Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea

Seino, Susumu

doi:10.1007/s00125-012-2562-9

Cited by 123 publications

(115 citation statements)

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“…It is likely that TRPM2 is regulated by EPAC in our study. Interaction of sulfonylurea receptor 1/EPAC2A protein-protein (27)(28)(29) and increased EPAC2A activity by sulfonylureas (30) has been reported. PKA-independent potentiation of insulin secretion by cAMP (presumably EPAC2A-dependent pathway) was attenuated in sulfonylurea receptor 1-deficient islets (31).…”

Section: Discussionmentioning

confidence: 99%

Involvement of cAMP/EPAC/TRPM2 Activation in Glucose- and Incretin-Induced Insulin Secretion

et al. 2014

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In pancreatic b-cells, closure of the ATP-sensitive K + (K ATP ) channel is an initial process triggering glucosestimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of K ATP channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose-and incretinactivated NSCC (TRPM2) works in concert with closure of the K ATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in b-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.It has been long proposed that glucose-stimulated insulin secretion in pancreatic b-cells is initiated by closure of the ATP-sensitive K + (K ATP ) channel, followed by membrane depolarization (1). In theory, closure of the K ATP channel is an important process but is not sufficient to induce the shift of the membrane potential toward a threshold level, as membrane potential is determined by the overall balance of outward and inward currents. Modest constitutive opening of background inward current through nonselective cation channels (NSCCs) is crucial to facilitate depolarization after K ATP channel closure (2). This idea suggests that further regulated opening of a class of NSCCs may bring about greater depolarization. However, whether glucose metabolism regulates NSCC activity remains unclear.The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), potentiate insulin secretion in association with increased intracellular Ca 2+ concentrations at insulin-secreting glucose concentrations (3-5). GLP-1 fails to increase insulin secretion from the islets of mice deficient in transmembrane receptor potential (TRP) melastatin 2 (TRPM2) (6,7), a type of NSCC, suggesting that the TRPM2 channel is essential for GLP-1-induced potentiation of glucose-stimulated insulin secretion (8). GLP-1 depolarizes the plasma membrane by the opening of NSCC in b-cells (2). Several types of NSCC (TRPs) are expressed in insulin-secreting cells (9). The aims of the current study were to determine 1) the type of NSCC activation (through TRPM2 or other TRPs) that is crucial for signaling after stimulation of the incretin receptor, 2) whether the NSCC is modulated by glucose

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Section: Discussionmentioning

confidence: 99%

Involvement of cAMP/EPAC/TRPM2 Activation in Glucose- and Incretin-Induced Insulin Secretion

et al. 2014

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“…Its chemical formula can be seen in Figure 2. Their mechanism of action is to trigger insulin release from pancreatic b-cells 45 In addition can decrease the hepatic glucose production and the uptake of hepatic insulin while can increase the glucagon secretion by pancreatic α-cells 5 The main drawback of SU is that can induce hypoglycemia due to the excess of insulin production and release. First generation drugs include acetohexamide, carbutamide, chlorpropamide, glycyclamide (tolhexamide), metahexamide, tolazamide and tolbutamide while as second generation drugs classified glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide and glyclopyramide.…”

Section: Sulfonylureasmentioning

confidence: 99%

Diabetes Mellitus: A Review on Pathophysiology, Current Status of Oral Pathophysiology, Current Status of Oral Medications and Future Perspectives

Okur¹,

Karantas²,

Sıafaka³

2017

actapharm

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“…Stimulation of the secretion of glucagon, but not insulin, by adenosine suggested that α-cells were more sensitive to adenosine than β-cells [330]. There have been some valuable reviews about various aspects of purinergic endocrine signalling in the pancreas over the years [50,66,133,219,228,337,382,411,479,515,524]. A recent one is available about purinergic signalling in diabetes ([67]; Fig.…”

Section: Pancreasmentioning

confidence: 99%

“…ATP increases [Ca 2+ ] i in clonal insulin-producing RINm5F cells [15]. ATP action was found to be glucose-dependent and was exerted via two different types of P2 receptors: P2X receptors on rat pancreatic β-cells transiently stimulated insulin release at low glucose concentrations and P2Y receptors potentiated glucose-stimulated insulin secretion ( [410]; see [479]). Electrophysiological and immunocytochemical evidence has been presented that P2X1 and P2X3 receptors are expressed by mouse pancreatic β-cells [484].…”

Section: β-Cellsmentioning

confidence: 99%

Purinergic signalling in endocrine organs

Burnstock

2013

Purinergic Signalling

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There is widespread involvement of purinergic signalling in endocrine biology. Pituitary cells express P1, P2X and P2Y receptor subtypes to mediate hormone release. Adenosine 5′-triphosphate (ATP) regulates insulin release in the pancreas and is involved in the secretion of thyroid hormones. ATP plays a major role in the synthesis, storage and release of catecholamines from the adrenal gland. In the ovary purinoceptors mediate gonadotrophin-induced progesterone secretion, while in the testes, both Sertoli and Leydig cells express purinoceptors that mediate secretion of oestradiol and testosterone, respectively. ATP released as a cotransmitter with noradrenaline is involved in activities of the pineal gland and in the neuroendocrine control of the thymus. In the hypothalamus, ATP and adenosine stimulate or modulate the release of luteinising hormone-releasing hormone, as well as arginine-vasopressin and oxytocin. Functionally active P2X and P2Y receptors have been identified on human placental syncytiotrophoblast cells and on neuroendocrine cells in the lung, skin, prostate and intestine. Adipocytes have been recognised recently to have endocrine function involving purinoceptors.

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Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea

Cited by 123 publications

References 109 publications

Involvement of cAMP/EPAC/TRPM2 Activation in Glucose- and Incretin-Induced Insulin Secretion

Involvement of cAMP/EPAC/TRPM2 Activation in Glucose- and Incretin-Induced Insulin Secretion

Diabetes Mellitus: A Review on Pathophysiology, Current Status of Oral Pathophysiology, Current Status of Oral Medications and Future Perspectives

Purinergic signalling in endocrine organs

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