508-P: The Metabolic Phenome of the Hepatoprotective HSD17B13 Splice Variant rs72613567:TA Suggests Higher Lactate Clearance
Authors: MENDEZ CARDENAS DANIA M. , BÓDIS KÁLMÁN , PRYSTUPA KATSIARYNA , YURCHENKO IRYNA , SCHÖN MARTIN , MÖSER CLARA , ZAHARIA OANA P. , PESTA DOMINIK , HENI MARTIN , PAFILI KALLIOPI , KUPRIYANOVA YULIYA , SCHRAUWEN-HINDERLING VERA , RODEN MICHAEL , KNEBEL BIRGIT , WAGNER ROBERT , AL-HASANI HADI , BOMBRICH MARIA 
Published: June 2024

Introduction & Objective: A common (~25%) splice variant rs72613567:TA in hydroxysteroid dehydrogenase 17-beta 13 (HSD17B13) was shown to reduce the risk of hepatic fibrosis and cirrhosis. The mechanism underlying the protective function remains unclear.
Methods: Carriers (n=647 of 1353) of the splice variant in the cohort of the German Diabetes Study (GDS) were identified by reverse transcription-polymerase chain reaction. Phenotyping comprised hepatic lipid content (HLC) and liver energy metabolism (inorganic phosphate (Pi), γATP by 1H/31P-magnetic resonance spectroscopy), insulin secretion, hepatic and whole-body insulin sensitivity (Botnia clamps with [6,6-²H2]glucose), physical fitness (spiroergometry with lactate assessment), resting energy expenditure during fasting and clamp (indirect calorimetry) including up to 2331 measurements and covering repeated visits over 15 years.
Results: Compared to non-carriers, carriers of the hepatoprotective minor allele showed similar hepatic insulin sensitivity and γATP, but higher HLC and Pi, lower alanine aminotransferase (ALT) levels and an attenuated lactate increase after reaching the anaerobic threshold (VO2AT) (pinteraction=2E-11). This genetic modification associates with post-exercise lactate rise and was driven by elevated fasting plasma glucose levels (pinteraction=5E-4). Fasting endogenous glucose production, insulinemia, glycemia, energy expenditure, insulin sensitivity (M-value) and secretion were similar between groups. Only female carriers showed lower physical fitness (VO2 peak and VO2AT).
Conclusion: Higher hepatic Pi suggests alterations of hepatic energy metabolism in carriers of the hepatoprotective variant. The blunted increase in lactate post VO2AT, depending on fasting glucose levels, highlights a potential link between the HSD17B13 variant and altered lactate kinetics during anaerobic exercise in diabetes.

Disclosure
D.M. Mendez Cardenas: None. K. Bódis: None. K. Prystupa: None. I. Yurchenko: None. M. Schön: None. C. Möser: None. O.P. Zaharia: None. D. Pesta: None. M. Heni: Research Support; Boehringer-Ingelheim. Advisory Panel; Amryt Pharma Plc. Speaker's Bureau; Amryt Pharma Plc. Advisory Panel; Boehringer-Ingelheim, Boehringer-Ingelheim. Speaker's Bureau; Lilly Diabetes, Novartis AG, Novo Nordisk, Sanofi. K. Pafili: None. Y. Kupriyanova: None. V. Schrauwen-Hinderling: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca. B. Knebel: None. R. Wagner: Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. H. Al-Hasani: None. M. Bombrich: None.