ECE2022 Poster Presentations Diabetes, Obesity, Metabolism and Nutrition (202 abstracts)
Objective: Treatment with metreleptin ameliorates hepatic steatosis in patients with lipodystrophy. The anti-steatotic effect of metreleptin is partially independent of its anorexic action, which suggests a direct effect of metreleptin on hepatic lipid metabolism. However, this mechanism is unknown. Based on previous findings in rodents, we hypothesized that metreleptin reduces hepatic lipid content by stimulating very-low density lipoprotein triglyceride (VLDL1-TG) secretion, a key mechanism that protects the liver from steatosis.
Methods: In this randomized, placebo-controlled, crossover trial we investigated the effects of a single acute subcutaneous metreleptin injection (0.1 mg/kg body weight) in overnight-fasted patients with lipodystrophy on VLDL1-TG secretion (primary outcome) and hepatocellular lipid content (HCL%, secondary outcome). VLDL1-TG secretion rate was assessed using an intralipid infusion test combined with density gradient ultracentrifugation. Changes in HCL% were measured by H1-magnetic resonance spectroscopy before and 3hrs after metreleptin or placebo injection. Patients previously on metreleptin treatment suspended injections for 14 days prior to the study. A two-sided paired t-test and the Wilcoxon signed rank test were used to analyze the differences after placebo vs. metreleptin injection in VLDL1-TG secretion and HCL%, respectively (statistical significance P<0.05).
Results: We recruited 5 patients with familial partial lipodystrophy: 4 females and 1 male; age range 27.958.6yrs; BMI 25.8±2.8 kg/m2 (mean±SD); all Caucasian; LMNA mutations confirmed in 2 cases; 2 previously on metreleptin treatment. An HCL >5% was detected in 3 patients. Hepatic VLDL1-TG secretion rate was higher after metreleptin in 5 out of 5 patients (mean±SD: 366±146 mg/h vs. 588±108 mg/h; placebo vs. metreleptin;P=0.019), whereas no statistically significant difference was observed in HCL% fold change within 3hrs post injection (median[IQR]: 1% [-7%;5%] vs. -6%[-11%;0%]; placebo vs. metreleptin;P=0.23)
Conclusion: Metreleptin markedly increases hepatic VLDL1-TG secretion in patients with lipodystrophy. This effect may play a role in the longterm antisteatotic action of metreleptin.
21 May 2022 - 24 May 2022