PKC Is Essential for Pancreatic -Cell Replication During Insulin Resistance by Regulating mTOR and Cyclin-D2

Adaptive -cell replication occurs in response to increased metabolic demand during insulin resistance. The intracellular mediators of this compensatory response are poorly defined and their identification could provide significant targets for -cell regeneration therapies. Here we show that glucose and insulin in vitro and insulin resistance in vivo activate protein kinase C (PKC) in pancreatic islets and -cells. PKC is required for glucose- and glucokinase activator-induced proliferation of rodent and human -cells in vitro. Furthermore, either kinase-dead PKC expression (KD-PKC) or disruption of PKC in mouse -cells blocks compensatory -cell replication when acute hyperglycemia/hyperinsulinemia is induced. Importantly, KD-PKC inhibits insulin resistance-mediated mammalian target of rapamycin (mTOR) activation and cyclin-D2 upregulation independent of Akt activation. In summary, PKC activation is key for early compensatory -cell replication in insulin resistance by regulating the downstream signals mTOR and cyclin-D2. This suggests that alterations in PKC expression or activity might contribute to inadequate -cell mass expansion and -cell failure leading to type 2 diabetes.