Endothelin-1 (ET-1)—potentiated insulin secretion: Involvement of protein kinase C and the ETA receptor subtype

Gregersen, Søren; Thomsen, Jan Lykke Scheel; Hermansen, Kjeld

doi:10.1016/s0026-0495(00)91585-3

Cited by 21 publications

(11 citation statements)

References 34 publications

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“…(The first phase insulin response is primarily cAMP and Ca 2+ -dependent). Extrinsic factors such as endothelin-1 could augment insulin secretion through PKC-dependent pathways [87].…”

Section: Pkc and Insulin Secretionmentioning

confidence: 99%

Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes

2001

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Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transduction and intracellular crosstalk by phosphorylating at serine/threonine residues an array of substrates, including cell-surface receptors, enzymes, contractile proteins, transcription factors and other kinases. Individual isozymes vary in their pattern of tissue and subcellular distribution, function and Ca 2+ /phospholipid cofactor requirements, and in diabetes there is widespread activation of the DAG-PKC pathway in metabolic, cardiovascular and renal tissues. In liver, muscle and adipose tissue, PKC isozymes have been implicated both as mediators and inhibitors of insulin action. Activation of DAG-sensitive PKC isoforms, such as PKC-v and PKC-e, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-z and PKC-l, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes.Glucose-induced de novo synthesis of (palmitaterich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-b) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription (in part by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e. g. vitamin E) and/or inhibit PKC isozymes (e. g. the b-selective inhibitor LY333 531) ameliorate the biochemical and functional consequences of DAG-PKC activation in experimental diabetes, for example improving retinal blood flow and albuminuria in parallel with reductions in membrane-associated PKC isozyme activities. Thus, a greater understanding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits. [Diabetologia (2001) 44: 659±673]

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“…(The first phase insulin response is primarily cAMP and Ca 2+ -dependent). Extrinsic factors such as endothelin-1 could augment insulin secretion through PKC-dependent pathways [87].…”

Section: Pkc and Insulin Secretionmentioning

confidence: 99%

Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes

2001

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“…The two main members of the G q /G 11 family, G q and G 11 , are ubiquitously expressed (16,17); their activation results in stimulation of phospholipase C β (PLC β) isoforms and consequent inositol 1,4,5-trisphosphate-mediated (IP 3 -mediated) intracellular calcium mobilization and PKC activation (18). Interestingly, β cells express in addition to M 3 a wide variety of other potentially G q /G 11 -coupled receptors (19)(20)(21), and most of these receptors have been shown to be involved in the potentiation of insulin secretion, such as receptors for fatty acids (22), cholecystokinin (23), arginine vasopressin (24,25), endothelin (26), extracellular nucleotides (27,28), calcium (29), or zinc (30). Though for many of these receptors, the physiological relevance in the regulation of insulin secretion is unclear, the sheer number of potentially G q /G 11 -coupled receptors expressed in β cells suggests an important role of this G protein family in regulation of β cell function.…”

Section: Introductionmentioning

confidence: 99%

The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice

Sassmann¹,

Gier²,

Gröne³

et al. 2010

J. Clin. Invest.

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A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that β cell-specific inactivation of the genes encoding the G protein α-subunits Gα q and Gα 11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Gα q /Gα 11 -deficient β cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished. Electrophysiological recordings revealed that glucose-induced depolarization of isolated β cells was impaired in the absence of Gα q /Gα 11 , and closure of K ATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of β cell-autonomous potentiation of insulin secretion through factors cosecreted with insulin. We identified as autocrine mediators involved in this process extracellular nucleotides such as uridine diphosphate acting through the G q /G 11 -coupled P2Y6 receptor and extracellular calcium acting through the calciumsensing receptor. Thus, the G q /G 11 -mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators. IntroductionThe adequate secretion of insulin from pancreatic β cells is essential for the maintenance of normoglycemia; impaired insulin secretion results in diabetes mellitus with hyperglycemia, dyslipidemia, and consequent long-term tissue damage (1). The on-demand release of insulin from β cells is mainly regulated by blood glucose levels: high concentrations of glucose result in enhanced intracellular glucose metabolism with accumulation of ATP and consecutive closure of ATP-sensitive K + channels, leading to the opening of voltage-operated Ca 2+ channels and Ca 2+ -mediated exocytosis of insulin-containing vesicles (2, 3).While the ATP-dependent mechanism is clearly the master regulator of insulin release, various mediators potentiate insulin release in response to glucose. For example, gastrointestinal hormones such as glucose-dependent insulinotropic polypeptide (GIP) or glucagon-like peptide-1 (GLP-1) potentiate insulin secretion by activation of GPCRs, which signal through the G s family of heterotrimeric G proteins (4-6). The potentiating effect of G s on glucose-induced insulin release depends on activation of adenylyl cyclase and consecutive phosphorylation of voltage-operated Ca 2+ channels (7, 8) or opening of nonselective cation channels (9).Another important group of modulators are neurotransmitters and neuropeptides (10, 11), most prominent among them being the neurotransmitter acetylcholine, which is released from vagal nerve terminals and potentiates insulin secretion through the muscarinic receptor subtype M 3 (12)(13)(14)(15). In contrast to the receptors for GIP and GLP-1, the M 3 receptor does not elicit G smediated adenylyl cyclase activation, but was shown to signal through the G q /G 11 family of heterotrimeric G proteins. Th...

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“…In recent years, the existence of cross-talk between insulin and ETs has received growing attention because of their effects on adrenal blood flow and the resultant modulation of glucose uptake (Baron et al 1995, Cardillo et al 1999, Gregersen et al 2000. Insulin stimulates ET-1 synthesis and secretion in cultured aortic endothelial cells (Hu et al 1993), and also increases serum ET-1 levels as well as the expression of ET receptors in a variety of smooth-muscle cells, both in control and STZ-induced diabetic rats (Frank et al 1993).…”

Section: Discussionmentioning

confidence: 99%

Regulatory effect of experimental diabetes on the expression of endothelin receptor subtypes and their gene transcripts in the rat adrenal gland

Ikeda

Wada²,

Sanematsu³

et al. 2001

Journal of Endocrinology

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Endothelins (ETs) mediate paracrine control of vascular tone and secretion of steroids and catecholamines in the adrenal gland through two ET receptor subtypes, ETA and ETB. The differential distribution and function of these subtypes are responsible for the multiplicity of endothelin actions in this tissue. This study examines the regulatory effects of experimental diabetes on the gene expression, subtype specificity and localization of ET receptor subtypes, ET isopeptides, and endothelinconverting enzyme-1 (ECE-1) in the rat adrenal gland. The densities, pharmacological properties and distribution of ET receptor subtypes ETA and ETB in adrenal glands from streptozotocin-induced diabetic, insulin-treated diabetic and age-matched control rats were investigated, using radioligand receptor binding and autoradiographic techniques. The gene expression of ETA and ETB receptors ET-1, ET-3 and ECE-1 was evaluated using relative multiplex reverse transcription/PCR. The induction of diabetes caused a marked reduction in body weight but no significant change in adrenal gland size. The density of ET receptors was significantly increased in the diabetic rat adrenal gland, mainly because of an increase in the expression of ETB receptors. Insulin treatment normalized the diabetes-induced changes in the expression levels of ET receptor subtypes to control levels. The expression level of ET-1 mRNA was up-regulated, whereas ET-3 mRNA was down-regulated in the diabetic adrenal gland compared with the controls. The ECE-1 mRNA level in the adrenal gland was not altered by the induction of diabetes. Autoradiographic studies showed that ETA and ETB are the predominant receptor subtypes in the adrenal medulla and cortex respectively. These results suggest that ETA and ETB receptors are differentially distributed and regulated in the diabetic rat adrenal gland.

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Endothelin-1 (ET-1)—potentiated insulin secretion: Involvement of protein kinase C and the ETA receptor subtype

Cited by 21 publications

References 34 publications

Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes

Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes

The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice

Regulatory effect of experimental diabetes on the expression of endothelin receptor subtypes and their gene transcripts in the rat adrenal gland

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