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.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Leptin/analogs & derivatives , Lipodystrophy/genetics , Adult , Diabetes Mellitus, Type 1/metabolism , Female , Glycated Hemoglobin/metabolism , Humans , Hyperglycemia/chemically induced , Hypolipidemic Agents/therapeutic use , Insulin/administration & dosage , Insulin Resistance/physiology , Insulin Secretion , Lamin Type A/genetics , Leptin/deficiency , Leptin/therapeutic use , Lipodystrophy/drug therapy , Male , Mutation/genetics , Syndrome , Triglycerides/metabolismABSTRACT
Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide GIP, and glucagon-like peptide-1 GLP-1. GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was a candidate as a therapeutic agent for this disease. A number of pharmacological strategies have been developed to provide continuous delivery of GLP-1 and to prevent degradation of GLP-1, including continuous administration of GLP-1, DPP-IV inhibitors and DPP-IV resistant GLP-1 analogues. Recent results of the most clinically advanced incretin mimetics confirmed their efficacy to improve glycemic control in type 2 diabetic patients. Further results are expected to confirm the efficacy/safety profile of these compounds, and to find their place in the therapeutic strategy of type 2 diabetes.
