Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca<sup>2+</sup> and ATP in rat islet β‐cells

Hashiguchi, Hiroshi; Nakazaki, Mitsuhiro; Koriyama, Nobuyuki; Fukudome, Michiyo; Aso, Katsumi

doi:10.1002/dmrr.580

Cited by 23 publications

(10 citation statements)

References 60 publications

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“…Using an Epac2-knockout mouse, Shibasaki et al (63) provided evidence that the Epac2-mediated activation of Rap1 in ␤-cells plays an essential role in the cAMPdependent potentiation of glucose-stimulated insulin secretion (GSIS). Thus, the existence of Epac2 in ␤-cells may explain prior reports that cAMP-elevating agents such as the blood glucose-lowering hormone glucagon-like peptide-1-(7-36) amide (GLP-1) exert novel PKA-independent actions to control rodent and possibly human islet function (3,15,20,34,39,42,44,48,51,60,64,71).…”

mentioning

confidence: 77%

PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of Langerhans

Chepurny

Kelley

Dzhura

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Potential insulin secretagogue properties of an acetoxymethyl ester of a cAMP analog (8-pCPT-2′- O-Me-cAMP-AM) that activates the guanine nucleotide exchange factors Epac1 and Epac2 were assessed using isolated human islets of Langerhans. RT-QPCR demonstrated that the predominant variant of Epac expressed in human islets was Epac2, although Epac1 was detectable. Under conditions of islet perifusion, 8-pCPT-2′- O-Me-cAMP-AM (10 μM) potentiated first- and second-phase 10 mM glucose-stimulated insulin secretion (GSIS) while failing to influence insulin secretion measured in the presence of 3 mM glucose. The insulin secretagogue action of 8-pCPT-2′- O-Me-cAMP-AM was associated with depolarization and an increase of [Ca2+]i that reflected both Ca2+ influx and intracellular Ca2+ mobilization in islet β-cells. As expected for an Epac-selective cAMP analog, 8-pCPT-2′- O-Me-cAMP-AM (10 μM) failed to stimulate phosphorylation of PKA substrates CREB and Kemptide in human islets. Furthermore, 8-pCPT-2′- O-Me-cAMP-AM (10 μM) had no significant ability to activate AKAR3, a PKA-regulated biosensor expressed in human islet cells by viral transduction. Unexpectedly, treatment of human islets with an inhibitor of PKA activity (H-89) or treatment with a cAMP antagonist that blocks PKA activation (Rp-8-CPT-cAMPS) nearly abolished the action of 8-pCPT-2′- O-Me-cAMP-AM to potentiate GSIS. It is concluded that there exists a permissive role for PKA activity in support of human islet insulin secretion that is both glucose dependent and Epac regulated. This permissive action of PKA may be operative at the insulin secretory granule recruitment, priming, and/or postpriming steps of Ca2+-dependent exocytosis.

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mentioning

confidence: 77%

PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of Langerhans

Chepurny

Kelley

Dzhura

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…Complicating matters, electric activity and secretion are not necessarily coupled. It has, for example, been shown that in pancreatic b cells, cyclic AMP works at a late stage of exocytosis, thereby exerting major effects on vesicle release despite only minor effects on electrical activity (75,76). This phenomenon has also been observed in a wide variety of other secretory cell types including neurons (77).…”

Section: Perspectivesmentioning

confidence: 94%

Central insulin action in energy and glucose homeostasis

Plum

Belgardt²,

Brüning³

2006

Journal of Clinical Investigation

368

271

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Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin's role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body's energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level. History and backgroundMore than 150 years ago, the French physiologist Claude Bernard identified the liver as a reservoir for glucose. Remarkably, he also showed in rabbits that "piqûre" (pricking) of the floor of the fourth ventricle of the brain resulted in glucosuria (1) and concluded that the CNS plays an essential role in the control of peripheral blood glucose levels. More recently, insulin signaling in neuronal cells has been shown to regulate life span, growth, reproduction, and energy homeostasis in primitive organisms such as Caenorhabditis elegans and Drosophila melanogaster (2, 3). The insulin/IGF-1 signal transduction pathway shows similar characteristics in C. elegans, D. melanogaster, rodents, and humans, pointing to an evolutionarily conserved mechanism (4). Signaling of the insulin/IGF-1 receptor homolog dauer formation-2 (DAF-2) via the class IA PI3K (AGE-1) pathway in C. elegans has been shown to control development, reproductive function, and longevity in response to environmental stimuli such as energy supply, a mechanism involving the forkhead-O transcription factor (FOXO) homolog 6). Likewise, the insulin receptor substrate (IRS) protein homolog CHICO in D. melanogaster regulates somatic growth, reproduction, and lipid metabolism (7).It has been shown that overexpression of D. melanogaster insulinlike peptides (dILPs) in the nervous system of fasted larvae suppresses the hunger-driven ingestion of food and that upregulation of D. melanogaster p70/S6 kinase (dS6K) activity in dILP neurosecretory cells leads to a diminished hunger response in fasted larvae (8). Furthermore, ablation of dILP neurons in the Drosophila brain was found to result in prolonged lifespan, reduced fertility, increased fasting glucose levels, increased storage of lipids and carbohydrates, and reduced tolerance to heat and cold (2, 9), clearly assigning neurosecretory cells a pivotal importance in the regulation of lifespan and fuel metabolism in D. melanogaster.The finding that insulin, like the adipocyte-derived hormone leptin, affects both neuropeptide expression in the hypothalamus and food intake has recently led to the appreciation of the brain as an insulin target tissue with regard t...

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“…The two primary downstream effectors of GLP-1R-induced cAMP are protein kinase A (PKA) and the cAMP-regulated guanine nucleotide exchange factor (cAMP-GEF), Epac. That PKA and Epac each play critical roles in GLP-1-mediated insulin release is evidenced by the ability of Epac or PKA specific activators (or inhibitors) to potentiate (or inhibit) glucosedependent insulin secretion [69][70][71][72]. Thus, the activity of the GLP-1R is transmitted through the actions of PKA and Epac.…”

Section: Consequences Of Camp Generationmentioning

confidence: 99%

GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

Meloni¹,

DeYoung²,

Lowe³

et al. 2012

Diabetes Obesity Metabolism

283

199

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The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self-regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β-cells by glucagon-like peptide 1 receptor (GLP-1R) agonists is known to be glucose-dependent. GLP-1R agonists potentiate glucose-stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose-regulated’ activity of GLP-1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non-regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP-1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP-1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP-1R signalling promotes insulin secretion from pancreatic β-cells via a glucose-dependent process.

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Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells

Abstract: Background Cyclic AMP (cAMP) plays a pivotal role in insulin secretion induced by incretins. The effects of the second messenger extend to many sites and there has been much controversy on the mechanisms. The aim of this study was to examine how cAMP amplified insulin exocytosis.

Cited by 23 publications

References 60 publications

PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of Langerhans

PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of Langerhans

Central insulin action in energy and glucose homeostasis

GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

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Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca2+ and ATP in rat islet β‐cells

Abstract: Background Cyclic AMP (cAMP) plays a pivotal role in insulin secretion induced by incretins. The effects of the second messenger extend to many sites and there has been much controversy on the mechanisms. The aim of this study was to examine how cAMP amplified insulin exocytosis.

Cited by 23 publications

References 60 publications

PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of Langerhans

PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of Langerhans

Central insulin action in energy and glucose homeostasis

GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

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Product

Resources

About

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells