An important goal in diabetes research is to understand the processes that trigger endogenous beta cell proliferation. Hyperglycemia induces beta cell replication, but the mechanism remains debated. A prime candidate is insulin, acting locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces beta cell proliferation via insulin signaling. Using mice lacking insulin signaling intermediate IRS2, we confirmed that hyperglycemia-induced beta cell proliferation requires IRS2 both in vivo and ex vivo. Surprisingly, insulin receptor activation was not required for glucose-induced proliferation, nor was insulin itself sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with MTOR and ERK activation by glucose and AKT activation by insulin. MTOR, but not ERK, activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced beta cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling were lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation

Read more »