Effect of extracellular pH on insulin secretion and glucose metabolism in neonatal and adult rat pancreatic islets

Hyder, Ayman; Laue, Christiane; Schrezenmeir, Jürgen

doi:10.1007/s592-001-8075-9

Cited by 18 publications

(18 citation statements)

References 29 publications

(41 reference statements)

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“…4B). However, intracellular acidification does not always enhance glucose-induced insulin secretion in islets (13,14). Further studies are required for the elucidation of OGR1-independent enhancement of insulin secretion.…”

Section: Discussionmentioning

confidence: 98%

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Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Nakakura¹,

Mogi²,

Tobo³

et al. 2012

Endocrinology

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Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of G q/11 proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca 2ϩ concentration. In conclusion, the OGR1/G q/11 protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl. (Endocrinology 153: 4171-4180, 2012)

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Section: Discussionmentioning

confidence: 98%

“…Insulin secretion has been shown to be regulated by intracellular and/or extracellular pH in vivo (12) and in vitro (13)(14)(15), although the pH effects are controversial. In the present study, we aimed to determine whether and, if so, how OGR1 is involved in insulin secretion in vivo and in vitro using OGR1-deficient mice and islets.…”

mentioning

confidence: 99%

Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Nakakura¹,

Mogi²,

Tobo³

et al. 2012

Endocrinology

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“…Insulin secretion caused by high glucose showed a bell-shaped dependence on extracellular pH with a peak at pH 7.4: the activity at pH 7.7 and 6.5 was about 50% of that of pH 7.4 [4]. A similar bell-shaped response to extracellular pH was confirmed [5]. Change in the extracellular pH is accompanied by a change in the intracellular pH, which has been thought to be a critical factor for insulin secretion.…”

mentioning

confidence: 54%

Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions

2014

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Abstract. Insulin secretion with respect to pH environments has been investigated for a long time but its mechanism remains largely unknown. Extracellular pH is usually maintained at around 7.4 and, its change has been thought to occur in non-physiological situations. Acidification takes place under ischemic and inflammatory microenvironments, where stimulation of anaerobic glycolysis results in the production of lactic acid. In addition to ionotropic ion channels, such as transient receptor potential V1 (TRPV1) and acid-sensing ion channels (ASICs), metabotropic proton-sensing G proteincoupled receptors (GPCRs) have also been identified recently as proton-sensing machineries. While ionotropic ion channels usually sense strong acidic pH, proton-sensing GPCRs sense pH of 7.6 to 6.0 and have been shown to mediate a variety of biological actions in neutral and mildly acidic pH environments. Studies with receptor knockout mice have revealed that proton-sensing receptors, including ovarian cancer G protein-coupled receptor 1 (OGR1), a proton-sensing GPCRs, play a role in the regulation of insulin secretion and glucose metabolism under physiological conditions. Small molecule 3,5-disubstituted isoxazoles have recently been identified as OGR1 agonists working at neutral pH and have been shown to stimulate pancreatic β-cell differentiation and insulin synthesis. Thus, proton-sensing OGR1 may be an important player for insulin secretion and a potential target for improving β-cell function.

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“…pH influences the conversion of proinsulin to insulin [133,134], insulin secretion [135], and the conversion of insulin to the zinc hexamer and its storage in the pancreas -the hexamer is a zinc-bound complex which is less active and more stable at relatively neutral pH. This availability of the zinc hexamer serves to ensure a controlled-release supply of insulin in response to glycaemic overload.…”

Section: Ph Influences the Levels Of Minerals And The Regulation Of Bmentioning

confidence: 99%

pH is a Neurally Regulated Physiological System. Increased Acidity Alters Protein Conformation and Cell Morphology and is a Significant Factor in the Onset of Diabetes and Other Common Pathologies

Ewing¹

2012

Open Sys Biol J

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Abstract:Background: The body's physiological stability is maintained by the influence of the autonomic nervous system and the dynamic interaction of the organ systems which regulate all aspects of the body's function. These physiological systems and their function have been overlooked by the genetic paradigm. A better understanding of these systems may lead to an improved understanding of the fundamental relationship involving sense perception, neural function and organ networks, and cellular and molecular biology. This article follows earlier articles by the author which illustrate that sleep, blood pressure and blood glucose are neurally regulated physiological systems. Aims:The purpose of this article is to discuss how Grakov's mathematical model of the physiological systems (i) influences the contemporary understanding of the processes which regulate the pH in biological systems i.e. that pH is a neurally regulated physiological system; (ii) is a significant factor in the emergence of changes to cell morphology and, ultimately, the onset of pathologies; and (iii) involves environmental factors more commonly associated with phenotype.Results: It considers the fundamental role played by pH e.g. regulating the levels and redox state of minerals, protein conformation, the activation of proteins and enzymes, and how this influences metabolic function. It considers the consequences of increased acidity, in particular from alcoholic beverages and acidified soft drinks, and how this influences the processes which regulate the body's physiological stability. Conclusions:The article concludes that the body's impaired ability to regulate its acidity, exascerbated by the consumption of highly acidic beverages, is a considerably underestimated factor in the subsequent development and onset of many common pathologies e.g. diabetes, cardiovascular diseases, alzheimer's disease, cancers, etc. Keywords:Cognitive, neuroregulation, top-down, systems biology, physiological systems. BACKGROUNDThe laws of chemistry characterise every chemical reaction. The prevailing reaction conditions influence the rate at which each reaction proceeds. In this article we consider whether the significance of pH has been significantly overlooked in biomedical research.Changes to the pH of a biochemical system or reaction often influences the structure of chemical components, their level, and subsequently the rate at which these components react. This determines the redox state of minerals; their ability to complex with DNA; their ability to activate enzymatic reactions; and their ability to be filtered and/or eliminated from the body. Altered pH influences protein conformation and the ability of proteins to react. It influences the characteristics of epigenetic reactions such as methylation, histone de-acetylation, acetylation, phosphorylation, etc.The body's homeostasis is maintained by neuroregulation of the various organ networks. These multiple physiological systems, their nature and structure, and the factors which *Address correspondence t...

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Effect of extracellular pH on insulin secretion and glucose metabolism in neonatal and adult rat pancreatic islets

Cited by 18 publications

References 29 publications

Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions

pH is a Neurally Regulated Physiological System. Increased Acidity Alters Protein Conformation and Cell Morphology and is a Significant Factor in the Onset of Diabetes and Other Common Pathologies

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