Discordant metabolic actions of insulin in extreme lipodystrophy of childhood.
Congenital lipodystrophy includes a group of disorders characterized by total or partial absence of adipose tissue and insulin resistance. In this study we investigated the nature of insulin resistance in an 11-yr-old girl with one form of congenital lipodystrophy. We examined in vivo insulin and glycemic responses to feeding and iv glucose and in vitro amino acid and thymidine incorporation responses of skin fibroblasts to insulin exposure. In addition, we used stable isotope infusions of glucose, glycerol, and amino acids to investigate the in vivo metabolic actions of insulin on carbohydrate, fat, and protein. At 5 yr of age, she first demonstrated clinical glucose intolerance. Her basal insulin levels were normal (129 and 114 pmol/L), but increased markedly (peak values, 1304 and 5045 pmol/L) after iv glucose and a mixed meal. Insulin antibodies were undetectable, and specific [125I]insulin binding to her skin fibroblasts was normal. Both [3H]aminoisobutyric acid transport and [3H]thymidine incorporation by her fibroblasts were similar to responses obtained using control cells. At 11 5/12 yr of age, while receiving an infusion of stable isotopes, infusions of insulin at doses of 0.1 and 0.3 U/kg BW.h were ineffective in reducing her blood glucose despite elevating her serum insulin level to approximately 2500 pmol/L. Resting metabolic rate, respiratory quotient, VCO2, carbohydrate and lipid oxidation rates, glucose production rate, glycerol appearance rate, and plasma glycerol concentrations were unperturbed by the insulin infusions. By contrast, the insulin infusions reduced plasma leucine concentrations (124.2 to 86.1 to 66.7 mumol/L) and 13CO2 production rates (0.034 to 0.017 to 0.011 mumol/kg/min; baseline, 0.1, and 0.3 U insulin/kg.h, respectively). The leucine appearance rate declined (1.96 to 1.72 mumol/kg.min) in response to the 0.1 U/kg.h dose, but did not decline further in response to the 0.3 U/kg.h dose. The leucine oxidation rate also declined (0.87 to 0.39 to 0.25 mumol/kg.min), and there was a dose-related reduction in most plasma amino acid concentrations. Finally, nonoxidative leucine disposal increased progressively (1.09, 1.34, and 1.48 mumol/kg.min), suggestive of an insulin-induced increase in protein synthesis. These data indicate profound metabolic resistance to the carbohydrate and lipid actions of insulin, with preservation of protein anabolism. These observations suggest that in this patient, the biological effects of insulin on carbohydrate, lipid, and protein are distinct metabolic actions, regulated independently.