| First Author | Alvarez-Perez JC | Year | 2014 |
| Journal | Mol Endocrinol | Volume | 28 |
| Issue | 12 | Pages | 2038-48 |
| PubMed ID | 25361392 | Mgi Jnum | J:218271 |
| Mgi Id | MGI:5617101 | Doi | 10.1210/me.2014-1207 |
| Citation | Alvarez-Perez JC, et al. (2014) Hepatocyte growth factor ameliorates hyperglycemia and corrects beta-cell mass in IRS2-deficient mice. Mol Endocrinol 28(12):2038-48 |
| abstractText | Insulin resistance, when combined with decreased beta-cell mass and relative insufficient insulin secretion, leads to type 2 diabetes. Mice lacking the IRS2 gene (IRS2(-/-) mice) develop diabetes due to uncompensated insulin resistance and beta-cell failure. Hepatocyte growth factor (HGF) activates the phosphatidylinositol 3-kinase/Akt signaling pathway in beta-cells without recruitment of IRS1 or IRS2 and increases beta-cell proliferation, survival, mass, and function when overexpressed in beta-cells of transgenic (TG) mice. We therefore hypothesized that HGF may protect against beta-cell failure in IRS2 deficiency. For that purpose, we cross-bred TG mice overexpressing HGF in beta-cells with IRS2 knockout (KO) mice. Glucose homeostasis analysis revealed significantly reduced hyperglycemia, compensatory hyperinsulinemia, and improved glucose tolerance in TG/KO mice compared with those in KO mice in the context of similar insulin resistance. HGF overexpression also increased glucose-stimulated insulin secretion in IRS2(-/-) islets. To determine whether this glucose homeostasis improvement correlated with alterations in beta-cells, we measured beta-cell mass, proliferation, and death in these mice. beta-Cell proliferation was increased and death was decreased in TG/KO mice compared with those in KO mice. As a result, beta-cell mass was significantly increased in TG/KO mice compared with that in KO mice, reaching levels similar to those in wild-type mice. Analysis of the intracellular targets involved in beta-cell failure in IRS2 deficiency showed Pdx-1 up-regulation, Akt/FoxO1 phosphorylation, and p27 down-regulation in TG/KO mouse islets. Taken together, these results indicate that HGF can compensate for IRS2 deficiency and subsequent insulin resistance by normalizing beta-cell mass and increasing circulating insulin. HGF may be of value as a therapeutic agent against beta-cell failure. |
