| First Author | Isaac R | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 7 | Pages | 1879-1889 |
| PubMed ID | 28424159 | Mgi Jnum | J:246321 |
| Mgi Id | MGI:5922683 | Doi | 10.2337/db16-0827 |
| Citation | Isaac R, et al. (2017) Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signaling Pathway Impairs beta-Cell Function In Vivo. Diabetes 66(7):1879-1889 |
| abstractText | Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-I signaling. We therefore examined the effects of mutation of five "inhibitory" Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic beta-cells, either wild-type (WT) or a mutated IRS2 protein (IRS25A). Islets size, number, and mRNA levels of catalase and superoxide dismutase were increased, whereas those of nitric oxide synthase were decreased, in 7- to 10-week-old IRS25A-beta mice compared with IRS2WT-beta mice. However, glucose homeostasis and insulin secretion in IRS25A-beta mice were impaired when compared with IRS2WT-beta mice or to nontransgenic mice. This was associated with reduced mRNA levels of Glut2 and islet beta-cell transcription factors such as Nkx6.1 and MafA Similarly, components mediating the unfolded protein response were decreased in islets of IRS25A-beta mice in accordance with their decreased insulin secretion. The beneficial effects of IRS25A on beta-cell proliferation and beta-cell transcription factors were evident only in 5- to 8-day-old mice. These findings suggest that elimination of inhibitory Ser phosphorylation sites of IRS2 exerts short-term beneficial effects in vivo; however, their sustained elimination leads to impaired beta-cell function. |
