1620-P: GDF15 Correlates with Insulin Sensitivity But Not with Features of Metabolic Dysfunction–Associated Steatotic Liver Disease

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Introduction and Objective: Growth Differentiation Factor 15 (GDF15) is a biomarker for metabolic diseases, including type-2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). GDF15 secretion is linked to hepatic mitochondrial stress in mice and to markers of insulin resistance in humans. MASLD is associated with both hepatic mitochondrial adaptations and insulin resistance. Here, we investigated whether GDF15 levels correlate with hepatic mitochondrial respiration and/or insulin sensitivity in participants with and without MASLD. Methods: Fasting blood samples were obtained from obese participants with and without (CON) biopsy-confirmed simple steatosis (MASL) or MASH (MASH) (n=20/group). Groups were matched for age (mean±SD: 41±11, 44±9, 42±10 years) and BMI (49±7, 48±6, 49±8 kg/m2). Whole-body insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamps, hepatic mitochondrial respiration via high-resolution respirometry and serum GDF15 by ELISA. Group differences were analyzed with one-way ANOVA or Kruskal-Wallis-Test and correlations with Pearson’s or Spearman’s methods. Results: Fasting GDF15 levels were similar between groups (616±353, 661±252, 635±292 pg/mL in CON, MASL, MASH; p=0.385), and correlated with age (r=0.414, p=0.001), but not with hepatic fatty acid- or NADH+succinate-linked mitochondrial respiration (p>0.05 for all respiration states). GDF15 correlated negatively with whole-body insulin sensitivity (M-value; r=-0.342, p=0.022) and positively with adipose tissue insulin resistance (Adipo-IR; r=0.338, p=0.012). Conclusion: GDF15 associates with whole-body and adipose tissue insulin resistance but not with liver oxidative capacity. In line, GDF15 levels were comparable in participants with and without simple steatosis or MASH. These findings may suggest a potential role for GDF15 in adipose tissue-mediated insulin resistance. Disclosure A. Giannakogeorgou: Research Support; Novo Nordisk. S. Kahl: Research Support; Boehringer-Ingelheim, Novo Nordisk A/S. C. Granata: None. G. Heilmann: None. L. Mastrototaro: None. B. Dewidar: None. I. Esposito: None. S. Trenkamp: None. F.A. Granderath: None. M. Schlensak: None. C.S. Mantzoros: Other Relationship; UpToDate. Research Support; LabCorp, Merck & Co., Inc, ESPERION Therapeutics, Inc., Massachusetts Life Sciences Center, Boehringer-Ingelheim. Other Relationship; TMIOA. Consultant; Novo Nordisk, Amgen Inc, Olympus, Genfit, Lumos, Madrigal Pharmaceuticals, Inc, ESPERION Therapeutics, Inc., ALIGOS Therapeutics, Regeneron Pharmaceuticals, 89bio, Inc, Corcept Therapeutics, Intercept Pharmaceuticals, Inc. Research Support; ANSH Labs. Other Relationship; Elsevier, Cardiometabolic Health Congress. Research Support; Abbott. M. Roden: Research Support; Boehringer-Ingelheim. Advisory Panel; Echosens. Speaker's Bureau; Madrigal Pharmaceuticals, Inc. Advisory Panel; MSD Life Science Foundation. Board Member; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. P. Schrauwen: Research Support; AstraZeneca, Pfizer Inc, Antaros Medical.

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