Context: Reduced insulin signaling in insulin secreting beta-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 = .46 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 beta-cell function and impairs glucose homeostasis.
Joint Effect of Insulin Signaling Genes on Insulin Secretion and Glucose Homeostasis / Prudente, S; Morini, E; Marselli, L; Baratta, R; Copetti, M; Mendonca, C; Andreozzi, F; Chandalia, M; Pellegrini, F; Bailetti, D; Alberico, F; Shah, H; Abate, N; Sesti, G; Frittitta, L; Marchetti, P; Doria, A; Trischitta, V.. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - STAMPA. - 98:6(2013), pp. E1143-E1147. [10.1210/jc.2012-4282]
Joint Effect of Insulin Signaling Genes on Insulin Secretion and Glucose Homeostasis
Prudente S;Morini E;Pellegrini F;Bailetti D;Sesti G;Trischitta V.
2013
Abstract
Context: Reduced insulin signaling in insulin secreting beta-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 = .46 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 beta-cell function and impairs glucose homeostasis.File | Dimensione | Formato | |
---|---|---|---|
Prudente_Joint-effect-ofinsulin_2013.pdf
solo gestori archivio
Note: Articolo
Tipologia:
Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza:
Tutti i diritti riservati (All rights reserved)
Dimensione
70.44 kB
Formato
Adobe PDF
|
70.44 kB | Adobe PDF | Contatta l'autore |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.