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Published on: April 19, 2013
Effects of TM6SF2 rs58542926 polymorphism on hepatocellular lipids and insulin resistance in early type 2 diabetes
Kálmán Bódis1, Maria Bombrich2, Martin Schön2
1Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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.
