Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy
Open Access
- 16 July 2018
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 128 (8), 3504-3516
- https://doi.org/10.1172/jci95476
Abstract
BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556 FUNDING. This research was supported by the intramural research program of the NIDDK.Keywords
Funding Information
- NIDDK Intramural Research Program (DK075084-05)
This publication has 48 references indexed in Scilit:
- Insulin Resistance Is a Sufficient Basis for Hyperandrogenism in Lipodystrophic Women with Polycystic Ovarian SyndromeJournal of Clinical Endocrinology & Metabolism, 2012
- Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric dietActa Endocrinologica, 2011
- Central Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese AdolescentsDiabetes Care, 2010
- Leptin Regulates Peripheral Lipid Metabolism Primarily through Central Effects on Food IntakeEndocrinology, 2008
- Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo‐controlled trialDiabetes, Obesity and Metabolism, 2005
- Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight LossScience, 2002
- Leptin-Replacement Therapy for LipodystrophyThe New England Journal of Medicine, 2002
- Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinaseNature, 2002
- Effects of Recombinant Leptin Therapy in a Child with Congenital Leptin DeficiencyThe New England Journal of Medicine, 1999
- Thermic effect of infused glucose and insulin in man. Decreased response with increased insulin resistance in obesity and noninsulin-dependent diabetes mellitus.JCI Insight, 1983