详细记录  
题名:Joint effect of insulin signaling genes on insulin secretion and glucose homeostasis.
作者: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;
来源:J Clin Endocrinol Metab. 2013 Jun;98(6):E1143-7. doi: 10.1210/jc.2012-4282. Epub [ IF= 0.00 ] ]
URL :10.1210/jc.2012-4282
日期:20130430
摘要: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 = .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 beta-cell function and
impairs glucose homeostasis.

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