This proposal is based on the belief that defects in insulin-mediated glucose disposal are closely related to abnormalities of insulin regulation of adipose tissue within an individual, and that these changes will have untoward consequences. The investigators plan to test the following four hypotheses: 1) non-diabetics who are resistant to insulin-mediated glucose disposal by muscle have a parallel defect in the ability of insulin to suppress adipose tissue lipolysis as assessed by free fatty acid turnover; 2) muscle insulin resistance in non-diabetic individuals is not secondary to enhanced tissue lipolysis and increased FFA concentrations, but is a manifestation of a more fundamental defect in insulin signaling; 3) glucose-induced pancreatic b-cell insulin secretion will be attenuated in non-diabetic subjects who have a defect in the ability of insulin to regulate adipose tissue lipolysis, and 4) abnormalities in the lipolytic response of adipose tissue and in pancreatic b-cell function associated with resistance to insulin-mediated glucose disposal in non-diabetic subjects will also be evident in non-diabetic first degree relatives of insulin resistant as compared to insulin sensitive individuals. To address these issues, 320 healthy, non-obese, non-diabetic volunteers will be recruited for a cross-sectional study in which they will quantify age, BMI, waist to hip ratio, insulin resistance, FFA turnover at basal and isoproterenol and with insulin suppression of isoproterenol lipolysis, and ad insulin secretion. They will additionally recruit 100 healthy nonobese nondiabetic first degree relatives of the probands; 50 from the highest and 50 from the lowest quartiles of insulin sensitivities. All measurements will be done on the relatives, also. Finally, measurements will be repeated in the 80 most insulin resistant probands after an increase in carbohydrate intake for 7 days. The results of the study should provide information to which defects in insulin mediated glucose disposal, lipolysis and insulin secretion occur together, the link between abnormalities, and role of familiarity.
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