title: Inhibition of PKCepsilon improves glucose-stimulated insulin secretion and reduces insulin clearance.
abstract: 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 PKCepsilon in beta cell dysfunction. Deletion of PKCepsilon augmented insulin secretion and prevented glucose intolerance in fat-fed mice. Importantly, a PKCepsilon-inhibitory peptide improved insulin availability and glucose tolerance in db/db mice with preexisting diabetes. Functional ablation of PKCepsilon 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, PKCepsilon deletion also augmented insulin availability by reducing both whole-body insulin clearance and insulin uptake by hepatocytes. Our findings implicate PKCepsilon 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 PKCepsilon to treat type 2 diabetes.
authors.affiliation: Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. c.schmitz-peiffer@garvan.org.au
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmitz-Peiffer
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
authors.forename: James G
authors.initials: JG
authors.lastname: Burchfield
authors.forename: Ebru
authors.initials: E
authors.lastname: Gurisik
authors.forename: Sakura
authors.initials: S
authors.lastname: Narasimhan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mitchell
authors.forename: David J
authors.initials: DJ
authors.lastname: Pedersen
authors.forename: Uschi
authors.initials: U
authors.lastname: Braun
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Biden
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D007328:Insulin; D051744:Protein Kinase C-epsilon; D005947:Glucose