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

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 beta-cell dysfunction (TCF7L2, WFS1) and visceral adiposity (11BHSD1) on beta-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-naive women. Oral glucose tolerance test, HbA1c, insulin indices, anthropometric data were evaluated. The effect of minor allele carrying of TCF7L2 (rs7903146); WFS1 (rs1801214) and 11BHSD1 (rs4844880) variants in combination with PTGC was studied on surrogate markers of beta-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(-4)). PTGC and HbA1 c values correlated in the entire study population (R= 0.58, p = 10 -4 ). 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; Dl(basal) R=-0.33, p=0.039; ISSI-2: R=-0.35, p=0.028). Surrogate : markers of beta-cell function (HOMA2-B, AUC(insulin)/AUC(glucose)) correlated significantly with PTGC in subjects with the following genotypes rs7903146: CC R=0.51, p= 0.022; rsl 8001214: 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(insulin)/AUC(glucose) (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 11BHSD1 on beta-cell dysfunction.The correlation between pancreatic lipid accumulation and HbAlc also indicates an important role for the latter pathology.