| First Author | Beith JL | Year | 2008 |
| Journal | Endocrinology | Volume | 149 |
| Issue | 5 | Pages | 2251-60 |
| PubMed ID | 18202127 | Mgi Jnum | J:326637 |
| Mgi Id | MGI:7316523 | Doi | 10.1210/en.2007-1557 |
| Citation | Beith JL, et al. (2008) Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology 149(5):2251-60 |
| abstractText | A relative decrease in beta-cell mass is key in the pathogenesis of type 1 diabetes, type 2 diabetes, and in the failure of transplanted islet grafts. It is now clear that beta-cell duplication plays a dominant role in the regulation of adult beta-cell mass. Therefore, knowledge of the endogenous regulators of beta-cell replication is critical for understanding the physiological control of beta-cell mass and for harnessing this process therapeutically. We have shown that concentrations of insulin known to exist in vivo act directly on beta-cells to promote survival. Whether insulin stimulates adult beta-cell proliferation remains unclear. We tested this hypothesis using dispersed primary mouse islet cells double labeled with 5-bromo-2-deoxyuridine and insulin antisera. Treating cells with 200-pm insulin significantly increased proliferation from a baseline rate of 0.15% per day. Elevating glucose from 5-15 mm did not significantly increase beta-cell replication. beta-Cell proliferation was inhibited by somatostatin as well as inhibitors of insulin signaling. Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by low, but not high (superphysiological), insulin doses. Insulin-stimulated mouse insulinoma cell proliferation was dependent on both phosphatidylinositol 3-kinase/Akt and Raf-1/MAPK kinase pathways. Overexpression of Raf-1 was sufficient to increase proliferation in the absence of insulin, whereas a dominant-negative Raf-1 reduced proliferation in the presence of 200-pm insulin. Together, these results demonstrate for the first time that insulin, at levels that have been measured in vivo, can directly stimulate beta-cell proliferation and that Raf-1 kinase is involved in this process. These findings have significant implications for the understanding of the regulation of beta-cell mass in both the hyperinsulinemic and insulin-deficient states that occur in the various forms of diabetes. |
