LIPID INTERACTIONS IN INSULIN SECRETION/SENSITIVITY

DESCRIPTION (Adapted from applicant's abstract): Non-insulin dependent diabetes is the most common form of diabetes and afflicts some 20 million people in the U.S. alone. The disease, which is generally associated with obesity, results in serious complications and is a major cause of premature death. It's public health and social costs are enormous. NIDDM is a polygenic disorder, which in its early stages is characterized by insulin resistance and hyperinsulinemia. In genetically susceptible individuals the pancreatic B-cell eventually becomes compromised, insulin output stagnates and the full blow picture of diabetes appears. It is generally believed that the underlying problem in the etiology of obesity/NIDDM syndromes is an inherited defect in muscle causing insulin resistance, and this in turn elicits compensatory hyperinsulinemia. The investigator believes the available evidence is more compatible with one or other of two alternative views; namely, that (i) both hyperinsulinemia and insulin resistance arise simultaneously from other primary defect; (ii) hyperinsulinemia is the earlier derangement and that this gives rise to insulin resistance. In either case, it is evident that hyperinsulinemia is a very early event. Recent data suggest that the availability of free fatty acids (FFA) is an important determinant of insulin secretion. They propose that excess FFA flux potentiates hyperinsulinemia and promotes excessive delivery of fat from liver to adipose tissue and muscle beds, resulting in hyperlipidemia, obesity and buildup of triglyceride in muscle. They further propose that elevated levels of fatty acyl-CoA and of fatty acid oxidation in muscle impair insulin-mediated glucose uptake, oxidation and storage as glycogen at this site. The investigators have recently develop a technique to specifically measure intramuscular glyceride content in humans and have validate the procedure in experimental animal models. The method, proton spectroscopy, is non- invasive and rapid. Previous studies have not found a relationship between muscle triglyceride content and insulin sensitivity. However, these measurements likely were confounded by contaminating adipose tissue. Using proton spectroscopy, the investigators plan to correlate insulin sensitivity with intramuscular triglyceride and rates of lipid oxidation in (lean and obese) normal and diabetic individuals genetically at risk for NIDDM. If the expected associations are confirmed, it is entirely possible that subjects at high risk for the development of NIDDm can be identified early and treated in such a way as to limit weight gain, improve insulin sensitivity, control hyperlipidemia and potentially forestall progression to frank diabetes.