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


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

Type Journal
ISBN 1550-4131 (Print)
Authors Schmitz-Peiffer, C.;Laybutt, D. R.;Burchfield, J. G.;Gurisik, E.;Narasimhan, S.;Mitchell, C. J.;Pedersen, D. J.;Braun, U.;Cooney, G. J.;Leitges, M.;Biden, T. J. :
Garvan Authors A/Prof Carsten Schmitz-Peiffer , Prof Gregory Cooney , A/Prof Ross Laybutt , Prof Trevor Biden
Publisher Name CELL METAB
Published Date 2007-01-01 00:00:00
Published Volume 6
Published Issue 4
Published Pages 320-8
Status Published In-print
OpenAccess Link Schmitz-Peiffer CM.pdf