在一项事后分析中，胰腺脂质含量与基因变异（TCF7L2、WFS1和11βHSD1）对中年女性B细胞功能的联合作用。
Combined effect of pancreatic lipid content and gene variants (TCF7L2, WFS1 and 11BHSD1) on B-cell function in Middle Aged Women in a Post Hoc Analysis.
作者信息
Nádasdi Ákos, Gál Viktor, Masszi Tamás, Patócs Attila, Igaz Peter, Somogyi Anikó, Firneisz Gábor
机构信息
Department of Internal Medicine and Haematology, Faculty of Medicine, Semmelweis University, Szentkirályi St 46, 1088, Budapest, Hungary.
Brain Imaging Centre, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary.
出版信息
Diabetol Metab Syndr. 2022 Jul 27;14(1):106. doi: 10.1186/s13098-022-00876-z.
BACKGROUND
TCF7L2 rs7903146 and PNPLA3 rs738409 gene variants confer the strongest risk for type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), respectively. Pancreatic triacylglycerol content (PTGC) was reported to have a role in T2DM development. We aimed to assess the correlation between PTGC and hepatic triacylglycerol content (HTGC) stratified by PNPLA3 rs738409 genotype and subsequently interactions between PTGC and gene variants associated with β-cell dysfunction (TCF7L2, WFS1) and visceral adiposity (11ΒHSD1) on β-cell function were also tested.
METHODS
PTGC and HTGC were assessed using MR in a post-hoc analysis of a genotype-based (PNPLA3 rs738409) recall study of 39 (lipid- and glucose lowering) drug-naïve women. Oral glucose tolerance test, HbA1c, insulin indices, anthropometric data were evaluated. The effect of minor allele carrying of TCF7L2 (rs7903146); WFS1 (rs1801214) and 11ΒHSD1 (rs4844880) variants in combination with PTGC was studied on surrogate markers of β-cell function. We used Spearman's rank-order, Mann-Whitney-U tests, and linear regression models.
RESULTS
PTGC and HTGC values were correlated after stratification by the rs738409 variant (only in CC genotype group R = 0.67, p = 10). PTGC and HbA1c values correlated in the entire study population (R = 0.58, p = 10). Insulin resistance, sensitivity and disposition indices were correlated with PTGC (HOMA2-IR: R = 0.42, p = 0.008; TyG: R = 0.38, p = 0.018; Matsuda: R= - 0.48, p = 0.002; DI: R=-0.33, p = 0.039; ISSI-2: R=-0.35, p = 0.028). Surrogate markers of β-cell function (HOMA2-B, AUC/AUC) correlated significantly with PTGC in subjects with the following genotypes rs7903146: CC R = 0.51, p = 0.022; rs18001214: CT + CC R = 0.55, p = 0.013; rs4844880: TA + AA R = 0.56, p = 0.016. The strongest interactions were found between PTGC and TCF7L2 rs7903146 effect on HOMA2-B (p = 0.001) and AUC/AUC (p = 0.013).
CONCLUSIONS
The PNPLA3 rs738409 genotype has a major effect on the correlation between PTGC and HTGC. Furthermore we first report the combined effect of PTGC and individual risk gene variants of TCF7L2, WFS1 and 11ΒHSD1 on β-cell dysfunction. The correlation between pancreatic lipid accumulation and HbA1c also indicates an important role for the latter pathology.
背景
转录因子7样蛋白2（TCF7L2）基因rs7903146变异和帕他汀样磷脂酶域蛋白3（PNPLA3）基因rs738409变异分别是2型糖尿病（T2DM）和非酒精性脂肪性肝病（NAFLD）的最强风险因素。据报道，胰腺甘油三酯含量（PTGC）在T2DM的发生发展中起作用。我们旨在评估PNPLA3基因rs738409基因型分层后的PTGC与肝脏甘油三酯含量（HTGC）之间的相关性，随后还测试了PTGC与β细胞功能相关基因变异（TCF7L2、WFS1）和内脏脂肪（11β羟类固醇脱氢酶1，11ΒHSD1）之间对β细胞功能的相互作用。
方法
在一项基于基因型（PNPLA3基因rs738409）的回顾性研究中，对39名未服用（降脂和降糖）药物的女性进行事后分析，使用磁共振成像评估PTGC和HTGC。评估口服葡萄糖耐量试验、糖化血红蛋白（HbA1c）、胰岛素指标和人体测量数据。研究携带TCF7L2基因（rs7903146）、WFS1基因（rs1801214）和11ΒHSD1基因（rs4844880）变异的次要等位基因与PTGC联合对β细胞功能替代指标的影响。我们使用了斯皮尔曼等级相关、曼-惠特尼U检验和线性回归模型。
结果
rs738409变异分层后，PTGC和HTGC值具有相关性（仅在CC基因型组中，R = 0.67，p = 0.010）。在整个研究人群中，PTGC与HbA1c值相关（R = 0.58，p = 0.010）。胰岛素抵抗、敏感性和处置指数与PTGC相关（稳态模型评估的胰岛素抵抗指数：HOMA2-IR：R = 0.42，p = 0.008；血糖胰岛素生成指数：TyG：R = 0.38，p = 0.018；松田指数：Matsuda：R = -0.48，p = 0.002；处置指数：DI：R = -0.33，p = 0.039；胰岛素敏感性指数2：ISSI-2：R = -0.35，p = 0.028）。在具有以下基因型的受试者中，β细胞功能替代指标（HOMA2-β、曲线下面积比/AUC）与PTGC显著相关：rs7903146：CC，R = 0.51，p = 0.022；rs18001214：CT + CC，R = 0.55，p = 0.013；rs4844880：TA + AA，R = 0.56，p = 0.016。在PTGC与TCF7L2基因rs7903146对HOMA2-β（p = 0.001）和曲线下面积比/AUC（p = 0.013）的影响之间发现了最强的相互作用。
结论
PNPLA3基因rs738409基因型对PTGC与HTGC之间的相关性有重要影响。此外，我们首次报告了PTGC与TCF7L2、WFS1和11ΒHSD1的个体风险基因变异联合对β细胞功能障碍的影响。胰腺脂质蓄积与HbA1c之间的相关性也表明后者在病理过程中起重要作用。
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