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UBC Theses and Dissertations

The role of insulin on beta-cell proliferation Beith, Jennifer Lynn


A relative decrease in β-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 β-cell duplication plays a dominant role in the regulation of adult β-cell mass. Knowledge of the endogenous regulators of β-cell replication is therefore critical for understanding the physiological control of β-cell mass and for harnessing this process therapeutically. We have shown that physiological concentrations of insulin act directly on β-cells to promote survival. Whether insulin stimulates adult β-cell proliferation remains unclear. We tested this hypothesis using dispersed primary mouse islet cells double-labeled with BrdU 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 mM to 15 mM did not significantly increase β-cell replication. β-cell proliferation was inhibited by somatostatin, as well as inhibitors of insulin signalling. Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by physiological, but not super-physiological insulin doses. Insulin-stimulated MIN6 cell proliferation was dependent on both PI3-kinase/Akt and the Raf-l/MEK pathways. Examination of the effects of insulin and its receptor pathway on cell cycle molecules was inconclusive. Together, these results demonstrate for the first time that insulin, at physiological levels, can directly stimulate β-cell proliferation and that Raf-l kinase is involved in this process. These findings have significant implications for the understanding of the regulation of β-cell mass in both the hyperinsulinemic and insulindeficient states that occur in the various forms of diabetes.

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