CONTEXT: Reduced insulin signaling in insulin secreting β-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 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 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 = 6607). RESULTS: Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .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) = 0.80, P < .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 β-cell function and impairs glucose homeostasis.
CONTEXT: Reduced insulin signaling in insulin secreting β-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 TRIB3Q84R, 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 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 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 = 6607). RESULTS: Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .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) = 0.80, P < .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 β-cell function and impairs glucose homeostasis.
Authors: Zenobia B Mehta; Nicholas Fine; Timothy J Pullen; Matthew C Cane; Ming Hu; Pauline Chabosseau; Gargi Meur; Antonio Velayos-Baeza; Anthony P Monaco; Lorella Marselli; Piero Marchetti; Guy A Rutter Journal: Am J Physiol Endocrinol Metab Date: 2016-06-21 Impact factor: 4.310
Authors: Zachary Fischer; Rahul Das; Anna Shipman; Jin-Yuan Fan; Laramie Pence; Samuel Bouyain; Leonard L Dobens Journal: Dis Model Mech Date: 2017-12-19 Impact factor: 5.758