Inhibition of PKCɛ Improves Glucose-Stimulated Insulin Secretion and Reduces Insulin Clearance
2007; Cell Press; Volume: 6; Issue: 4 Linguagem: Inglês
10.1016/j.cmet.2007.08.012
ISSN1932-7420
AutoresCarsten Schmitz‐Peiffer, D. Ross Laybutt, James G. Burchfield, Ebru Gurisik, S. R. Narasimhan, Chris J. Mitchell, David J. Pedersen, Uschi Braun, Gregory J. Cooney, Michael Leitges, Trevor J. Biden,
Tópico(s)FOXO transcription factor regulation
ResumoSummary 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 PKCɛ in β cell dysfunction. Deletion of PKCɛ augmented insulin secretion and prevented glucose intolerance in fat-fed mice. Importantly, a PKCɛ-inhibitory peptide improved insulin availability and glucose tolerance in db / db mice with preexisting diabetes. Functional ablation of PKCɛ 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, PKCɛ deletion also augmented insulin availability by reducing both whole-body insulin clearance and insulin uptake by hepatocytes. Our findings implicate PKCɛ 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 PKCɛ to treat type 2 diabetes.
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