OR18-04 Leptin Decreases Gluconeogenesis And Gluconeogenic Substrate Availability In Patients With Lipodystrophy

Disclosure: E. Quaye: None. S. Chacko: None. M. Startzell: None. R.J. Brown: Other; Self; Metreleptin for the study was donated by Amryt Pharma. Leptin is an adipocyte-derived hormone that signals overall energy sufficiency. In patients with lipodystrophy, treatment with recombinant leptin (metreleptin) improved measures of glycemia and decreased energy expenditure. We hypothesized that metreleptin in patients with lipodystrophy would decrease gluconeogenesis (GNG) and gluconeogenic substrates through improvements in peripheral and hepatic insulin sensitivity. We conducted a single-arm prospective study of metreleptin administration in 9 patients with lipodystrophy from 2013-2018. The main outcomes of this study were basal and insulin-mediated suppression of GNG, carbon sources for GNG (glycerol rate of appearance (R(a)) measured with isotope tracers, and plasma alanine and lactate), palmitate R(a) (a driver of GNG, measured with isotope tracers), and peripheral and hepatic insulin sensitivity (measured as glucose disposal during a hyperinsulinemic clamp, and % suppression of glucose R(a) during the clamp, respectively). Peripheral insulin sensitivity increased 2-fold (by 115±134%; P=0.001) after 6 months of metreleptin. Hepatic insulin sensitivity increased from 61% to 81% after 6 months of metreleptin with a trend toward statistical significance (P=0.08; 6 months vs. baseline). Basal GNG decreased by 16±12%, from 12.4±3.9 to 10.9±2.6 µmol/kgLBM/min, after 2 weeks of metreleptin (P=0.02) but did not change after 6 months (P=0.2). Metreleptin increased insulin-mediated suppression of GNG during the hyperinsulinemic clamp from 73% at baseline to 91% after 2 weeks (P<0.002; 2 weeks vs. baseline), and 94% after 6 months (P<0.001; 6 months vs. baseline). Alanine was unchanged after 2 weeks of metreleptin (P=0.1) but decreased by 21±22% after 6 months (P=0.005). There was a positive correlation between alanine and GNG at baseline (r=0.8, P=0.01), 2 weeks (r=0.8, P=0.03) and 6 months (r=0.9, P=0.002). Lactate decreased by 20±18% after 2 weeks (P=0.014) and 21±24% (P=0.001) after 6 months of metreleptin. There was no significant decrease in glycerol or palmitate R(a) after 2 weeks of metreleptin, but palmitate R(a) decreased after 6 months (P=0.04). Metreleptin treatment in patients with lipodystrophy reduced basal GNG and increased insulin mediated suppression of GNG. Reduced GNG may be mediated by improved insulin sensitivity leading to reductions in alanine and lactate, which are carbon sources for GNG. Associations between alanine and GNG persisted after metreleptin, suggesting that potential therapeutic interventions to reduce protein turnover in insulin-resistant states may improve glucose homeostasis. Presentation: Saturday, June 17, 2023