Leptin Decreases Gluconeogenesis and Gluconeogenic Substrate Availability in Patients With Lipodystrophy

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: alanine; gluconeogenesis; lactate; leptin; lipodystrophy; lipolysis.

Figure 1.

Effects of metreleptin in patients with lipodystrophy (solid lines: partial lipodystrophy; dotted lines: generalized lipodystrophy). A) Peripheral insulin sensitivity and B) Hepatic insulin sensitivity increased after 6 months of metreleptin administration. C) Fasting glucose, D) Insulin, and E) HbA1c decreased after metreleptin. F) Basal gluconeogenesis (GNG) decreased after 2 weeks but not after 6 months of metreleptin administration. G) Insulin-mediated suppression of GNG during a hyperinsulinemic-euglycemic clamp increased after 2 weeks and 6 months of metreleptin. H) Alanine decreased after 6 months of metreleptin. I) Lactate decreased after 2 weeks and 6 months of metreleptin. Linear mixed-effects regression was used for comparisons of >2 timepoints. Data show mean ± SD for normally distributed metrics and median [25th percentile, 75th percentile] for skewed metrics. P < .05 represented statistical significance. All P values are 2-sided and reflect post hoc comparisons (2 weeks vs baseline; 6 months vs baseline).

Figure 2.

Correlations with GNG at baseline, and after 2 weeks and 6 months of metreleptin administration (closed circles: partial lipodystrophy; open squares: generalized lipodystrophy). A, B, C) Alanine was positively correlated with GNG at baseline (r = 0.8, P = .01), 2 weeks (r = 0.8, P = .03) and 6 months (r = 0.9, P = .002). D, E, F) There was a trend toward a positive correlation between lactate and GNG at baseline (r = 0.6, P = .09), but no significant correlations were observed after 2 weeks and 6 months. G, H, I) No significant correlations were observed between peripheral insulin sensitivity and GNG at baseline, and after 2 weeks and 6 months of metreleptin treatment. P < .05 represented statistical significance. Abbreviations: GNG, gluconeogenesis; LBM, lean body mass.