Leptin decreases gluconeogenesis and gluconeogenic substrate availability in patients with lipodystrophy

Authors: QUAYE, EMMANUEL - NATIONAL INSTITUTES OF HEALTH (NIH); CHACKO, SHAJI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); STARTZELL, MEGAN - NATIONAL INSTITUTES OF HEALTH (NIH); BROWN, REBECCA - NATIONAL INSTITUTES OF HEALTH (NIH)

Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/29/2023
Publication Date: 8/4/2023
Citation: Quaye, E., Chacko, S., Startzell, M., Brown, R.J. 2023. Leptin decreases gluconeogenesis and gluconeogenic substrate availability in patients with lipodystrophy. Journal of Clinical Endocrinology and Metabolism. 109(1):e209-e215. https://doi.org/10.1210/clinem/dgad445.
DOI: https://doi.org/10.1210/clinem/dgad445

Interpretive Summary: Lipodystrophy is a rare disease where the body doesn't have enough fat tissue and a hormone called leptin. This can cause problems with metabolism similar to what happens in obesity. In patients with lipodystrophy, treatment with synthetic leptin reduces blood glucose level and decreases energy expenditure. The objective of this research was to determine whether synthetic leptin treatment in patients with lipodystrophy would reduce glucose production in the liver, an energy-requiring process by decreasing carbon sources such as lactate, alanine and glycerol. Scientists in Houston, Texas demonstrated that synthetic leptin treatment in lipodystrophy patients reduced glucose production in the liver likely through decreased availability of carbon sources such as alanine, lactate and glycerol. This also improved how sensitive the patients' bodies were to insulin and made their blood sugar levels better. These findings provide insights for future research to find effective treatments for leptin deficient condition. It also suggests that treatments targeting the breakdown of proteins might help improve how the body handles sugar in conditions like insulin resistance.

Technical Abstract: 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. To determine the effects of metreleptin on GNG and GNG substrates. 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). 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. 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.