TY - JOUR
T1 - Effects of TM6SF2 rs58542926 polymorphism on hepatocellular lipids and insulin resistance in early type 2 diabetes
AU - Bódis, Kálmán
AU - Bombrich, Maria
AU - Schön, Martin
AU - Knebel, Birgit
AU - Zaharia, Oana Patricia
AU - Bönhof, Gidon
AU - Karusheva, Yanislava
AU - Strassburger, Klaus
AU - Kupriyanova, Yuliya
AU - Kotzka, Jörg
AU - Guthoff, Rainer
AU - Schrauwen-Hinderling, Vera
AU - Al-Hasani, Hadi
AU - Burkart, Volker
AU - Szendroedi, Julia
AU - Wagner, Robert
AU - Markgraf, Daniel F.
AU - Roden, Michael
AU - GDS study group
N1 - Funding Information:
The research of the authors is supported in part by grants from the German Federal Ministry of Health (BMG), the Ministry of Culture and Science of the State North Rhine-Westphalia (MKW NRW) to German Diabetes Center (DDZ) and the German Federal Ministry of Education and Research (BMBF) to German Center for Diabetes Research (DZD e. V.). The research of M.R. is further supported by grants from the European Funds for Regional Development (EFRE-0400191) and the German Science Foundation (DFG; CRC/SFB 1116/2 B 12 ; RTG/GRK 2576 vivid, Project 3) and the Schmutzler Stiftung. The funding sources had neither influence on design and conduct of this study, collection, analysis and interpretation of the data; nor on the preparation, review, or approval of this article.
Publisher Copyright:
© 2023
PY - 2023/9
Y1 - 2023/9
N2 - Background and aims: Increased hepatocellular lipid content (HCL) is linked to insulin resistance, risk of type 2 diabetes and related complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2-gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. This case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during early course of diabetes. Methods and results: Males with recent-onset type 2 diabetes with (TM6SF2EK: n = 16) or without (TM6SF2EE: n = 16) the heterozygous TM6SF2-polymorphism of similar age and body mass index, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body-, hepatic- and adipose tissue-insulin sensitivity. HCL was assessed with 1H-magnetic-resonance-spectroscopy. A subset of both groups (n = 24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic- and adipose tissue-insulin sensitivity and 27% higher whole-body-insulin sensitivity than TM6SF2EE. After 5 years, whole-body-insulin sensitivity, HCL were similar between groups, while adipose tissue-insulin sensitivity decreased by 87% and 55% within both groups and circulating triacylglycerol increased in TM6SF2EE only. Conclusions: The TM6SF2-polymorphism rs58542926 dissociates HCL from insulin resistance in recent-onset type 2 diabetes, which is attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over effects of the TM6SF2-polymorphism during early course of diabetes and NAFLD.
AB - Background and aims: Increased hepatocellular lipid content (HCL) is linked to insulin resistance, risk of type 2 diabetes and related complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2-gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. This case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during early course of diabetes. Methods and results: Males with recent-onset type 2 diabetes with (TM6SF2EK: n = 16) or without (TM6SF2EE: n = 16) the heterozygous TM6SF2-polymorphism of similar age and body mass index, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body-, hepatic- and adipose tissue-insulin sensitivity. HCL was assessed with 1H-magnetic-resonance-spectroscopy. A subset of both groups (n = 24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic- and adipose tissue-insulin sensitivity and 27% higher whole-body-insulin sensitivity than TM6SF2EE. After 5 years, whole-body-insulin sensitivity, HCL were similar between groups, while adipose tissue-insulin sensitivity decreased by 87% and 55% within both groups and circulating triacylglycerol increased in TM6SF2EE only. Conclusions: The TM6SF2-polymorphism rs58542926 dissociates HCL from insulin resistance in recent-onset type 2 diabetes, which is attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over effects of the TM6SF2-polymorphism during early course of diabetes and NAFLD.
KW - Hepatocellular lipid content
KW - Insulin sensitivity
KW - Nonalcoholic fatty liver disease
KW - Transmembrane 6 superfamily member 2
KW - Type 2 diabetes
U2 - 10.1016/j.numecd.2023.06.004
DO - 10.1016/j.numecd.2023.06.004
M3 - Article
C2 - 37495452
SN - 0939-4753
VL - 33
SP - 1785
EP - 1796
JO - Nutrition Metabolism and Cardiovascular Diseases
JF - Nutrition Metabolism and Cardiovascular Diseases
IS - 9
ER -