Department 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.
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.
Nutr Metab Cardiovasc Dis. 2023 Sep;33(9):1785-1796. doi: 10.1016/j.numecd.2023.06.004. Epub 2023 Jun 9.
Increased hepatocellular lipid content (HCL) is linked to insulin resistance, risk of type 2 diabetes and related complications. Conversely, a single-nucleotide polymorphism (TM6SF2; 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.
Males with recent-onset type 2 diabetes with (TM6SF2: n = 16) or without (TM6SF2: n = 16) the heterozygous TM6SF2-polymorphism of similar age and body mass index, underwent Botnia-clamps with [6,6-H]glucose to measure whole-body-, hepatic- and adipose tissue-insulin sensitivity. HCL was assessed with H-magnetic-resonance-spectroscopy. A subset of both groups (n = 24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2 had similar hepatic- and adipose tissue-insulin sensitivity and 27% higher whole-body-insulin sensitivity than TM6SF2. 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 TM6SF2 only.
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.
肝细胞内脂质含量（HCL）的增加与胰岛素抵抗、2 型糖尿病风险及其相关并发症有关。相反，跨膜 6 超家族成员 2 基因中的单核苷酸多态性（TM6SF2；rs58542926）与非酒精性脂肪性肝病（NAFLD）相关，但心血管风险较低。本病例对照研究旨在检测该多态性在 2 型糖尿病早期病程中对组织特异性胰岛素敏感性的作用。
近期诊断的 2 型糖尿病男性（TM6SF2：n=16）或无（TM6SF2：n=16）杂合 TM6SF2 多态性、年龄和体重指数相似的男性，进行 Botnia 夹闭试验，并用[6,6-H]葡萄糖测量全身、肝和脂肪组织胰岛素敏感性。采用 H 磁共振波谱法评估 HCL。两组中有一部分（n=24）在 5 年后重新评估。尽管 HCL 增加了一倍，但 TM6SF2 的肝和脂肪组织胰岛素敏感性与 TM6SF2 相似，全身胰岛素敏感性高 27%。5 年后，两组间全身胰岛素敏感性、HCL 相似，而两组内脂肪组织胰岛素敏感性分别下降 87%和 55%，仅 TM6SF2 内循环三酰甘油增加。
TM6SF2 多态性 rs58542926 使 2 型糖尿病近期发病时 HCL 与胰岛素抵抗分离，而疾病持续时间会减弱这种分离。这表明，糖尿病相关的代谢改变在糖尿病早期和 NAFLD 期间，比 TM6SF2 多态性的影响更占主导地位。
