Changes After Leptin Administration in Partial Lipodystrophy and Factors Associated With Hepatic and Metabolic Response

Abstract

Context: Partial lipodystrophy (PL) is a rare disease characterized by selective loss of subcutaneous fat.

Objective: To evaluate changes in apolipoproteins, hepatokines, hormones, appetite regulators, and inflammatory markers in patients with PL treated with leptin, assess postprandial metabolism and 24-hour dynamics, and identify predictors of hepatic and metabolic response to therapy.

Methods: We studied 19 subjects from our previous clinical study (NCT01679197), which investigated the effect of leptin on metabolic dysfunction-associated steatohepatitis associated with PL. A mixed-meal test was performed in a subgroup of 14 patients, and paired 24-hour frequent sampling with standardized meals was completed in 5 individuals.

Results: Leptin treatment led to reductions in apolipoproteins B, CII, CIII, and E (P < .05). Levels of ANGPTL3 tended to decrease after leptin treatment (P = .079). The mixed-meal test revealed significant reductions in triglyceride area under the curve (P = .017) and glucose excursions at several postmeal time points (P < .05). The immediate GIP secretion in response to a meal attenuated after leptin therapy (P = .005 at 60 minutes). Ghrelin levels showed an increase after leptin administration. The response to leptin treatment was associated with several factors, including baseline carbohydrate intake, leptin and triglyceride levels and triglyceride-rich apolipoproteins, and changes in triglyceride-rich apolipoproteins (P < .05 for all). Changes in IGF-1 levels were correlated with improvements in metabolic and liver parameters (P < .05).

Conclusion: Leptin therapy modulates lipid metabolism, postprandial glucose regulation, and appetite signaling in patients with PL, with responses associated with metabolic parameters and carbohydrate intake.

Keywords: MASH; incretins; leptin; partial lipodystrophy; response.

Figure 1.

Study diagram. Abbreviations: APL, acquired partial lipodystrophy; FPLD, familial partial lipodystrophy; MASH, metabolic disease-associated steatohepatitis.

Figure 2.

Levels of apolipoproteins, ANGPTL3, and IGF-1 over the 12-month treatment period with exogenous leptin. Levels of apolipoprotein B (A), apolipoprotein CII (B), apolipoprotein CIII (C), apolipoprotein E (D), ANGPTL3 (E), and IGF-1 (F) in subjects with partial lipodystrophy treated with metreleptin for 1 year. The F-statistic and P value are reported from a repeated-measures ANOVA. *Adjusted P < .05 vs baseline (Tukey post hoc test). Paired t-test was used to compare month 12 values to baseline (without multiplicity correction) as the change at 12 months vs baseline was a prespecified endpoint. Tests are run on log-transformed data for apolipoprotein CII, apolipoprotein CIII, and apolipoprotein E. The data are reported as mean ± SD.

Figure 3.

Mixed-meal testing results. A subset of subjects (n = 14) underwent mixed-meal testing. Levels of (A) glucose, (B) insulin, (C) triglycerides, (D) free fatty acids (FFAs), (E) GIP, (F) ghrelin, (G) GLP-1, and (H) peptide YY are presented at baseline ○ and following 12 months of metreleptin therapy ▴. The values are presented as mean ± SD if data of all time points show a normal distribution (glucose, FFAs, GIP, and ghrelin). Otherwise, the data are presented as geometric mean ± geometric SD (insulin, triglycerides, GLP-1, and peptide YY). P_AUC values are shown for comparisons of the area under the curve (AUC). Specific time point comparisons are denoted with * if P < .05 at the specific time point. Abbreviations: FFA, free fatty acids; GIP, glucose insulinotropic peptide; GLP-1, glucagon-like peptide.

Figure 4.

A 24-hour frequent sampling substudy. The effects of acute and chronic leptin administration on serum leptin (A), peptide YY (B), GLP-1 (C), GIP (D), and ghrelin (E) were analyzed in 5 individuals on the first day of treatment initiation and 1 year after leptin treatment. The arrow indicates the timing of leptin injection. Abbreviations: GIP, glucose insulinotropic peptide; GLP-1, glucagon-like peptide; PYY, peptide YY.

Figure 5.

Correlation of baseline triglycerides, HbA1c, and levels of apolipoproteins and ANGPTL3 with changes in triglycerides and HbA1c after treatment with exogenous leptin. Correlation of baseline triglycerides with changes in triglycerides (A) after treatment with exogenous leptin. Correlation of baseline levels of apolipoproteins CII (B) and E (C), and ANGPTL3 (D) with percent changes in triglycerides after treatment with exogenous leptin. Correlation of baseline triglycerides (E), and apolipoproteins CII (F), CIII (G), and E (H), and ANGPTL3 (I) with changes in HbA1c.

Figure 6.

IGF-1 levels and correlation of changes in IGF-1 with baseline leptin and improvements in NASH score and liver fat. IGF-1 levels at baseline and after exogenous leptin in patients with a remarkable metabolic response (A). Correlation of changes in IGF-1 with baseline leptin (B), and changes in NASH score (C) and liver fat (D).