Children’s Nutrition Research Center Staff Publications

Language

English

Publication Date

12-21-2023

Journal

The Journal of Clinical Endocrinology & Metabolism

DOI

37515588

PMID

37515588

PMCID

PMC10735288

PubMedCentral® Posted Date

7-29-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Context: The effects of leptin, an adipocyte-derived hormone that signals overall energy sufficiency, can only be studied in leptin-deficient conditions. In patients with lipodystrophy, a rare disease and unique model of leptin deficiency, treatment with recombinant leptin (metreleptin) improves glycemia and decreases energy expenditure. We hypothesized that these improvements might be mediated by reduced gluconeogenesis (GNG), an energy-requiring process.

Objective: To determine the effects of metreleptin on GNG and GNG substrates.

Methods: This was a single-arm prospective study of metreleptin administration in 15 patients with lipodystrophy, 9 of whom had data on GNG (NIH, 2013-2018). We analyzed total GNG, insulin-mediated suppression of GNG, glycerol, palmitate, alanine, lactate, peripheral and hepatic insulin sensitivity, and markers of glycemia (eg, HbA1c, glucose, fasting insulin).

Results: Metreleptin administration decreased basal GNG, increased insulin-mediated suppression of GNG, and improved insulin sensitivity and markers of glycemic control. Metreleptin reduced carbon sources for GNG, including plasma alanine and lactate, and rate of appearance (Ra) of glycerol, and decreased Ra of palmitate, a driver of GNG. Glycerol and palmitate Ra correlated with GNG prior to but not during metreleptin administration. Alanine strongly correlated with GNG both before and during metreleptin administration.

Conclusions: Metreleptin treatment in patients with lipodystrophy reduced GNG likely through decreased availability of carbon sources for gluconeogenesis, such as alanine, lactate, and glycerol. Associations between alanine and GNG persisted after metreleptin treatment while correlations with glycerol and palmitate Ra did not persist, suggesting reduced importance of lipolysis as a driver of GNG in the leptin-replete state.

Trial registration: ClinicalTrials.gov NCT01778556.

Keywords

Humans, Alanine, Carbon, Gluconeogenesis, Glycerol, Insulin, Insulin Resistance, Lactic Acid, Leptin, Lipodystrophy, Palmitates, Prospective Studies, gluconeogenesis, lipodystrophy, leptin, lipolysis, alanine, lactate

Published Open-Access

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