Insulin resistance in total lipodystrophy: evidence for a pre-receptor defect in insulin action

The cause of insulin resistance in lipodystrophic diabetes is unknown but has generally been ascribed to dysfunction at either the receptor or post receptor level. In a 14 year-old girl with total acquired lipodystrophy, subcutaneous and intravenous insulin requirements approximated 600 units daily. However, circulating total and free insulin levels were not increased, and during testing by the euglycemic clamp method, the glucose response to increasing free insulin concentrations was within the range found in eight subjects with insulin-dependent diabetes. Insulin clearance during the euglycemic clamp was 43, 98, 115, and 116 mL/kg/min at each of four insulin infusion rates compared to means of 13, 13, 12, and 11 in the control subjects with diabetes. No detectable degrading activity was present in serum, and serum inhibited insulin degradation normally. Binding of insulin to IgG, IgM, and IgE was not increased, insulin binding to monocytes and erythrocytes was not sufficiently abnormal to account for the the insulin resistance, and insulin receptor increased insulin clearance or accelerated degradation of insulin by tissues.