scholarly journals γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion

2020 ◽  
Vol 295 (16) ◽  
pp. 5419-5426
Author(s):  
Qian Yu ◽  
Bao Khanh Lai ◽  
Parvin Ahooghalandari ◽  
Anders Helander ◽  
Erik Gylfe ◽  
...  
Keyword(s):  
Glucagon Secretion ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Human Islets ◽  
Glucagon Release ◽  
Paracrine Factors ◽  
Glucose Inhibition ◽  
Mouse Islets ◽  
Blood Glucose Concentrations ◽  
Effect Of Glucose

Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.

Calcitonin modulation of insulin and glucagon secretion in man

1982 ◽  
Vol 242 (3) ◽  
pp. E206-E213 ◽  
Author(s):  
D. Giugliano ◽  
N. Passariello ◽  
S. Sgambato ◽  
R. Torella ◽  
F. D'Onofrio
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Insulin Response ◽  
Glucagon Secretion ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Acute Insulin Response ◽  
Insulin Responses ◽  
Effect Of Glucose

These studies were undertaken to evaluate the effect of different doses of calcitonin on insulin and glucagon responses to intravenous glucase loads and to assess the mechanism/s by which calcitonin inhibits insulin secretion in man. In our studies, even the infusion of the 1-U dose of calcitonin was found to inhibit by 45% the acute insulin response to a glucose (20 g) pulse. This effect was associated with a significant decrease in glucose disappearance rates. These negative effects of calcitonin on both insulin secretion and glucose tolerance were dose-related. The inhibition of the acute insulin response to glucose was 65% and up to 90% with the infusion of the 4- and 8-U doses, respectively. The suppressive effect of glucose on glucagon secretion was significantly reduced by calcitonin. The inhibitory effect of calcitonin on insulin responses to glucose (5 g) and glucose tolerance was reversed by both theophylline and calcium. By contrast, infusion of lysine acetylsalicylate to block the synthesis of endogenous prostaglandins did not diminish the inhibitory effect of calcitonin on insulin secretion. These results demonstrate that a) calcitonin inhibits glucose-induced insulin responses and deteriorates glucose tolerance in normal humans in a dose-dependent manner; b) calcitonin reduces the suppressive effect of glucose on glucagon secretion in a dose-related fashion; and c) both theophylline and calcium reverse the inhibitory effect of calcitonin on insulin secretion. It is hypothesized that calcitonin effects on insulin and glucagon release are mediated via a change in calcium redistribution in the islet cells.

scholarly journals Paracrine regulation of glucagon secretion: the β/α/δ model

2016 ◽  
Vol 310 (8) ◽  
pp. E597-E611 ◽  
Author(s):  
Margaret Watts ◽  
Joon Ha ◽  
Ofer Kimchi ◽  
Arthur Sherman
Keyword(s):  
Mathematical Model ◽  
Potassium Channels ◽  
Mathematical Models ◽  
Glucagon Secretion ◽  
Inhibitory Effect ◽  
Β Cells ◽  
Paracrine Regulation ◽  
Intrinsic Mechanism ◽  
Effect Of Glucose ◽  
Do So

The regulation of glucagon secretion in the pancreatic α-cell is not well understood. It has been proposed that glucose suppresses glucagon secretion either directly through an intrinsic mechanism within the α-cell or indirectly through an extrinsic mechanism. Previously, we described a mathematical model for isolated pancreatic α-cells and used it to investigate possible intrinsic mechanisms of regulating glucagon secretion. We demonstrated that glucose can suppress glucagon secretion through both ATP-dependent potassium channels (KATP) and a store-operated current (SOC). We have now developed an islet model that combines previously published mathematical models of α- and β-cells with a new model of δ-cells and use it to explore the effects of insulin and somatostatin on glucagon secretion. We show that the model can reproduce experimental observations that the inhibitory effect of glucose remains even when paracrine modulators are no longer acting on the α-cell. We demonstrate how paracrine interactions can either synchronize α- and δ-cells to produce pulsatile oscillations in glucagon and somatostatin secretion or fail to do so. The model can also account for the paradoxical observation that glucagon can be out of phase with insulin, whereas α-cell calcium is in phase with insulin. We conclude that both paracrine interactions and the α-cell's intrinsic mechanisms are needed to explain the response of glucagon secretion to glucose.

scholarly journals Alloxan reversibly impairs glucagon release and glucose oxidation by pancreatic A2-cells

1980 ◽  
Vol 188 (1) ◽  
pp. 201-206 ◽  
Author(s):  
Claes-Göran Östenson
Keyword(s):  
B Cell ◽  
Glucose Oxidation ◽  
Cell Types ◽  
Suppressive Effect ◽  
Bovine Insulin ◽  
Glucagon Release ◽  
High Concentration ◽  
Islet Cell Types ◽  
Effect Of Glucose

Alloxan is known as a selective B-cell cytotoxic substance, and there is so far little evidence for a direct toxic effect on the other islet cell types. To elucidate further whether such effects occur, the actions of alloxan on glucagon release and glucose oxidation were studied in isolated normal or A2-cell-rich pancreatic islets of the guinea pig. The A2-cell-rich islets were obtained from animals injected with streptozotocin 1–2 weeks before islet isolation. After exposure to alloxan (2 or 5mm) in vitro for 30min at 4°C, the islets were incubated in media containing either 1.7mm-glucose or 16.7mm-glucose plus 30m-i.u. of bovine insulin/ml. In both types of islet, alloxan abolished the ability of glucose and insulin both to decrease glucagon release and to increase the rate of glucose oxidation. A high concentration of glucose (28mm) during exposure to alloxan protected against these injurious effects. Tissue culture of alloxan-treated islets for 24h in 5.5mm-glucose restored neither the suppressive effect of glucose on glucagon release nor the inhibition of glucose oxidation of the A2-cells. However, culture for 1 week completely normalized both the glucagon-secretory response and glucose oxidation by both kinds of islets. It is therefore concluded that alloxan affects the secretory mechanism of not only the B-cell but also of the islet A2-cell, although this latter cell type is not primarily destroyed by the drug. The data furthermore support the concept of a relationship between glucose metabolism and the glucose-mediated glucagon release of the A2-cell.

scholarly journals Glucose Stimulates Glucagon Release in Single Rat α-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in β-Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4861-4870 ◽  
Author(s):  
Hervør Lykke Olsen ◽  
Sten Theander ◽  
Krister Bokvist ◽  
Karsten Buschard ◽  
Claes B. Wollheim ◽  
...  
Keyword(s):  
Katp Channel ◽  
Channel Blocker ◽  
Adenine Nucleotides ◽  
Glucagon Secretion ◽  
Katp Channels ◽  
Suppressive Effect ◽  
Na Channel ◽  
Glucagon Release ◽  
Stimulatory Action ◽  
Isolated Rat

In isolated rat pancreatic α-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P < 0.05; n = 5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker ω-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. ω-Conotoxin suppressed glucagon release to 15 mm K+, whereas a combination of ω-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mm K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments, exocytosis was stimulated by reducing the cytoplasmic ADP concentration, whereas changes of the ATP concentration in the physiological range had little effect. We conclude that glucose stimulates glucagon release from isolated rat α-cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+ channels. Glucose also stimulated exocytosis by an amplifying mechanism, probably involving changes in adenine nucleotides. The stimulatory action of glucose in isolated α-cells contrasts with the suppressive effect of the sugar in intact islets and highlights the primary importance of islet paracrine signaling in the regulation of glucagon release.

Insulin, glucagon and somatostatin in the perfused rat pancreas and the effects of HB 699 (4-(2-(5-chloro-2 metoxy-benzamido)-ethyl)-benzoic acid)

1981 ◽  
Vol 98 (4) ◽  
pp. 573-579 ◽  
Author(s):  
Suad Efendić ◽  
Franz Enzmann ◽  
Mark Gutniak ◽  
Anita Nylén ◽  
Manfred Zoltobrocki
Keyword(s):  
Benzoic Acid ◽  
Insulin Release ◽  
Basal Insulin ◽  
Glucagon Secretion ◽  
Inhibitory Effect ◽  
Glucagon Release ◽  
Stimulatory Action ◽  
Perfused Rat Pancreas ◽  
Rat Pancreas

Abstract. HB 699 (100 μg/ml), almost identical with the left residue of the sulphonylurea glibenclamide, enhanced basal insulin and somatostatin release from the perfused rat pancreas. The compound also augmented both the early and the late insulin release stimulated by 6.7 mm glucose, while with 16.7 and 33.3 mm glucose only late insulin release was increased. Furthermore, HB699 enhanced both phases of glucose induced somatostatin release irrespective of whether 6.7, 16.7 or 33.3 mM glucose were used. As for glucagon release, HB 699 suppressed basal and arginine stimulated glucagon secretion. The present findings imply that the sulphonylurea moiety of glibenclamide is not a prerequisite for its stimulatory action on insulin and somatostatin release. It is suggested that the enhanced somatostatin release mediates the inhibitory effect of the compound on glucagon release.

Effect of somatostatin suppression of glucagon secretion on glucose production in sheep

1979 ◽  
Vol 57 (8) ◽  
pp. 848-852 ◽  
Author(s):  
Ronald P. Brockman
Keyword(s):  
Marked Reduction ◽  
Hepatic Glucose Production ◽  
Insulin Response ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Inhibitory Effect ◽  
Plasma Glucagon ◽  
Hepatic Glucose ◽  
Glucagon And Insulin ◽  
Blood Glucose Concentrations

The effect of somatostatin (SRIF) on glucagon and insulin secretion was examined in fed and fasted sheep. This was related to changes in glucose production. Infusion of SRIF at 80 μg/h caused a marked reduction in plasma glucagon concentrations. However, the insulin response to SRIF infusion was not consistent; its concentrations decreased occasionally, but often did not change. The depression of glucagon was not associated with a significant reduction in blood glucose concentrations in either fed or fasted sheep, but was associated with a reduction in glucose production by 12–15%. The inhibitory effect of insulin on glucose production was not markedly increased by glucagon deficiency. Infusion of insulin at 1.17 U/h with SRIF decreased glucose production only an additional 10%. Thus, it appears that under basal conditions pancreatic hormonal influences on hepatic glucose production were relatively small in sheep. This implies that under normal conditions in sheep, substrate supply has a much greater impact on hepatic glucogenesis than do hormones.

Insulin as a physiological modulator of glucagon secretion

2008 ◽  
Vol 295 (4) ◽  
pp. E751-E761 ◽  
Author(s):  
Pritpal Bansal ◽  
Qinghua Wang
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Β Cells ◽  
Receptor System ◽  
Glucose Levels

Glucose homeostasis is regulated primarily by the opposing actions of insulin and glucagon, hormones that are secreted by pancreatic islets from β-cells and α-cells, respectively. Insulin secretion is increased in response to elevated blood glucose to maintain normoglycemia by stimulating glucose transport in muscle and adipocytes and reducing glucose production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting hepatic glucose production and ultimately raising blood glucose levels. Diabetic hyperglycemia occurs as the result of insufficient insulin secretion from the β-cells and/or lack of insulin action due to peripheral insulin resistance. Remarkably, excessive secretion of glucagon from the α-cells is also a major contributor to the development of diabetic hyperglycemia. Insulin is a physiological suppressor of glucagon secretion; however, at the cellular and molecular levels, how intraislet insulin exerts its suppressive effect on the α-cells is not very clear. Although the inhibitory effect of insulin on glucagon gene expression is an important means to regulate glucagon secretion, recent studies suggest that the underlying mechanisms of the intraislet insulin on suppression of glucagon secretion involve the modulation of KATP channel activity and the activation of the GABA-GABAA receptor system. Nevertheless, regulation of glucagon secretion is multifactorial and yet to be fully understood.

Interaction between cortisol and arachidonic acid on the secretion of LH from ovine pituitary tissue

1991 ◽  
Vol 131 (1) ◽  
pp. 87-94 ◽  
Author(s):  
A. W. Nangalama ◽  
G. P. Moberg
Keyword(s):  
Arachidonic Acid ◽  
Plasma Membrane ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Adrenal Steroids ◽  
Membrane Phospholipids ◽  
Pituitary Tissue ◽  
Receptor Sites ◽  
Lh Release ◽  
Gonadotrophin Releasing Hormone

ABSTRACT In several species, glucocorticoids act directly on the pituitary gonadotroph to suppress the gonadotrophin-releasing hormone (GnRH)-induced secretion of the gonadotrophins, especially LH. A mechanism for this action of these adrenal steroids has not been established, but it appears that the glucocorticoids influence LH release by acting on one or more post-receptor sites. This study investigated whether glucocorticoids disrupt GnRH-induced LH release by altering the liberation of arachidonic acid from plasma membrane phospholipids, a component of GnRH-induced LH release. Using perifused ovine pituitary tissue, it was established that exposure of gonadotrophs to 1–1000 nmol cortisol/l for 4 h or longer significantly reduced GnRH-stimulated LH release with the maximal inhibitory effect being observed after 6 h of exposure to cortisol. This suppressive effect of cortisol could be reversed by administration of arachidonic acid, which in its own right could stimulate LH release from ovine pituitary tissue. Furthermore, the inhibitory effect of cortisol on GnRH-stimulated LH release could be directly correlated with decreased pituitary responsiveness to GnRH-stimulated arachidonic acid liberation, consistent with our hypothesis that glucocorticoids can suppress GnRH-induced secretion of LH by reducing the amount of arachidonic acid available for the exocytotic response of GnRH. Journal of Endocrinology (1991) 131, 87–94

Induction of renal phosphoenolpyruvate carboxykinase mRNA: suppressive effect of glucose

1989 ◽  
Vol 257 (1) ◽  
pp. F145-F151
Author(s):  
A. S. Pollock
Keyword(s):  
Metabolic Acidosis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Suppressive Effect ◽  
Oral Glucose ◽  
Prolonged Fasting ◽  
Glucose Loading ◽  
Glucose Administration ◽  
Liver And Kidney ◽  
Gluconeogenic Enzyme ◽  
Effect Of Glucose

The mRNA for the important gluconeogenic enzyme phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32) is expressed in liver and kidney. In the kidney, acidosis is a unique and potent stimulus, whereas insulin, the major counterregulatory hormone of gluconeogenesis, has no effect. In this study, we find that oral glucose administration to rats rapidly decreases the abundance of renal PEPCK mRNA by 50–72%. This reduction takes place in normal euglycemic, in insulin-induced hypoglycemic, and in streptozotocin-induced hyperglycemic diabetic animals. The effect of glucose is not seen in the presence of metabolic acidosis, whether induced by NH4Cl or by prolonged fasting. Therefore, it appears that oral glucose loading is a physiological suppressor of renal PEPCK message abundance, although not in acidosis.

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