Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy

Abstract

Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat. This disease is associated with hypertriglyceridemia, hepatic steatosis, and severe insulin resistance that often results in diabetes (1-3). Shimomura et al. have demonstrated that leptin treatment reversed insulin resistance in a fat-specific aP2-SREBP-1c knockout mouse model of congenital generalized lipodystrophy (4). More recently, Arioglu Oral et al. found that human recombinant leptin therapy reduced hyperglycemia and hypertriglyceridemia and increased the rate of glucose disappearance during an intravenous insulin tolerance test in nine lipodystrophic patients (5). In order to definitively examine whether or not leptin treatment might improve insulin sensitivity in these patients, as well as the potential mechanism, we studied a subset of three of these patients before and after leptin treatment. Insulin sensitivity in liver and muscle was assessed by a hyperinsulinemic-euglycemic clamp study performed in conjunction with [6,6-2 H 2 ]glucose turnover measurements, and patient responses were compared with those of a group of age-and weight-matched control subjects. In addition, the effects of leptin treatment on fat metabolism were assessed by measuring rates of wholebody lipolysis, as assessed by [ 2 H 5 ]glycerol turnover measurements before and after leptin treatment, along with 1 H NMR measurements of liver and muscle triglyceride content.