is to test the hypothesis that the low fat, high carbohydrate diets recommended in the treatment of NIDDM will increase the postprandial concentration of chylomicron and chylomicron remnants in these patients. Since these particles appear to be atherogenic, and CHD is the major cause of morbidity and mortality in NIDDM an answer to this question is essential to devise a dietary approach to decrease the risk of CHD in this patient population. The third major goal of this research proposal is to evaluate the role that insulin resistance and hyperinsulinemia play in blood pressure regulation and the dyslipidemia associated with hypertension. In order to accomplish this task, normotensive individuals, who have a family history of hypertension and are slightly obese, will be studied. These individuals are both at increased risk to develop high blood pressure and likely to be insulin resistant. They will be studied on a low carbohydrate diet, during which time they will have low plasma insulin levels, as well as when hyperinsulinemia has been produced by a high carbohydrate diet. It is postulated that the hyperinsulinemia produced by the high carbohydrate diet will lead to sodium retention, an increase in blood pressure, and an increase in plasma triglyceride and a decrease in plasma high-density lipoprotein concentration. In summary, the experiments outlined in this research proposal will evaluate three possible ways in which resistance to insulin- stimulated glucose uptake and compensatory hyperinsulinemia may increase risk of CHD.
| Stuhlinger, Markus C; Abbasi, Fahim; Chu, James W et al. (2002) Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287:1420-6 |
