肝胰岛素清除的决定因素 - 孟德尔随机化研究的结果。

Determinants of hepatic insulin clearance - Results from a Mendelian Randomization study.

机构信息

Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.

Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, Eberhard Karls University Tübingen, Tübingen, Germany.

出版信息

Metabolism. 2021 Jun;119:154776. doi: 10.1016/j.metabol.2021.154776. Epub 2021 Apr 20.

DOI:10.1016/j.metabol.2021.154776

PMID:33862045

Abstract

AIMS/HYPOTHESIS: Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome.

METHODS

HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes).

RESULTS

HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (N = 1054, N = 2254; N = 1985, N = 2251). BMI-related SNPs were causally associated with HIC (N = 2772, N = 2259, p < 0.001) but not waist circumference-SNPs (N = 2751, N = 2280). Genetically determined insulin sensitivity was not causally related to HIC (N = 2752, N = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (N = 2660, N = 2240; N = 2694, N = 2275).

CONCLUSIONS

This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.

摘要

目的/假设：除了胰岛素抵抗，2 型糖尿病还与肝胰岛素清除率（HIC）降低有关。我们现在测试了 HIC 与肝脂肪堆积或代谢综合征特征的因果关系。

方法

通过“口服 C 肽和胰岛素最小模型”（n=3311）从口服葡萄糖耐量试验中得出 HIC。通过磁共振波谱（n=1211）定量肝脂肪。采用已建立的单核苷酸多态性（SNP；115 个用于肝脂肪、155 个丙氨酸氨基转移酶、37 个胰岛素敏感性、37 个胰岛素分泌、72 个空腹胰岛素、5285 个 BMI、163 个内脏脂肪、270 个腰围、442 个甘油三酯、620 个高密度脂蛋白胆固醇、193 个 C 反应蛋白、53 个脂肪营养不良样表型）进行孟德尔随机化。

结果

HIC 与肝脂肪（p<0.003）和胰岛素敏感性（p<0.0001）呈负相关。肝脂肪和 HIC 均与胰岛素敏感性独立相关（p<0.0001）。孟德尔随机化（N=1054，N=2254；N=1985，N=2251）表明，肝脂肪和丙氨酸氨基转移酶均与 HIC 无因果关系。与 BMI 相关的 SNP 与 HIC 有因果关系（N=2772，N=2259，p<0.001），而腰围 SNP 则没有（N=2751，N=2280）。遗传决定的胰岛素敏感性与 HIC 无因果关系（N=2752，N=2286）。C 反应蛋白和高密度脂蛋白与 HIC 有因果关系，较高的 C 反应蛋白和较低的高密度脂蛋白导致较高的 HIC（N=2660，N=2240；N=2694，N=2275）。