275-OR: Higher Liver Fat and Whole-Body Insulin Sensitivity in Newly Diagnosed Type 2 Diabetes Patients with a Variant in Transmembrane 6 Superfamily Member 2 Protein

Abstract

Knockdown of the gene encoding transmembrane 6 superfamily member 2 protein (TM6SF2) in mice increases hepatocellular lipid content (HCL) and decreases very low-density lipoprotein secretion. Humans with TM6SF2 mutations are at higher risk of nonalcoholic fatty liver disease, but lower risk of cardiovascular disease. The relevance of TM6SF2 mutations for HCL and insulin sensitivity in type 2 diabetes is less clear. This study aimed at elucidating the relevance of the E167K (SNP rs58542926) mutation in the gene encoding TM6SF2 for HCL, hepatic insulin sensitivity and whole-body insulin sensitivity in type 2 diabetes. We compared male patients with recently diagnosed type 2 diabetes with (n=16) or without (n=16) E167K mutation, matched for age and BMI (50±1 vs. 48±3 years; 32±1 vs. 32±2 kg/m2) from the German Diabetes Study. Whole-body and hepatic insulin sensitivity were assessed by Botnia-clamp tests with [6,6-2H2]glucose, HCL by 1H magnetic resonance spectroscopy and hepatic fibrosis by the fibrosis-4 index (FIB4). Patients with and without TM6SF2 mutation had comparable levels of HbA1c (6.2±0.2 vs. 5.9±0.1%) and serum triglycerides (136±14 vs. 149±14 mg/dl). Carriers of TM6SF2 mutation had higher HCL (9.0±1.9 vs. 4.6±0.4%, p<0.05) and whole-body insulin sensitivity (7.1±0.6 vs. 5.4±0.2 mg/(kg*min), p<0.05), but similar hepatic insulin sensitivity (1.6±0.1 vs. 1.6±0.1 mg/(kg*min)) and fibrosis score (1.2±0.1 vs. 1.0±0.1). In conclusion, the E167K mutation of the TM6SF2 gene dissociates liver steatosis from whole-body insulin sensitivity. This may result from favored trapping of triglycerides within the liver, which would in turn protect peripheral tissues from insulin resistance induced by liver-derived lipids. Disclosure K. Bodis: None. J. Szendroedi: None. J.M. Ahlers: None. Y. Karusheva: None. O.P. Zaharia: None. S. Antoniou: None. B. Knebel: None. Y. Kupriyanova: None. J. Hwang: None. V. Burkart: None. K. Muessig: None. H. Al-Hasani: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. D.F. Markgraf: Research Support; Self; Sanofi.