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Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signaling Pathway Impairs β-Cell
Roi Isaac1, Yaron Vinik1, Sigalit Boura-Halfon1
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
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 β-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-β mice compared with IRS2WT-β mice. However, glucose homeostasis and insulin secretion in IRS25A-β mice were impaired when compared with IRS2WT-β mice or to nontransgenic mice. This was associated with reduced mRNA levels of Glut2 and islet β-cell transcription factors such as Nkx6.1 and MafA Similarly, components mediating the unfolded protein response were decreased in islets of IRS25A-β mice in accordance with their decreased insulin secretion. The beneficial effects of IRS25A on β-cell proliferation and β-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 β-cell function.
Insights
Eliminating inhibitory phosphorylation sites on insulin receptor substrate 2 (IRS2) initially boosts pancreatic beta-cell growth but ultimately impairs glucose control and insulin secretion in mice.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Research
Background:
- Cellular stress and inflammation trigger inhibitory phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites, hindering insulin and IGF-I signaling.
- IRS proteins are crucial mediators of insulin and insulin-like growth factor signaling pathways.
Purpose of the Study:
- To investigate the functional consequences of mutating inhibitory Ser phosphorylation sites on IRS2 in pancreatic beta-cells.
- To assess the impact of sustained IRS2 inhibitory site elimination on beta-cell function and glucose homeostasis in vivo.
Main Methods:
- Generation of transgenic mice selectively overexpressing wild-type (WT) or mutated IRS2 (IRS2 5A) in pancreatic beta-cells.
- Analysis of islet morphology, gene expression (catalase, superoxide dismutase, nitric oxide synthase, Glut2, Nkx6.1, MafA), glucose homeostasis, and insulin secretion.
Main Results:
- IRS2 5A mice exhibited increased islet size and specific antioxidant enzyme mRNA levels, but decreased nitric oxide synthase mRNA compared to IRS2WT mice.
- Impaired glucose homeostasis and insulin secretion were observed in IRS2 5A mice, linked to reduced Glut2 and key beta-cell transcription factor (Nkx6.1, MafA) mRNA levels.
- Beneficial effects on beta-cell proliferation and transcription factors were transient, observed only in young (5-8 day old) mice.
Conclusions:
- Sustained elimination of IRS2 inhibitory Ser phosphorylation sites leads to impaired beta-cell function and glucose metabolism.
- While short-term benefits on beta-cell proliferation exist, long-term disruption of IRS2 phosphorylation negatively impacts insulin secretion and homeostasis.