cAMP-independent decrease of ATP-sensitive K+ channel activity by GLP-1 in rat pancreatic β-cells

Suga, Sechiko; Kanno, Takahiro; Ogawa, Yoshiji; Takeo, Teruko; Kamimura, Noritaka; Wakui, Makoto

doi:10.1007/s004240000279

Cited by 30 publications

(34 citation statements)

References 41 publications

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“…Contact of the ␤-cell with adequate glucose levels (Ͼ7-8 mmol/l) elicits a sequence of metabolic events resulting in ATP generation, closure of K ATP channels, membrane depolarization, and Ca 2ϩ -dependent exocytosis of insulincontaining granules (3). GLP-1 directly modifies the activity of K ATP and L-type Ca 2ϩ channels, mobilizes extra-and intracellular Ca 2ϩ sources, and recruits and primes insulin-containing granules, thereby enforcing the overall insulin output (3,12,13,(22)(23)(24)(25). However, despite the many effects GLP-1 exerts in favor of promoting insulin secretion, it is incapable of triggering insulin secretion itself.…”

Section: Discussionmentioning

confidence: 99%

Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1

2007

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Section: Discussionmentioning

confidence: 99%

Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1

2007

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“…K ATP channels are reported to be inhibited by GLP-1 (50). Various mechanisms have been put forward to account for this inhibition, including phosphorylation of SUR1/Kir6.2 subunits by PKA (although phosphorylation by PKA [51] or by PKC [52] is also reported to increase the open probability of K ATP channels), by direct binding of G-protein ␤␥ subunits to SUR1 (53), by stimulation of glucose transport or metabolism (50), and by increasing the sensitivity of K ATP channels to inhibitory ATP (54). We think the simple explanation that loss of a potential GLP-1 target, i.e., K ATP channels, can account for the observed loss of incretin sensitivity is unlikely.…”

Section: Discussionmentioning

confidence: 99%

cAMP-Activated Protein Kinase-Independent Potentiation of Insulin Secretion by cAMP Is Impaired in SUR1 Null Islets

Nakazaki

Crane

et al. 2002

Diabetes

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Whereas the loss of ATP-sensitive K؉ channel (K ATP channel) activity in human pancreatic ␤-cells causes severe hypoglycemia in certain forms of hyperinsulinemic hypoglycemia, similar channel loss in sulfonylurea receptor-1 (SUR1) and Kir6.2 null mice yields a milder phenotype that is characterized by normoglycemia, unless the animals are stressed. While investigating potential compensatory mechanisms, we found that incretins, specifically glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic peptide (GIP), can increase the cAMP content of Sur1KO islets but do not potentiate glucose-stimulated insulin release. This impairment is secondary to a restriction in the ability of Sur1KO I nsulin secretion is a unique example of exocytosis controlled by metabolic, ionic, and hormonal pathways. An imbalance in insulin release due to disruption of these pathways can produce the profound changes in glucose homeostasis associated with either hyperglycemia (diabetes) or hypoglycemia (e.g., hyperinsulinemic hypoglycemia [HI]). In pancreatic ␤-cells, ATPsensitive K ϩ channels (K ATP channels), composed of Kir6.2 and the sulfonylurea receptor-1 (SUR1), and voltage-gated Ca 2ϩ channels are key players linking increased glucose metabolism to elevation of cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] i ). Membrane depolarization induced by closure of K ATP channels, secondary to changes in ADP/ ATP resulting from glucose metabolism, leads to the generation of Ca 2ϩ -dependent action potentials and [Ca 2ϩ ] i oscillations, which are considered to be a major mediator of insulin secretion. Sulfonylureas that block ␤-cell K ATP channels are commonly used to restore insulin secretion in type 2 diabetes. The loss or constitutive closure of ␤-cell K ATP channels, as a result of mutations in either subunit, is a cause of both dominant and recessive forms of HI (HI-SUR1 or HI-Kir6.2), characterized by elevated plasma insulin values inconsistent with the observed hypoglycemia (reviewed in 1,2). Studies on islets isolated from patients diagnosed with HI are consistent with hypersecretion of insulin (3,4). By comparison, the clinical phenotype of mice lacking ␤-cell/neuronal K ATP channels is strikingly normal. Kir6.2 null (Kir6.2KO) (5) and Sur1KO (6) mice are normoglycemic when fed, displaying only mild glucose intolerance, consistent with their loss of first phase and attenuated second phase of insulin release. Sur1KO mice exhibit greater hypoglycemia upon fasting, consistent with their inability to rapidly repolarize their ␤-cells and reduce insulin release (6). No compensating ionic mechanisms have been identified, and the electrophysiological phenotype of isolated K ATP KO mouse ␤-cells, i.e., constant membrane depolarization, presence of Ca 2ϩ -dependent action potentials, and elevated oscillating [Ca 2ϩ ] i in low glucose, is quite similar to that of ␤-cells from HI neonates (compare 5-7); therefore, it is unclear why K ATP KO islets lack the elevated basal insulin release observed in HI islets (3,4).In a search for dif...

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“…This action of GLP-1 is cAMPdependent and is mediated by PKA. In contrast, GLP-1 acts independently of PKA to increase the channel's sensitivity to ATP, thereby closing the channel [31].…”

Section: Glp-1 Inhibits K-atp Channel Functionmentioning

confidence: 98%

“…GLP-1 interacts with glucose metabolism to promote mitochondrial ATP production [29], thereby increasing the cytosolic [ATP]/[ADP] concentration ratio. GLP-1 also modifies the adenine nucleototide-sensitivity of K-ATP channels, reducing their sensitivity to ADP while increasing their sensitivity to ATP [30,31]. The net effect is glucose-dependent K-ATP channel closure, membrane depolarization and Ca 2+ influx.…”

Section: Glp-1 As An Insulin Secretagogue Hormonementioning

confidence: 99%

“…This action of GLP-1 may result from interactions of Epac2 with insulin granule-associated proteins (Rim2, Piccolo) [41,42] or with SUR1 [43]. Since direct protein-protein interactions of Epac2 and SUR1 are demonstrable [43], it seems likely that cAMPGEFs may also confer cAMP-dependent inhibition of K-ATP channel activity, possibly by increasing the channel's sensitivity to ATP [31]. In summary, some actions of GLP-1 are Epac-mediated and may be independent of Rap G-proteins.…”

Section: Pka and Epac-mediated Signaling Properties Of The Glp-1 Recementioning

confidence: 99%

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New Insights Concerning the Glucose-dependent Insulin Secretagogue Action of Glucagon-like Peptide-1 in Pancreatic β-Cells

Holz

2004

Horm Metab Res

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The GLP-1 receptor is a Class B heptahelical G-protein-coupled receptor that stimulates cAMP production in pancreatic β-cells. GLP-1 utilizes this receptor to activate two distinct classes of cAMP-binding proteins: protein kinase A (PKA) and the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs). Actions of GLP-1 mediated by PKA and Epac include the recruitment and priming of secretory granules, thereby increasing the number of granules available for Ca 2+ -dependent exocytosis. Simultaneously, GLP-1 promotes Ca 2+ influx and mobilizes an intracellular source of Ca 2+ . GLP-1 sensitizes intracellular Ca 2+ release channels (ryanodine and IP 3 receptors) to stimulatory effects of Ca 2+ , thereby promoting Ca 2+ -induced Ca 2+ release (CICR). In the model presented here, CICR activates mitochondrial dehydrogenases, thereby upregulating glucose-dependent production of ATP. The resultant increase in cytosolic [ATP]/[ADP] concentration ratio leads to closure of ATP-sensitive K + channels (K-ATP), membrane depolarization, and influx of Ca 2+ through voltage-dependent Ca 2+ channels (VDCCs). Ca 2+ influx stimulates exocytosis of secretory granules by promoting their fusion with the plasma membrane. Under conditions where Ca 2+ release channels are sensitized by GLP-1, Ca 2+ influx also stimulates CICR, generating an additional round of ATP production and K-ATP channel closure. In the absence of glucose, no "fuel" is available to support ATP production, and GLP-1 fails to stimulate insulin secretion. This new "feed-forward" hypothesis of β-cell stimulussecretion coupling may provide a mechanistic explanation as to how GLP-1 exerts a beneficial blood glucose-lowering effect in type 2 diabetic subjects.

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cAMP-independent decrease of ATP-sensitive K+ channel activity by GLP-1 in rat pancreatic β-cells

Cited by 30 publications

References 41 publications

Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1

Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1

cAMP-Activated Protein Kinase-Independent Potentiation of Insulin Secretion by cAMP Is Impaired in SUR1 Null Islets

New Insights Concerning the Glucose-dependent Insulin Secretagogue Action of Glucagon-like Peptide-1 in Pancreatic β-Cells

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