One‐year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes

Abstract

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy

“…In patients with lipodystrophy, metreleptin therapy ameliorates metabolic abnormalities by reducing food intake (3,12,13), improving insulin resistance and diabetes (4,(13)(14)(15), and reducing ectopic lipid (7). These improvements in glucose and lipid metabolism are likely due in part to the reduction in food intake, but the clinical effects of metreleptin that are independent of changes in food intake have been poorly explored in humans.…”

Resveratrol attenuates triglyceride accumulation associated with upregulation of Sirt1 and lipoprotein lipase in 3T3-L1 adipocytes

“…For instance, leptin increases energy expenditure and reduces food intake [25]. Furthermore, physiological increase in plasma leptin level has been shown to increase insulin secretion [26]. Adiponectin increases glucose uptake in muscles and insulin sensitivity, suppresses gluconeogenesis in hepatocytes and increases β-oxidation [27].…”

The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline

“…In one study, metreleptin reduced hypertriglyceridemia and improved glycemia in severely hypoleptinemic patients with partial lipodystrophy and severe metabolic derangements (baseline HbA1c >8%, triglycerides >500 mg/dL, leptin <4 ng/mL) (46). In a second study, metreleptin improved triglycerides and indices of insulin sensitivity and secretion in FPLD2 patients with moderate to severe hypoleptinemia (56). However, in a third study, no glycemic improvement was observed in FPLD2 patients with serum leptin <7 ng/mL (57).…”