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Deletion of PKCζ selectively enhances the amplifying pathways of glucose-stimulated insulin secretion via increased lipolysis in mouse β-cells
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Deletion of PKCζ selectively enhances the amplifying pathways of glucose-stimulated insulin secretion via increased lipolysis in mouse β-cells
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Deletion of PKCζ selectively enhances the amplifying pathways of glucose-stimulated insulin secretion via increased lipolysis in mouse β-cells
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Journal Article
Deletion of PKCζ selectively enhances the amplifying pathways of glucose-stimulated insulin secretion via increased lipolysis in mouse β-cells
2009
Overview
OBJECTIVE--Insufficient insulin secretion is a hallmark of type 2 diabetes, and exposure of G-cells to elevated lipid levels (lipotoxicity) contributes to secretory dysfunction. Functional ablation of protein kinase Cζ (PKCζ) has been shown to improve glucose homeostasis in models of type 2 diabetes and, in particular, to enhance glucose-stimulated insulin secretion (GSIS) after lipid exposure. Therefore, we investigated the lipid-dependent mechanisms responsible for the enhanced GSIS after inactivation of PKCζ. RESEARCH DESIGN AND METHODS--We cultured islets isolated from PKCζ knockout (PKCcKO) mice in palmitate prior to measuring GSIS, [Ca.sup.2+] responses, palmitate esterification products, lipolysis, lipase activity, and gene expression. RESULTS--The enhanced GSIS could not be explained by increased expression of another PKC isoform or by alterations in glucose-stimulated [Ca.sup.2+] influx. Instead, an upregulation of the amplifying pathways of GSIS in lipid-cultured PKCζKO β-cells was revealed under conditions in which functional ATP-sensitive [K.sup.+] channels were bypassed. Furthermore, we showed increased esterification of palmitate into triglyceride pools and an enhanced rate of lipolysis and triglyceride lipase activity in PKCζKO islets. Acute treatment with the lipase inhibitor orlistat blocked the enhancement of GSIS in lipid-cultured PKCζKO islets, suggesting that a lipolytic product mediates the enhancement of glucose-amplified insulin secretion after PKCs deletion. CONCLUSIONS--Our findings demonstrate a mechanistic link between lipolysis and the amplifying pathways of GSIS in murine β-cells, and they suggest an interaction between PKCζ and lipolysis. These results further highlight the therapeutic potential of PKCζ inhibition to enhance GSIS from the β-cell under conditions of lipid excess. Diabetes 58:1826-1834, 2009
Publisher
American Diabetes Association
