Inhibition of PKCε improves glucose-stimulated insulin secretion and reduces insulin clearance

In type 2 diabetes, pancreatic 0 cells fail to secrete sufficient insulin to overcome peripheral insulin resistance. Intracellular lipid accumulation contributes to 0 cell failure through poorly defined mechanisms. Here we report a role for the lipid-regulated protein kinase C isoform PKC epsilon in beta cell dysfunction. Deletion of PKC epsilon augmented insulin secretion and prevented glucose intolerance in fat-fed mice. Importantly, a PKC epsilon-inhibitory peptide improved insulin availability and glucose tolerance in db/db mice with preexisting diabetes. Functional ablation of PKC epsilon selectively enhanced insulin release ex vivo from diabetic or lipid-pretreated islets and optimized the glucose-regulated lipid partitioning that amplifies the secretory response. Independently, PKC epsilon deletion also augmented insulin availability by reducing both whole-body insulin clearance and insulin uptake by hepatocytes. Our findings implicate PKC epsilon in the etiology of beta cell dysfunction and highlight that enhancement of insulin availability, through separate effects on liver and 0 cells, provides a rationale for inhibiting PKC epsilon to treat type 2 diabetes.