Joint Effect of Insulin Signaling Genes on Insulin Secretion and Glucose Homeostasis

Sabrina Prudente, Eleonora Morini, Lorella Marselli, Roberto Baratta, Massimiliano Copetti, Christine Mendonca, Francesco Andreozzi, Manisha Chandalia, Fabio Pellegrini, Diego Bailetti, Federica Alberico, Hetal Shah (+6 others)
2013 Journal of Clinical Endocrinology and Metabolism  
Context: Reduced insulin signaling in insulin secreting ␤-cells causes defective insulin secretion and hyperglycemia in mice. Objective: We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH). Design: Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829
more » ... est (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n ϭ 92) or glibenclamide (n ϭ 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n ϭ 6607). Results: Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P ϭ .005); 2) glucose and glibenclamide SI (P ϭ .046 and P ϭ .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P ϭ .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R 2 ϭ 0.80, P Ͻ .001). Conclusions: Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces ␤-cell function and impairs glucose homeostasis. (J Clin Endocrinol Metab 98: E1143-E1147, 2013)
doi:10.1210/jc.2012-4282 pmid:23633196 fatcat:v7eghrka4vbqfpeynkcxeparke