Inhibition of PKCε Improves Glucose-Stimulated Insulin Secretion and Reduces Insulin Clearance

Carsten Schmitz-Peiffer, D. Ross Laybutt, James G. Burchfield, Ebru Gurisik, Sakura Narasimhan, Christopher J. Mitchell, David J. Pedersen, Uschi Braun, Gregory J. Cooney, Michael Leitges, Trevor J. Biden

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79 Citations (Scopus)


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

Original languageEnglish
Pages (from-to)320-328
Number of pages9
JournalCell Metabolism
Issue number4
Publication statusPublished - 3 Oct 2007
Externally publishedYes



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