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. MethodsSubjects.Three patients with severe, generalized lipodystrophy (fasting leptin concentration less than 4 ng/ml) associated with diabetes were studied.Six healthy nonsmoking women of similar age, weight, and body mass index were studied as normal control subjects (Table 1).Lipodystrophic patient NIH-1.The patient designated NIH-1 was a 17-year-old Caucasian female with a severe form of acquired lipodystrophy associated with type 2 diabetes and severe hypertriglyceridemia (plasma triglyceride concentrations greater than 15,000 mg/dl).She exhibited hyperphagia, irregular menses, massive hepatomegaly, multiple xanthomas, and lack of any subcutaneous fat or features of secondary sexual development.Lipodystrophic patient NIH-3.A 26-year-old Caucasian female with congenital generalized lipodystrophy and moderate hypertriglyceridemia (plasma triglycerides approximately 1,200 mg/dl).Her diabetes was treated with metformin (500 mg twice a day) and insulin (25 units Humulin 70/30 subcutaneously at bed time).She had no history of hyperphagia and reported normal menstrual periods.