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

ABSTRACT: 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.

SUBMITTER: Lakshmipathi J 

PROVIDER: S-EPMC4839210 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature