An examination of the contribution of visceral adiposity to insulin resistance in humans.

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The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has particular importance. Visceral fat cells are different to other fat cells; they are very metabolically active and 'spill out' fatty acids indiscriminately contributing to insulin resistance in liver and muscle; they also produce hormones which may modify the action of insulin. We will study people undergoing abdominal surgery. Participants will be (1) normal weight and sensitive to insulin, (2) abdominally overweight and insulin resistant, (3) insulin resistant with Type 2 diabetes. We will document abdominal fat, circulating lipid and hormone levels and insulin action. At surgery fat biopsies will be obtained from (a) inside the abdominal cavity, (b) the fat layer under the abdominal skin and (c) fat in the buttock. The activity of a large number of genes in the fat tissue will be assessed in 8 subjects using DNA array (4 each from Groups 1 and 2). Then a small number of genes will be selected on the basis of different activity in visceral fat from buttock fat, and between insulin sensitive and insulin resistant people. The activity of these genes will be determined in all subjects in the 3 groups. We anticipate identifying a few (perhaps 3) genes whose activity is closely associated with insulin resistance and will examine their capability to block insulin action in a series of animal and cellular studies. These studies should identify specific mechanisms by which visceral fat creates insulin resistance. This would be an important step towards prevention and improved medication for Type 2 diabetes.