PKCepsilon mediates glucose-regulated insulin production in pancreatic beta-cells

Warwar, Nasim; Dov, Avital; Abramovitch, Eva; Wu, Ren Huang; Jmoudiak, Marina; Haber, Esther Piltcher; Cerasi, Erol; Нешер, Ронит

doi:10.1016/j.bbamcr.2008.04.007

Cited by 9 publications

(10 citation statements)

References 26 publications

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“…Numerous studies have shown that ␤-cells express multiple PKC isoforms (23,24). PKC knock-out studies revealed that PKC plays a key role in the regulation of insulin secretion (44,45). However, because PKC appears to affect a variety of targets involved in regulation of insulin secretion (24), it makes it difficult to assign a definite role for the PKC-mediated downregulation of K ATP channels.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Endocytic Recycling and Protein Kinase C-mediated Lysosomal Degradation Control KATP Channel Surface Density

Manna¹,

Smith²,

Taneja

et al. 2010

Journal of Biological Chemistry

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Pancreatic ATP-sensitive potassium (K ATP ) channels control insulin secretion by coupling the excitability of the pancreatic ␤-cell to glucose metabolism. Little is currently known about how the plasma membrane density of these channels is regulated. We therefore set out to examine in detail the endocytosis and recycling of these channels and how these processes are regulated. To achieve this goal, we expressed K ATP channels bearing an extracellular hemagglutinin epitope in human embryonic kidney cells and followed their fate along the endocytic pathway. Our results show that K ATP channels undergo multiple rounds of endocytosis and recycling. Further, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate significantly decreases K ATP channel surface density by reducing channel recycling and diverting the channel to lysosomal degradation. These findings were recapitulated in the model pancreatic ␤-cell line INS1e, where activation of PKC leads to a decrease in the surface density of native K ATP channels. Because sorting of internalized channels between lysosomal and recycling pathways could have opposite effects on the excitability of pancreatic ␤-cells, we propose that PKC-regulated K ATP channel trafficking may play a role in the regulation of insulin secretion.The ATP-sensitive potassium (K ATP ) channel plays a key role in the regulation of glucose-induced insulin secretion by the pancreatic ␤-cells (1-3). Central to this role is its unique ability to couple changes in the metabolism of glucose to changes in membrane potential. A rise in blood glucose levels increases the uptake and metabolism of glucose, resulting in an increase in the intracellular [ATP]/[ADP] ratio and inhibition of K ATP channels. This leads to depolarization of the ␤-cell membrane (caused by inhibition of K ϩ efflux), stimulating opening of voltage-activated calcium channels, Ca 2ϩ influx, and insulin release (4). Regulation of K ATP channel function by products of metabolism (e.g. nucleotides) as well as other cellular signals (e.g. protein kinases, lipids) has been extensively studied (1,5,6). By comparison, little is known about how the number of channels at the plasma membrane of the cell is controlled, although there is growing evidence that changes in the membrane density of the channel underlie disease states (7,8).Structurally, K ATP channels exist as octamers formed from four subunits of the inwardly rectifying potassium channel Kir6.1 or Kir6.2, together with four sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits (5, 9 -11). The pancreatic K ATP channel comprises Kir6.2 and SUR1 subunits, which are encoded by the genes KCNJ11 and ABCC8, respectively (5, 6, 10, 11). Mutations in both of these genes are associated with disorders of insulin secretion including congenital hyperinsulinism and neonatal diabetes (4, 7). Studies have shown that although some mutations affect the nucleotide regulation of the channel (12-14), others alter the density of the channels at the cell surface by affecting traffickin...

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Section: Discussionmentioning

confidence: 99%

Constitutive Endocytic Recycling and Protein Kinase C-mediated Lysosomal Degradation Control KATP Channel Surface Density

Manna¹,

Smith²,

Taneja

et al. 2010

Journal of Biological Chemistry

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“…A role for PKCε in the control of insulin biosynthesis is reported (Warwar et al , 2008), but there are conflicting data concerning what role PKCε plays in regulated insulin secretion. Published findings demonstrate that PKCε translocates to insulin-containing secretory granules in response to elevated levels of glucose, whereas over expression of a dominant-negative PKCε abolishes GSIS (Mendez et al , 2003; Zaitsev et al , 1995).…”

Section: Rap1 Effectors and Their Potential Roles In The Control mentioning

confidence: 99%

Epac2-Dependent Rap1 Activation and the Control of Islet Insulin Secretion by Glucagon-Like Peptide-1

Leech

Chepurny

Holz

2010

Vitamins &Amp; Hormones

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Glucagon-like peptide-1 (GLP-1) binds its Class II G protein-coupled receptor to stimulate cyclic adenosine monophosphate (cAMP) production and to potentiate the glucose metabolismdependent secretion of insulin from pancreatic β cells located within the islets of Langerhans. Prior clinical studies demonstrate that this cAMP-mediated action of GLP-1 to potentiate glucosestimulated insulin secretion (GSIS) is of major therapeutic importance when evaluating the abilities of GLP-1 receptor (GLP-1R) agonists to lower levels of blood glucose in type 2 diabetic subjects. Surprisingly, recent in vitro studies of human or rodent islets of Langerhans provide evidence for the existence of a noncanonical mechanism of β cell cAMP signal transduction, one that may explain how GLP-1R agonists potentiate GSIS. What these studies demonstrate is that a cAMP-regulated guanine nucleotide exchange factor designated as Epac2 couples β cell cAMP production to the protein kinase A-independent stimulation of insulin exocytosis. Provided here is an overview of the Epac2 signal transduction system in β cells, with special emphasis on Rap1, a Ras-related GTPase that is an established target of Epac2.

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“…This enhancement was observed in both dietary and genetic mouse models of type 2 diabetes and when using ex vivo models of β-cell dysfunction (18). Others have also reported a role for PKCε in the maturation of proinsulin to insulin (21). Because the mechanisms by which PKCε deletion improves GSIS remain unclear, our current aim was to investigate the potential role of alterations in β-cell lipid metabolism.…”

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confidence: 96%

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

et al. 2009

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OBJECTIVEInsufficient 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 METHODSWe cultured islets isolated from PKCε knockout (PKCεKO) mice in palmitate prior to measuring GSIS, Ca2+ responses, palmitate esterification products, lipolysis, lipase activity, and gene expression.RESULTSThe enhanced GSIS could not be explained by increased expression of another PKC isoform or by alterations in glucose-stimulated Ca2+ 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.CONCLUSIONSOur 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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PKCepsilon mediates glucose-regulated insulin production in pancreatic beta-cells

Cited by 9 publications

References 26 publications

Constitutive Endocytic Recycling and Protein Kinase C-mediated Lysosomal Degradation Control KATP Channel Surface Density

Constitutive Endocytic Recycling and Protein Kinase C-mediated Lysosomal Degradation Control KATP Channel Surface Density

Epac2-Dependent Rap1 Activation and the Control of Islet Insulin Secretion by Glucagon-Like Peptide-1

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

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