OBJECTIVE Leptin administration may directly modulate pancreatic -cell function in leptin-deficient rodent models. significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, -cell glucose sensitivity, rate sensitivity, or insulin clearance. CONCLUSIONS In contrast to the suppressive effects of leptin on -cell function in rodents, 16C20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or -cell function in leptin-deficient individuals with lipodystrophy. Introduction Leptin, an adipocyte-derived hormone, affects glucose homeostasis in part by directly modulating pancreatic -cell function (1C3). Systemic leptin infusion acutely decreases insulin secretion and impairs glucose tolerance in rodents (4). Loss of these suppressive actions of leptin in mice with selective absence of leptin receptors in the pancreas leads to fasting 1439399-58-2 hyperinsulinemia and increased responsiveness to glucose- and incretin-stimulated insulin secretion (5C7). These findings have led some 1439399-58-2 to speculate that the diminished responsiveness of pancreatic -cells to the negative effects of leptin partly contributes to the hyperinsulinemia typically observed in obesity (4,7,8). However, whether leptin negatively affects -cell function in humans is unclear. Lipodystrophy, characterized by selective deficiency of adipose tissue, is a hypoleptinemic state associated with hyperinsulinemia, severe insulin resistance, glucose intolerance, and dyslipidemia (1). Leptin replacement in patients with lipodystrophy attenuates insulin resistance, hyperinsulinemia, and hyperglycemia (1,9,10). Although insulin secretion was not assessed in these studies, reductions in insulin levels (fasting and glucose induced) were attributed to improvements in insulin sensitivity (11,12). A solitary study has reported the effects of leptin replacement on insulin secretion in a genetically leptin-deficient adult male (13). In this patient, insulin secretion, but not insulin sensitivity, elevated the entire week after leptin replacement. Aside from this single record, we don’t realize studies evaluating the short-term ramifications of leptin substitute on -cell function. To that final end, we record the early ramifications Ptprc of short-term (16C20 weeks) metreleptin (an analog of individual leptin) administration on -cell function in sufferers with lipodystrophy. Analysis Design and Strategies Study Style and 1439399-58-2 Study Topics The study process (initiated in July 2000) was accepted by the institutional review panel of the Country wide Institute of Diabetes and Digestive and Kidney Illnesses. Written up to date consent was extracted from all topics or their legal guardian, and assent was extracted from individuals under 18 years. Patients were through the U.S. and a genuine amount of various other countries in European countries, Asia, the center East, and SOUTH USA. Study topics reported listed below are from an open-label, potential, currently ongoing research evaluating the long-term protection and clinical ramifications of metreleptin treatment in sufferers with congenital or obtained lipodystrophy (9,11,12). Sufferers with HIV-associated lipodystrophy weren’t studied within this protocol. The explanation, inclusion criteria, and research style have already been referred to (9 previously,11). Inclusion requirements for leptin substitute included hypoleptinemia ( 12 ng/mL), metabolic abnormalities such as for example hypertriglyceridemia and/or lipoatrophic diabetes, 1439399-58-2 and the capability to stick to the leptin substitute process. Metreleptin was supplied by Amgen (Thousands of Oaks, CA) primarily and Amylin Pharmaceuticals (NORTH PARK, CA) eventually (9,11). Leptin therapy was supplied being a self-administered once- or twice-daily subcutaneous shot as previously referred to (9,11). Sufferers were seen on the Clinical Analysis Center from the Country wide Institutes of Wellness every 4C6 a few months for the initial year and then every 6C12 months thereafter. Laboratory data were collected during each visit. The current study examined the early effects of leptin replacement on -cell function derived from oral glucose tolerance test (OGTT) data. In this report, we include a subgroup of patients (= 13) who.