GLP-I(7–36) Amide Augments Ba2+ Current Through L-Type Ca2+ Channel of Rat Pancreatic β-Cell in a cAMP-Dependent Manner

Suga, Sechiko; Kanno, Takahiro; Nakano, Kyoko; Takeo, Teruko; Dobashi, Y; Wakui, Makoto

doi:10.2337/diab.46.11.1755

Cited by 50 publications

(30 citation statements)

References 36 publications

(49 reference statements)

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“…These results suggest that β‐cell function is actually well activated with combined use of sulfonylurea drugs and DPP‐4 inhibitors, although the effect of sitagliptin to lower glucagon 4 might also contribute to the reduced sulfonylurea doses. It is coming to be understood that incretin not only promotes the insulin release reaction in β‐cells 5,23 , but it also stimulates the insulin secretion response through multiple actions 24 , such as promoting adenosine triphosphate generation in mitochondria 25 , and both sulfonylurea and incretin act on exchange protein directly activated by cyclic adenosine monophosphate 2A in β‐cells 26,27 . Therefore, incretin and sulfonylurea are supposed to stimulate insulin secretion in coordinated and synergistic manners, and the present results appear to reflect these stimulatory effects of incretin and sulfonylureas on pancreatic β‐cells.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

Kubota

Maeda

Kanamori

et al. 2012

J of Diabetes Invest

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(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012) Aims/Introduction: To determine the efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients after 3 months’ therapy.Materials and Methods: A retrospective, observational study of 741 type 2 diabetes patients was carried out; 110 received sitagliptin monotherapy, and 631 received combination therapy with sitagliptin when other oral medications were insufficient. The primary outcome measure was glycated hemoglobin (HbA1c) measured at 0, 4 and 12 weeks of sitagliptin therapy.Results: In the monotherapy and combination therapy groups, HbA1c decreased significantly after 12 weeks. Target HbA1c (<7%) was achieved in 39.1% overall. On logistic regression analysis, baseline HbA1c was the strongest contributing factor for achieving target HbA1c; baseline body mass index and duration of diabetes were also significant factors. A total of 82 patients (11%) were unresponsive to sitagliptin. These patients’ baseline body mass index was significantly higher and their baseline HbA1c was significantly lower than those of patients who responded to sitagliptin. The most commonly co‐administered drugs were sulfonylureas (508 patients). In these patients, the dose of sulfonylurea decreased with time. In 66 patients whose sulfonylurea dosage was reduced when sitagliptin was started, HbA1c and bodyweight decreased significantly after 12 weeks. A total of 24 patients receiving sulfonylureas had mild hypoglycemia, but none discontinued sitagliptin.Conclusions: Sitagliptin was effective and safe as both monotherapy and combination therapy in Japanese type 2 diabetes patients. When sulfonylureas were ineffective, sitagliptin improved glycemic control. In patients whose sulfonylurea dose was reduced at the start of sitagliptin, blood glucose improved and bodyweight decreased after 12 weeks.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

Kubota

Maeda

Kanamori

et al. 2012

J of Diabetes Invest

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“…Identification of ␤ cells from other islet cells was carried out by detecting the excitatory electrical response of the cells to 15 mM glucose or to 0.5 mM tolbutamide. The patch clamp method was used to record membrane currents and membrane potential with an EPC-7 patch-clamp amplifier (List Electronic, Germany) (36,37). The resistance of electrodes made of borosillicate glass capillaries was 2-4 megaohms.…”

Section: Methodsmentioning

confidence: 99%

NADH Shuttle System Regulates KATPChannel-dependent Pathway and Steps Distal to Cytosolic Ca2+ Concentration Elevation in Glucose-induced Insulin Secretion

Eto¹,

Suga²,

Wakui³

et al. 1999

Journal of Biological Chemistry

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The NADH shuttle system is composed of the glycerol phosphate and malate-aspartate shuttles. We generated mice that lack mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a rate-limiting enzyme of the glycerol phosphate shuttle. Application of aminooxyacetate, an inhibitor of the malate-aspartate shuttle, to mGPDH-deficient islets demonstrated that the NADH shuttle system was essential for coupling glycolysis with activation of mitochondrial ATP generation to trigger glucose-induced insulin secretion.The present study revealed that blocking the NADH shuttle system severely suppressed closure of the ATPsensitive potassium (K ATP ) channel and depolarization of the plasma membrane in response to glucose in ␤ cells, although properties of the K ATP channel on the excised ␤ cell membrane were unaffected. In mGPDHdeficient islets treated with aminooxyacetate, Ca 2؉ influx through the plasma membrane induced by a depolarizing concentration of KCl in the presence of the K ATP channel opener diazoxide restored insulin secretion. However, the level of the secretion was only ϳ40% of wild-type controls. Thus, glucose metabolism through the NADH shuttle system leading to efficient ATP generation is pivotal to activation of both the K ATP channeldependent pathway and steps distal to an elevation of cytosolic Ca 2؉ concentration in glucose-induced insulin secretion.In pancreatic ␤ cells, glucose metabolism in glycolysis and in mitochondria is pivotal to glucose-induced insulin secretion. Thus, mutations in the glucokinase gene (1, 2) and mitochondrial DNA (3) can cause type 2 diabetes mellitus, which is characterized by insufficient insulin secretion in response to glucose. Moreover, abrogation of ␤ cell-specific glucokinase in mice (4, 5) and mitochondrial DNA in insulinoma cell lines (6 -9) was associated with defective insulin secretion in response to glucose. The following cascade has been generally accepted as the glucose-induced insulin secretory pathway (10 -13). Glucose-stimulated increase in cytosolic ATP or in the ratio of ATP to ADP closes ATP-sensitive potassium (K ATP ) 1 channels, which depolarizes the plasma membrane potential above a threshold, leading to Ca 2ϩ entry into the cytosol through activation of voltage-dependent Ca 2ϩ channels (VDCCs). The rise in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] c ) is thought to finally trigger exocytosis of insulin from secretory vesicles.It has been known that pyruvate, an end product of aerobic glycolysis, cannot stimulate insulin secretion although it is oxidized as efficiently as glucose in ␤ cells (14,15). Studies with an inhibitor of pyruvate transport into mitochondria or an inhibitor of the tricarboxylic acid cycle suggested that metabolism of glucose-derived pyruvate in mitochondria or in the tricarboxylic acid cycle was not well correlated with glucoseinduced insulin secretion (16,17). These results suggested that glycolysis-derived factor(s) other than pyruvate are required for activation of mitochondrial metabolism and for generation of the metabolic ...

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“…These include an inhibition of the ATP-sensitive K + (K ATP ) channels (Holz et al 1993;Gromada et al 1997), an acceleration of the voltage-gated L-type Ca 2+ channels (Britsch et al 1995;Suga et al 1997), the stimulation of Ca 2+ mobilization from intracellular stores (Gromada et al 1995), and a potentiation of Ca…”

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confidence: 99%

Involvement of Calmodulin in Glucagon‐Like Peptide 1(7‐36) Amide‐Induced Inhibition of the ATP‐Sensitive K⁺ Channel in Mouse Pancreatic β‐Cells

Ding

Kitasato

Matsuura

2001

Experimental Physiology

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The present investigation was designed to examine whether calmodulin is involved in the inhibition of the ATP‐sensitive K+ (KATP) channel by glucagon‐like peptide 1(7‐36) amide (GLP‐1) in mouse pancreatic β‐cells. Membrane potential, single channel and whole‐cell currents through the KATP channels, and intracellular free Ca2+ concentration ([Ca2+]i) were measured in single mouse pancreatic β‐cells. Whole‐cell patch‐clamp experiments with amphotericin‐perforated patches revealed that membrane conductance at around the resting potential is predominantly supplied by the KATP channels in mouse pancreatic β‐cells. The addition of 20 nM GLP‐1 in the presence of 5 mM glucose significantly reduced the membrane KATP conductance, accompanied by membrane depolarization and the generation of electrical activity. A calmodulin inhibitor N‐(6‐aminohexyl)‐5‐chloro‐1‐naphthalenesulphonamide (W‐7, 20 μM) completely reversed the inhibitory actions of GLP‐1 on the membrane KATP conductance and resultant membrane depolarization. Cell‐attached patch recordings confirmed the inhibition of the KATP channel activity by 20 nM GLP‐1 and its restoration by 20 μM W‐7 or 10 μM calmidazolium at the single channel level. Bath application of 20 μM W‐7 also consistently abolished the GLP‐1‐evoked increase in [Ca2+]i in the presence of 5 mM glucose. These results strongly suggest that the mechanisms by which GLP‐1 inhibits the KATP channel activity accompanied by the initiation of electrical activity in mouse pancreatic β‐cells include a calmodulin‐dependent mechanism in addition to the well‐documented activation of the cyclic AMP‐protein kinase A system.

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GLP-I(7–36) Amide Augments Ba2+ Current Through L-Type Ca2+ Channel of Rat Pancreatic β-Cell in a cAMP-Dependent Manner

Cited by 50 publications

References 36 publications

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

NADH Shuttle System Regulates KATPChannel-dependent Pathway and Steps Distal to Cytosolic Ca2+ Concentration Elevation in Glucose-induced Insulin Secretion

Involvement of Calmodulin in Glucagon‐Like Peptide 1(7‐36) Amide‐Induced Inhibition of the ATP‐Sensitive K⁺ Channel in Mouse Pancreatic β‐Cells

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GLP-I(7–36) Amide Augments Ba2+ Current Through L-Type Ca2+ Channel of Rat Pancreatic β-Cell in a cAMP-Dependent Manner

Cited by 50 publications

References 36 publications

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

NADH Shuttle System Regulates KATPChannel-dependent Pathway and Steps Distal to Cytosolic Ca2+ Concentration Elevation in Glucose-induced Insulin Secretion

Involvement of Calmodulin in Glucagon‐Like Peptide 1(7‐36) Amide‐Induced Inhibition of the ATP‐Sensitive K+ Channel in Mouse Pancreatic β‐Cells

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Involvement of Calmodulin in Glucagon‐Like Peptide 1(7‐36) Amide‐Induced Inhibition of the ATP‐Sensitive K⁺ Channel in Mouse Pancreatic β‐Cells