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Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells

OBJECTIVE: Insufficient insulin secretion is a hallmark of type 2 diabetes, and exposure of β-cells to elevated lipid levels (lipotoxicity) contributes to secretory dysfunction. Functional ablation of protein kinase C ε (PKCε) has been shown to improve glucose homeostasis in models of type 2 diabete...

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Autores principales: Cantley, James, Burchfield, James G., Pearson, Gemma L., Schmitz-Peiffer, Carsten, Leitges, Michael, Biden, Trevor J.
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712791/
https://www.ncbi.nlm.nih.gov/pubmed/19401415
http://dx.doi.org/10.2337/db09-0132
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author Cantley, James
Burchfield, James G.
Pearson, Gemma L.
Schmitz-Peiffer, Carsten
Leitges, Michael
Biden, Trevor J.
author_facet Cantley, James
Burchfield, James G.
Pearson, Gemma L.
Schmitz-Peiffer, Carsten
Leitges, Michael
Biden, Trevor J.
author_sort Cantley, James
collection PubMed
description OBJECTIVE: Insufficient insulin secretion is a hallmark of type 2 diabetes, and exposure of β-cells to elevated lipid levels (lipotoxicity) contributes to secretory dysfunction. Functional ablation of protein kinase C ε (PKCε) 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 PKCε. RESEARCH DESIGN AND METHODS: We cultured islets isolated from PKCε knockout (PKCεKO) mice in palmitate prior to measuring GSIS, Ca(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(2+) influx. Instead, an upregulation of the amplifying pathways of GSIS in lipid-cultured PKCεKO β-cells was revealed under conditions in which functional ATP-sensitive K(+) channels were bypassed. Furthermore, we showed increased esterification of palmitate into triglyceride pools and an enhanced rate of lipolysis and triglyceride lipase activity in PKCεKO islets. Acute treatment with the lipase inhibitor orlistat blocked the enhancement of GSIS in lipid-cultured PKCεKO islets, suggesting that a lipolytic product mediates the enhancement of glucose-amplified insulin secretion after PKCε 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 PKCε and lipolysis. These results further highlight the therapeutic potential of PKCε inhibition to enhance GSIS from the β-cell under conditions of lipid excess.
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spelling pubmed-27127912010-08-01 Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells Cantley, James Burchfield, James G. Pearson, Gemma L. Schmitz-Peiffer, Carsten Leitges, Michael Biden, Trevor J. Diabetes Original Article OBJECTIVE: Insufficient insulin secretion is a hallmark of type 2 diabetes, and exposure of β-cells to elevated lipid levels (lipotoxicity) contributes to secretory dysfunction. Functional ablation of protein kinase C ε (PKCε) 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 PKCε. RESEARCH DESIGN AND METHODS: We cultured islets isolated from PKCε knockout (PKCεKO) mice in palmitate prior to measuring GSIS, Ca(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(2+) influx. Instead, an upregulation of the amplifying pathways of GSIS in lipid-cultured PKCεKO β-cells was revealed under conditions in which functional ATP-sensitive K(+) channels were bypassed. Furthermore, we showed increased esterification of palmitate into triglyceride pools and an enhanced rate of lipolysis and triglyceride lipase activity in PKCεKO islets. Acute treatment with the lipase inhibitor orlistat blocked the enhancement of GSIS in lipid-cultured PKCεKO islets, suggesting that a lipolytic product mediates the enhancement of glucose-amplified insulin secretion after PKCε 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 PKCε and lipolysis. These results further highlight the therapeutic potential of PKCε inhibition to enhance GSIS from the β-cell under conditions of lipid excess. American Diabetes Association 2009-08 2009-04-28 /pmc/articles/PMC2712791/ /pubmed/19401415 http://dx.doi.org/10.2337/db09-0132 Text en © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Article
Cantley, James
Burchfield, James G.
Pearson, Gemma L.
Schmitz-Peiffer, Carsten
Leitges, Michael
Biden, Trevor J.
Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells
title Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells
title_full Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells
title_fullStr Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells
title_full_unstemmed Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells
title_short Deletion of PKCε Selectively Enhances the Amplifying Pathways of Glucose-Stimulated Insulin Secretion via Increased Lipolysis in Mouse β-Cells
title_sort deletion of pkcε selectively enhances the amplifying pathways of glucose-stimulated insulin secretion via increased lipolysis in mouse β-cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712791/
https://www.ncbi.nlm.nih.gov/pubmed/19401415
http://dx.doi.org/10.2337/db09-0132
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