Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6-²H₂]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance. NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.

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