Abstract
Disclosure: E. Finn: None. K.N. Fuller: None. L.A. Knaub: None. Y. Garcia Reyes: None. S.C. Derderian: None. J. Schoen: None. T. Inge: None. J.E. Reusch: Advisory Board Member; Self; Medtronic Diabetes. K. Nadeau: None. M. Cree: None. Introduction: The severity of metabolic disease in youth with obesity is varied and determinants of disease progression are not known. Non-alcoholic fatty liver disease appears to be central to the development of cardiometabolic disease in youth with severe obesity. We tested the hypothesis that hepatic mitochondrial respiratory capacity would correlate with cardiometabolic measures in youth with severe obesity and a range of glycemia. Methods: Adolescents with severe obesity and a range of dysglycemia undergoing bariatric surgery were enrolled. Participants underwent anthropomorphic assessments, fasting labs, and a 4-hour mixed meal tolerance test (MMTT, 45 g carbs, 14 g protein, and 14 g fat) over 30 minutes followed by serial measures of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and free fatty acids. Liver biopsies obtained at time of vertical sleeve gastrectomy surgery were analyzed for mitochondrial respiration. Permeabilized liver tissue was assessed for mitochondrial oxygen consumption by respirometry (Oxygraph-2k, OROBOROS) under both pyruvate (carbohydrate) and palmitoyl-carnitine (lipids) substrate conditions. Results: Fifteen youth with severe obesity (female=60%, mean age 16.9 ± 1.5 years, mean BMI 47.4 ± 7.2 kg/m(2)) were enrolled. Lower hepatic carbohydrate-supported respiration relates to higher serum glucose concentrations throughout the 4-hr MMTT (P=< 0.001 to 0.05) as well as higher fasting serum triglycerides (p =<0.001-0.05). Lower liver lipid-supported respiration is associated with higher C-peptide levels (p =0.001-0.01) throughout MMTT, increased Matsuda Index (p =0.001-0.05), and higher fasting hepatic transaminases, alanine aminotransferase (p =0.006-0.04), aspartame aminotransferase (p =0.007-0.02), and gamma-glutamyl transferase (p =0.01-0.03). Insulin, GLP-1, and free fatty acids are not correlated with mitochondrial respiration. Conclusion: Consistent with findings in adults and animals, youth with severe obesity have lower hepatic mitochondrial respiration which correlates with markers of poorer cardiometabolic health including higher triglycerides, higher glucose concentraions, lower insulin sensitivity, higher insulin secretion (C-peptide), and higher liver transaminases. Based on these findings, dysregulated hepatic mitochondrial respiration should be further explored as a possible contributor to the development of early liver disease and glucose dysregulation. Presentation: Friday, June 16, 2023