[Note: To read some of the authors’ comments on these findings, see “Solving a Critical Part of the Insulin Puzzle.”]
In type 2 diabetes, pancreatic ß cells fail to secrete sufficient insulin to overcome peripheral insulin resistance. Intracellular lipid accumulation contributes to ß cell failure through poorly defined mechanisms.
Here we report a role for the lipid-regulated protein kinase C isoform PKCe in ß cell dysfunction.
Deletion of PKCe augmented insulin secretion and prevented glucose intolerance in fat-fed mice. Importantly, a PKCe-inhibitory peptide improved insulin availability and glucose tolerance in db/db mice with preexisting diabetes. Functional ablation of PKCe 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, PKCe deletion also augmented insulin availability by reducing both whole-body insulin clearance and insulin uptake by hepatocytes.
Our findings implicate PKCe in the etiology of ß cell dysfunction and highlight that enhancement of insulin availability, through separate effects on liver and ß cells, provides a rationale for inhibiting PKCe to treat type 2 diabetes.
Source: Cell Metabolism. October 3, 2007. Vol 6, pp. 320-328, by Carsten Schmitz-Peiffer C, Laybutt DR, Burchfield JG, Gurisik E, Narasimhan S, Mitchell CJ, Pedersen DJ, Braun U, Cooney GJ, Leitges M, Biden TJ. Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Biotechnology Centre of Oslo, University of Oslo, Oslo Norway. [E-mail: firstname.lastname@example.org and email@example.com