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Marc Y Donath - One of the best experts on this subject based on the ideXlab platform.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium channe
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional β-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, β-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1β and/or high-glucose-induced β-cell production of IL-1β. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the β-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1β-induced apoptosis and impaired function in human β-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1β, or 10 and 100 μmol/l of the sulfonylurea tolbutamide induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1β were blocked by 200 μmol/l diazoxide as well as by 3 and 30 μmol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 μmol/l NN414. Similarly, 1 μmol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 μmol/l of the l-type Ca 2+ Channel blocker nimodipine prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca 2+ influx and ERK dependent and can be prevented by the β-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1beta induced beta cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.

Jeppe Sturis - One of the best experts on this subject based on the ideXlab platform.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium channe
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional β-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, β-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1β and/or high-glucose-induced β-cell production of IL-1β. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the β-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1β-induced apoptosis and impaired function in human β-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1β, or 10 and 100 μmol/l of the sulfonylurea tolbutamide induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1β were blocked by 200 μmol/l diazoxide as well as by 3 and 30 μmol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 μmol/l NN414. Similarly, 1 μmol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 μmol/l of the l-type Ca 2+ Channel blocker nimodipine prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca 2+ influx and ERK dependent and can be prevented by the β-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1beta induced beta cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.

  • nn414 a sur1 kir6 2 selective Potassium Channel Opener reduces blood glucose and improves glucose tolerance in the vdf zucker rat
    Diabetes, 2003
    Co-Authors: Richard D. Carr, John Bondo Hansen, Christian L Brand, T. B. Bödvarsdottir, Jeppe Sturis
    Abstract:

    A novel Potassium Channel Opener compound, NN414, selective for the SUR1/Kir6.2 subtype of the ATP-sensitive Potassium Channel, was used to examine the effect of reducing β-cell workload in the male Vancouver diabetic fatty (VDF) Zucker rat model of mild type 2 diabetes. Two chronic dosing protocols of NN414 of 3 weeks’ duration were compared with appropriate vehicle-treated controls. In the first group, rats received NN414 (continued group; 1.5 mg/kg p.o. twice daily), during which an oral glucose tolerance test (OGTT) (on day 19 of dosing) was performed and insulin secretion from an in situ perfused pancreas preparation (on day 21) was measured. The second group received NN414 (discontinued group; same dose), but active treatment was replaced by vehicle treatment 2 days before the OGTT and for a further 2 days before the perfused pancreas study. Basal glucose was significantly reduced by NN414, with the fall averaging 0.64 mmol/l after 3 weeks of treatment ( P < 0.0001). The glucose excursion and hyperinsulinemia during the OGTT were significantly different between the continued, discontinued, and vehicle groups (glucose area under the curve [AUC]: 640 ± 29, 740 ± 27, and 954 ± 82 mmol · l−1 · min−1, respectively, P < 0.0001; insulin AUC: 38.9 ± 4.2, 44.2 ± 4.2, and 55.1 ± 2.6 nmol · l−1 · min−1, respectively, P < 0.0001). Hyperinsulinemia during the pancreas perfusion with 4.4 mmol/l glucose was significantly reduced in both treatment groups versus vehicle ( P < 0.0005). Insulin secretory responsiveness to a step increase in glucose from 4.4 to 16.6 mmol/l, calculated relative to basal, was significantly improved in the continued group versus vehicle ( P < 0.01). In conclusion, administration of NN414 for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an OGTT and improves insulin secretory responsiveness ex vivo. NN414 may therefore represent a novel approach to the prevention and treatment of impaired glucose tolerance and type 2 diabetes.

  • nn414 a sur1 kir6 2 selective Potassium Channel Opener reduces blood glucose and improves glucose tolerance in the vdf zucker rat
    Diabetes, 2003
    Co-Authors: Richard D. Carr, John Bondo Hansen, Christian L Brand, T. B. Bödvarsdottir, Jeppe Sturis
    Abstract:

    A novel Potassium Channel Opener compound, NN414, selective for the SUR1/Kir6.2 subtype of the ATP-sensitive Potassium Channel, was used to examine the effect of reducing beta-cell workload in the male Vancouver diabetic fatty (VDF) Zucker rat model of mild type 2 diabetes. Two chronic dosing protocols of NN414 of 3 weeks' duration were compared with appropriate vehicle-treated controls. In the first group, rats received NN414 (continued group; 1.5 mg/kg p.o. twice daily), during which an oral glucose tolerance test (OGTT) (on day 19 of dosing) was performed and insulin secretion from an in situ perfused pancreas preparation (on day 21) was measured. The second group received NN414 (discontinued group; same dose), but active treatment was replaced by vehicle treatment 2 days before the OGTT and for a further 2 days before the perfused pancreas study. Basal glucose was significantly reduced by NN414, with the fall averaging 0.64 mmol/l after 3 weeks of treatment (P < 0.0001). The glucose excursion and hyperinsulinemia during the OGTT were significantly different between the continued, discontinued, and vehicle groups (glucose area under the curve [AUC]: 640 +/- 29, 740 +/- 27, and 954 +/- 82 mmol. l(-1). min(-1), respectively, P < 0.0001; insulin AUC: 38.9 +/- 4.2, 44.2 +/- 4.2, and 55.1 +/- 2.6 nmol.l(-1).min(-1), respectively, P < 0.0001). Hyperinsulinemia during the pancreas perfusion with 4.4 mmol/l glucose was significantly reduced in both treatment groups versus vehicle (P < 0.0005). Insulin secretory responsiveness to a step increase in glucose from 4.4 to 16.6 mmol/l, calculated relative to basal, was significantly improved in the continued group versus vehicle (P < 0.01). In conclusion, administration of NN414 for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an OGTT and improves insulin secretory responsiveness ex vivo. NN414 may therefore represent a novel approach to the prevention and treatment of impaired glucose tolerance and type 2 diabetes.

Kathrin Maedler - One of the best experts on this subject based on the ideXlab platform.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium channe
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional β-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, β-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1β and/or high-glucose-induced β-cell production of IL-1β. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the β-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1β-induced apoptosis and impaired function in human β-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1β, or 10 and 100 μmol/l of the sulfonylurea tolbutamide induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1β were blocked by 200 μmol/l diazoxide as well as by 3 and 30 μmol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 μmol/l NN414. Similarly, 1 μmol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 μmol/l of the l-type Ca 2+ Channel blocker nimodipine prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca 2+ influx and ERK dependent and can be prevented by the β-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1beta induced beta cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.

Hai Wang - One of the best experts on this subject based on the ideXlab platform.

  • A new ATP-sensitive Potassium Channel Opener protects endothelial function in cultured aortic endothelial cells. Cardiovasc Res 2007;73:497–503
    2020
    Co-Authors: Hai Wang, Chaoliang Long, Yingli Zhang
    Abstract:

    ABSTRACT Some Potassium Channel Openers (KCOs) are potent vasodilators that mainly target the ATP-sensitive Potassium Channels in vascular smooth muscle cells. Their lack of tissue selectivity limits their clinical use in hypertension therapy. Iptakalim [2,3-dimethyl-n-(1-methylethyl)-2-butylamine], which belongs to a novel chemical type of KCO, possesses unique pharmacological characteristics. In vitro experiments have shown that iptakalim could limit its vasorelaxing actions to resistance vessels. In this study, we investigate the antihypertensive effects of iptakalim on two different experimental hypertensive models: stroke-prone, spontaneously hypertensive rats (SHRsps) and two-kidney with one-clip renal hypertensive dogs (2K1C RHD). In acute hypotensive tests, iptakalim showed stable, long-lasting antihypertensive effects in SHRsps and 2K1C RHDs. Meanwhile, it had little effect on heart rate when compared with pinacidil, nifedipine, captopril, or bisoprolol. In experimental therapeutic tests, repeated doses in SHRsps for 30 days or in 2K1C RHDs for 14 days produced consistent antihypertensive effects without causing tolerance. In separate experiments, chronic administration of iptakalim resulted in reversing hypertensive vascular remodeling in spontaneously hypertensive rats and hypertensive cardiac remodeling in SHRsps. These results suggest that iptakalim is a promising antihypertensive drug. Hypertension is a substantial public health problem, affecting about 25% of the adult population in the world, and it is an important risk factor for death from stroke, myocardial infarction, congestive heart failure, and renal failure By opening K ATP Channels in vascular smooth muscles, KCOs would induce membrane hyperpolarization and a decrease of intracellular Ca 2ϩ levels, thereby relaxing the vessels and suppressing blood pressure. KCOs exhibit extreme chemical diversity and comprise a number of different structural classes, such as benzopyrans, cyanoguanidines, thioformamides, and pyrimidines ABBREVIATIONS: KCO, Potassium Channel Opener; K ATP , ATP-sensitive Potassium; iptakalim, 2,3-dimethyl-n-(1-methylethyl)-2-butylamine; SHR, spontaneously hypertensive rat; SHRsp, stroke-prone spontaneously hypertensive rat; 2K1C RHD, two-kidney with one-clip renal hypertensive dog; SBP, systolic blood pressure; HR, heart rate; DBP, diastolic blood pressure; NTR, normotensive rat; M, media thickness; L, lumen diameter; LV, left ventricle; S, septum; BW, body weight; MAP, mean blood pressure; bpm, beats per minute

  • iptakalim an atp sensitive Potassium Channel Opener confers neuroprotection against cerebral ischemia reperfusion injury in rats by protecting neurovascular unit cells
    Journal of Zhejiang University-science B, 2011
    Co-Authors: Yuhua Ran, Hai Wang
    Abstract:

    Objective: To investigate the role of iptakalim, an ATP-sensitive Potassium Channel Opener, in transient cerebral ischemia/reperfusion (I/R) injury and its involved mechanisms. Methods: Intraluminal occlusion of middle cerebral artery (MCAO) in a rat model was used to investigate the effect of iptakalim at different time points. Infarct volume was measured by staining with 2,3,5-triphenyltetrazolium chloride, and immunohistochemistry was used to evaluate the expressions of Bcl-2 and Bax. In vitro, neurovascular unit (NVU) cells, including rat primary cortical neurons, astrocytes, and cerebral microvascular endothelial cells, were cultured and underwent oxygen-glucose deprivation (OGD). The protective effect of iptakalim on NVU cells was investigated by cell viability and injury assessments, which were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and release of lactate dehydrogenase. Caspase-3, Bcl-2 and Bax mRNA expressions were evaluated by real-time polymerase chain reaction (PCR). Results: Administration of iptakalim 0 or 1 h after reperfusion significantly reduced infarct volumes, improved neurological scores, and attenuated brain edema after cerebral I/R injury. Iptakalim treatment (0 h after reperfusion) also reduced caspase-3 expression and increased the ratio of Bcl-2 to Bax by immunohistochemistry. Iptakalim inhibited OGD-induced cell death in cultured neurons and astrocytes, and lactate dehydrogenase release from cerebral microvascular endothelial cells. Iptakalim reduced mRNA expression of caspase-3 and increased the ratio of Bcl-2 to Bax in NVU cells. Conclusions: Iptakalim confers neuroprotection against cerebral I/R injury by protecting NVU cells via inhibiting of apoptosis.

  • targeting hypertension with a new adenosine triphosphate sensitive Potassium Channel Opener iptakalim
    Journal of Cardiovascular Pharmacology, 2010
    Co-Authors: Jinghui Huang, Chaoliang Long, Yanfang Zhang, Hai Wang
    Abstract:

    : Hypertension is the most common cardiovascular disease. The discovery of the antihypertensive action of adenosine triphosphate-sensitive Potassium (K(ATP)) Channel Openers was a significant advance in the treatment of hypertension. Iptakalim is a novel K(ATP) Channel Opener with a unique chemical structure that differs from other K(ATP) Openers. Among the 3 different subtypes of K(ATP) Channels heterologously expressed in human embryonic kidney cells and Xenopus oocytes, iptakalim exhibits significant selectivity for SUR2B/Kir6.1 Channels, mild effects on SUR2A/Kir6.2 Channels, and fails to open SUR1/Kir6.2 Channels. Iptakalim is a more potent activator of the SUR2B/Kir6.1 subtype of K(ATP) Channels than diazoxide and pinacidil, the 2 most commonly studied K(ATP) Channel Openers. Iptakalim selectively produces arteriolar vasodilation with essentially no effect on the capacitance vessels. It can preferentially relax arterioles and small arteries, without affecting large arteries. Furthermore, iptakalim strongly lowers the blood pressure of hypertensive rodents and humans but has little effect on normotensive rodents and humans. Selective antihypertensive action is not observed with pinacidil or diazoxide and may be due to the high selectivity of iptakalim for the SUR2B/Kir6.1 subtype of K(ATP) Channels, as well as its selective relaxation of resistance vessels. In pulmonary arterial smooth muscle cells, iptakalim inhibits the increase of cytoplasmic free Ca2+ concentration, as well as cell proliferation induced by endothelin-1. Furthermore, iptakalim has exerted protective effects against hypertensive damage to target organs in rats and improves endothelial dysfunction associated with cardiovascular diseases by selective activation of the SUR2B/Kir6.1 subtype of K(ATP) Channels expressed in the endothelium. Clinical trials of iptakalim in the treatment of mild-moderate hypertension have been completed in China. In additional to strong antihypertensive efficacy, iptakalim seems to have a favorable safety and tolerability profile. Iptakalim is a promising new generation antihypertensive drug.

  • a new atp sensitive Potassium Channel Opener protects endothelial function in cultured aortic endothelial cells
    Cardiovascular Research, 2007
    Co-Authors: Hai Wang, Chaoliang Long, Zhibian Duan, Yingli Zhang
    Abstract:

    Objective : Endothelial dysfunction is an early risk factor for cardiovascular disease and hypertension. Mechanisms that participate in endothelial dysfunction include reduced nitric oxide (NO) generation and increased endothelin-1 (ET-1) generation. Endothelial ATP-sensitive Potassium (KATP) Channels are responsible for maintaining the resting potential of endothelial cells and modulating the release of vasoactive compounds. We hypothesized that activation of endothelial KATP Channels might result in the protection against endothelial dysfunction. Methods : Using cultured bovine or rat aortic endothelial cells, we examined the effects of a new KATP Channels Opener, iptakalim, on the secretion of vasoactive substances. We also investigated its effects on the expression of adhesion molecules in metabolically disturbed cultured endothelial cells. Results : In cultured aortic endothelial cells, iptakalim caused a concentration-dependent inhibition of ET-1 release and synthesis that correlated with reduced levels of mRNA for ET-1 and endothelin-converting enzyme. These effects of iptakalim were significantly inhibited by pretreatment with glibenclamide (a KATP Channel blocker) for 1 h. Similarly, iptakalim enhanced the release of NO in a concentration-dependent manner and increased basal levels of free intracellular calcium. Iptakalim at the concentrations of 100 and 1000 μM increased the activities of NO synthase (NOS) significantly. After the activity of NOS was blocked by l- N ω-nitro-arginine methyl ester (l-NAME), the inhibition of iptakalim on ET-1 release was abolished. In endothelial cell models of metabolic disturbance induced by low-density lipoprotein, homocysteine, or hyperglycemia, treatment with iptakalim could inhibit the overexpression of monocyte chemoattractant protein-1 (MCP-1), Intercellular adhesive molecule-1 (ICAM-1), and vascular cell adhesive molecule-1 (VCAM-1) mRNA. Conclusion : Iptakalim is a promising drug that could protect against endothelial dysfunction through activating KATP Channels in endothelial cells.

  • hypoxic pulmonary hypertension hph and iptakalim a novel atp sensitive Potassium Channel Opener targeting smaller arteries in hypertension
    Cardiovascular Drug Reviews, 2006
    Co-Authors: Hai Wang, Yuan Tang, Yingli Zhang
    Abstract:

    Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating chronic disorder of the pulmonary circulation. Attempts to use drugs in the therapy of hypoxic pulmonary hypertension indicated the importance of prevention or reduction of vasoconstriction as well as of the reversal of remodeling within the cardiovascular system. Iptakalim (2,3-dimethyl-N-(1-methylethyl)-2-butylamine), a novel ATP-sensitive Potassium Channel Opener, has the desired effects on hypoxic pulmonary arteries. Iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Moreover, iptakalim has selective antihypertensive effects: it significantly lowers arterial pressure in hypertensive animals, but has little if any effect in normotensive animals. In HPH iptakalim has selective effects on smaller arteries. Long-term iptakalim therapy decreases expression of sulfonylurea receptor 2 and of mRNA of inwardly rectifying Potassium Channel in smaller arteries of spontaneously hypertensive rats. Iptakalim inhibits the effects of endothelin-1, reduces the intracellular calcium concentration and inhibits the cell cycle in smooth muscle cells of pulmonary arteries. There is no evidence for the development of tolerance to the long-lasting antihypertensive action of iptakalim. At therapeutic doses iptakalim has no effects on the central nervous, respiratory, digestive, or endocrine systems. It has a broad therapeutic range, so that it can be safely used in the therapy of HPH.

Joachim Storling - One of the best experts on this subject based on the ideXlab platform.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium channe
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional β-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, β-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1β and/or high-glucose-induced β-cell production of IL-1β. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the β-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1β-induced apoptosis and impaired function in human β-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1β, or 10 and 100 μmol/l of the sulfonylurea tolbutamide induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1β were blocked by 200 μmol/l diazoxide as well as by 3 and 30 μmol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 μmol/l NN414. Similarly, 1 μmol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 μmol/l of the l-type Ca 2+ Channel blocker nimodipine prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca 2+ influx and ERK dependent and can be prevented by the β-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1β induced β cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.

  • glucose and interleukin 1beta induced beta cell apoptosis requires ca2 influx and extracellular signal regulated kinase erk 1 2 activation and is prevented by a sulfonylurea receptor 1 inwardly rectifying k Channel 6 2 sur kir6 2 selective Potassium Channel Opener in human islets
    Diabetes, 2004
    Co-Authors: Kathrin Maedler, Joachim Storling, Jeppe Sturis, Giatgen A Spinas, Per O G Arkhammar, Richard A. Zuellig, Thomas Mandruppoulsen, Marc Y Donath
    Abstract:

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the Potassium Channel Opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel Potassium Channel Opener NN414, selective for the beta-cell Potassium Channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) Channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective Potassium Channel Opener NN414.