A nutrient-regulated cytosolic calcium oscillator in endocrine pancreatic glucagon-secreting cells

Bode, Hans-Peter; Weber, Stefanie; Fehmann, Hans-Christoph; Göke, Burkhard

doi:10.1007/s004240050786

Cited by 26 publications

(27 citation statements)

References 47 publications

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“…Importantly, we demonstrate here for the first time that glucose and insulin modulate the frequency of Ca 2ϩ oscillations in clonal mouse ␣-cells. This contrasts with earlier reports in lnR1-G9 glucagonoma cells (42), where nutrients were found principally to affect the amplitude of oscillations. Although the sample sizes in both the current and an earlier (41) study were not sufficiently large to quantify the changes in primary mouse ␣-cells, such frequency modulation nonetheless provides a potential mechanism through which glucose may regulate the pulsatile release of glucagon.…”

Section: Discussioncontrasting

confidence: 99%

Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells

Ravier

Rutter²

2005

Diabetes

251

269

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The mechanisms by which hypoglycemia stimulates glucagon release are still poorly understood. In particular, the relative importance of direct metabolic coupling versus paracrine regulation by ␤-cell secretory products is unresolved. Here, we compare the responses to glucose of 1) ␣-cells within the intact mouse islet, 2) dissociated ␣-cells, and 3) clonal ␣TC1-9 cells. G lucagon is the key counterregulatory hormone responsible for opposing the glucose-lowering effects of insulin (1). Thus, glucagon stimulates both glycogen breakdown and gluconeogenesis by the liver (2) while decreasing hepatic triglyceride synthesis (3,4). Appropriate stimulation of glucagon release from pancreatic islet ␣-cells is particularly important to minimize the impact of acute insulin-induced hypoglycemia, a major complication and the cause of 2-4% of all deaths in type 1 diabetes (5,6).Glucagon release is normally stimulated as blood glucose concentrations fall, a response that is progressively diminished in type 1 diabetes (7,8). This loss of responsiveness, which leads to increased incidence and severity of hypoglycemia with time, does not involve an apparent change in total ␣-cell mass (9,10) but rather the development of "hypoglycemia blindness" in existing ␣-cells.Although the molecular mechanisms involved in the regulation of insulin secretion are increasingly well understood (11-13), knowledge of those that mediate the inhibition of glucagon release remains fragmentary. In particular, the respective roles of 1) glucose, acting directly on individual ␣-cells; 2) insulin (5,14,15); or 3) other factors, including ␥-aminobutyric acid (16) secreted from neighboring ␤-cells, are uncertain, as is 4) the contribution of autonomic inputs (5). Against an important role for a paracrine mechanism, the stimulation of glucagon release from the perfused rat pancreas after a decrease (5.5-4.4 mmol/l) in glucose concentration was unaffected by perfusion with anti-insulin antiserum (17). Similarly, a larger decrease in glucose concentration (5.5-1.4 mmol/l) prompted the same increment in glucagon release in pancreata from control or streptozotocin-induced diabetic rats (18). On the other hand, retrograde perfusion at slightly elevated glucose concentrations increased both insulin and glucagon release, suggesting an inhibitory role for ␤-cell factors at elevated glucose concentrations (19). Moreover, cessation of ␤-cell secretion is required for the activation of glucagon release during hypoglycemia in rats (20). Finally, a recent study (21) implicated the release of Zn 2ϩ ions from ␤-cells, based on the ability of micromolar concentrations of these ions to reverse the stimulatory effects of pyruvate on glucagon release from the perfused rat pancreas and the reversal of the effects of monomethyl succinate with calcium EDTA, a broad-range divalent metal ion chelator.Glucose-induced increases in total cellular ATP content and in the ATP-to-ADP(AMP) ratio have been reported in isolated pancreatic ␤-cells (22) as well as rodent islets (23-25). These ...

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Section: Discussioncontrasting

confidence: 99%

Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells

Ravier

Rutter²

2005

Diabetes

251

269

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“…Our previous studies have demonstrated that the GLUTag cell line responds appropriately to the regulatory factors known to control glu gene expression and GLP-1 synthesis and secretion in primary gut endocrine cells, including cAMP/protein kinase A, glucose-dependent insulinotropic peptide, and bethanechol (26,40,50,51). Likewise, the ␣-TC-1 and InR1-G9 cell lines have been routinely used as ␣ cell models to study glu gene expression and glucagon synthesis and secretion (19,20,30,(52)(53)(54)(55)(56). In these cell lines, for example, glucagon secretion is repressed by retinol and retinoic acid (52) and activated by phorbol esters (54), cytosolic calcium oscillations are inhibited by high glucose, and glu mRNA expression and glucagon synthesis are inhibited by insulin (55).…”

Section: Discussionmentioning

confidence: 99%

TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β

Brubaker

Jin

2005

Journal of Biological Chemistry

388

329

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The proglucagon gene (glu) encodes glucagon, expressed in pancreatic islets, and the insulinotropic hormone GLP-1, expressed in the intestines. These two hormones exert critical and opposite effects on blood glucose homeostasis. An intriguing question that remains to be answered is whether and how glu gene expression is regulated in a cell type-specific manner. We reported previously that the glu gene promoter in gut endocrine cell lines was stimulated by ␤-catenin, the major effector of the Wnt signaling pathway, whereas glu mRNA expression and GLP-1 synthesis were activated via inhibition of glycogen synthase kinase-3␤, the major negative modulator of the Wnt pathway (Ni, Z

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“…Apparently, paracrine interactions do not suffice to explain the observed alterations of glucagon secretion. Glucose inhibits glucagon secretion from clonal glucagonreleasing cells [5,11,17], and studies of pancreatic islets and cells have provided additional evidence that glucose regulates glucagon release by a direct effect on the alpha cell [5,[8][9][10][12][13][14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis was recently extended, showing that Ca 2+ filling of the endoplasmic reticulum inhibits a depolarising storeoperated current that may control voltage-dependent Ca 2+ influx and glucagon release [15]. Another proposal involves glucose control of the membrane potential via stimulation of electrogenic sodium-potassium counter transport [11]. The two latter alternatives are consistent with glucose shutting off voltage-dependent Ca 2+ entry and glucagon release by hyperpolarising the alpha cell [12,14,15].…”

Section: Introductionmentioning

confidence: 93%

“…Fundamentally different theories about glucose regulation of glucagon secretion have emerged, which can be classified in three not mutually exclusive categories. One involves direct effects of glucose on the alpha cell [8][9][10][11][12][13][14][15][16][17]. Another is based on an indirect action mediated by release of insulin [17][18][19][20][21][22], γ-aminobutyric acid (GABA) [22][23][24], Zn 2+ [25,26] or somatostatin [18,27].…”

Section: Introductionmentioning

confidence: 99%

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Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells

2006

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Aims/hypothesis The mechanisms by which glucose regulates glucagon release are poorly understood. The present study aimed to clarify the direct effects of glucose on the glucagon-releasing alpha cells and those effects mediated by paracrine islet factors. Materials and methods Glucagon, insulin and somatostatin release were measured from incubated mouse pancreatic islets and the cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) recorded in isolated mouse alpha cells. Results Glucose inhibited glucagon release with maximal effect at 7 mmol/l. Since this concentration corresponded to threshold stimulation of insulin secretion, it is unlikely that inhibition of glucagon secretion is mediated by beta cell factors. Although somatostatin secretion data seemed consistent with a role of this hormone in glucose-inhibited glucagon release, a somatostatin receptor type 2 antagonist stimulated glucagon release without diminishing the inhibitory effect of glucose. In islets exposed to tolbutamide plus 8 mmol/l K + , glucose inhibited glucagon secretion without stimulating the release of insulin and somatostatin, indicating a direct inhibitory effect on the alpha cells that was independent of ATP-sensitive K + channels. Glucose lowered [Ca 2+ ] i of individual alpha cells independently of somatostatin and beta cell factors (insulin, Zn 2+ and γ-aminobutyric acid). Glucose suppression of glucagon release was prevented by inhibitors of the sarco(endo)plasmic reticulum Ca 2+ -ATPase, which abolished the [Ca 2+ ] i -lowering effect of glucose on isolated alpha cells. Conclusions/interpretation Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion. We instead propose that glucose has a direct inhibitory effect on mouse alpha cells by suppressing a depolarising Ca 2+ store-operated current.

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A nutrient-regulated cytosolic calcium oscillator in endocrine pancreatic glucagon-secreting cells

Cited by 26 publications

References 47 publications

Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells

Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells

TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β

Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells

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