Early perturbations in lipid metabolism in insulin resistance

Abstract: Subjects with the Metabolic Syndrome with or without type 2 diabetes are at excess risk for developing cardiovascular disease. The mechanisms are still not completely understood. Resistance to insulin-stimulated glucose uptake is associated with several metabolic and hemostatic risk factors for cardiovascular disease. Heredity for type 2 diabetes is associated with insulin resistance and increased risk for type 2 diabetes. Therefore, relatives of type 2 diabetic patients are important to study in order to understand the early perturbations associated with insulin resistance before type 2 diabetes develops. The aims of this thesis were: 1) To study insulin resistance and early clinical manifestations of the pre-diabetic state. (Paper I); 2) To characterize the postprandial triglyceride-rich lipoprotein (TRL) metabolism in the same study population (Paper II); 3) To study the effect of an enhanced first-phase insulin secretion on postprandial TRL metabolism (Paper III). First-degree relatives of type 2 diabetic patients were studied in all three papers, only men in papers I and II. In papers I and II, the men were pair-wise matched to male control subjects, lacking known diabetes heredity, for fasting triglycerides, BMI and age. The methods included hyperinsulinemic euglycemic clamp, intravenous glucose tolerance test, computerized tomography, physical capacity test (peak VO2), 7-day food record and a fat-rich meal tolerance test with density ultracentrifugation and apoB assessment. Healthy men with heredity for type 2 diabetes were characterized by insulin resistance along with an impaired relative insulin secretion. There were no detectable differences in body composition, dietary intake or physical capacity between the groups. The strongest phenotypic predictors for the insulin resistance seen in this non-obese population were fat accumulation in the liver, heredity for type 2 diabetes and low physical capacity. Further, postprandial accumulation of large TRL (VLDL1, Sf 60-400) from both liver and intestine was shown to represent yet another early facet of insulin resistance. The large TRL from the liver were inversely related to insulin sensitivity and small dense LDL. Augmenting the insulin secretion pharmacologically did not reduce the postprandial TRL response. In conclusion, insulin resistance in men with heredity for type 2 diabetes is seen in the absence of increased abdominal or total fat mass, along with an impaired relative insulin secretion. Enhanced postprandial concentrations of large TRL from both liver and intestine were found to represent a novel, and early, clinical manifestation in insulin resistance. Longitudinal studies are warranted to elucidate whether postprandial dyslipidemia contributes to the increased risk for cardiovascular disease in insulin-resistant states.