K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

Kullin, M; Li, Zhanchun; Hansen, John Bondo; Björk, Erik; Sandler, Stellan; Karlsson, F A

doi:10.2337/diabetes.49.7.1131

Cited by 42 publications

(40 citation statements)

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“…Treatment with the insulin secretion inhibitor diazoxide prevents impairment of beta cell function in rats administered a 48 h glucose infusion [22], in 90% pancreatectomised diabetic rats [23] and in streptozotocintreated rats [24]. Furthermore, treatment of patients with type 2 diabetes with diazoxide or somatostatin resulted in improved glucagon-and tolbutamide-induced insulin secretion [25] and restored insulin pulsatility and the insulin/ proinsulin ratio in vitro [26].…”

Section: Ermentioning

confidence: 99%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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Section: Ermentioning

confidence: 99%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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“…However, most of the early K ATP channel openers were associated with marked hypotension, which made their continuous and frequent clinical use difficult. Recently, more ␤-cell-specific drugs with only minor effects on blood pressure have been developed (10,11).…”

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KATP Channels and Pancreatic Islet Blood Flow in Anesthetized Rats

et al. 2003

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K ATP channels are important for insulin secretion and depolarization of vascular smooth muscle. In view of the importance of drugs affecting K ATP channels in the treatment of diabetes, we investigated the effects of these channels on splanchnic blood perfusion in general and pancreatic islet blood flow in particular. We treated anesthetized Sprague-Dawley rats with the K ATP channel openers diazoxide or NNC 55-0118 or the K ATP channel closer glipizide. Both diazoxide and NNC 55-0118 dose-dependently increased total pancreatic and islet blood flow in the presence of moderate hyperglycemia, but had no effects on the blood perfusion of other splanchnic organs. Diazoxide markedly lowered the mean arterial blood pressure and thus increased vascular conductance in all organs studied. NNC 55-0118 had much smaller effects on the blood pressure. Glipizide did not affect total pancreatic blood flow, but decreased islet blood flow by 50% in the presence of hypoglycemia. We conclude that K ATP channels actively participate in the blood flow regulation of the pancreatic islets and that substances affecting such channels may also influence islet blood flow.

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“…We recently observed a protective effect of diazoxide and a new KCO, NNC 55-0118, selective for the SUR1/Kir6.2 K ATP of the beta cell, against the toxic action of streptozotocin on rat islets in vitro [7]. Concentrations of KCOs higher than those needed for inhibition of insulin release provided protection, which could indicate that K ATP channels not only in the plasma membrane, but also in mitochondria were involved.…”

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confidence: 99%

“…Stimulated insulin release experiments were carried out as previously described [7]. Briefly, triplicates of five islets were transferred to 200 µl of KRBH with 2 mg/ml BSA and 16.7 mmol/l glucose and incubated for 60 min in air with 5% CO 2 at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Diazoxide (Sigma) and NNC 55-0118 (Novo Nordisk, Copenhagen, Denmark) were prepared as stock solutions of 100 mg/ml in DMSO (final concentration 0.08%) and added to the dishes to a final concentration of 0.3 mmol/l, the concentration at which protective effects against streptozotocin had previously been observed [7]. Islets were incubated for 30 min in air with 5% CO 2 at 37°C with or without KCOs and then either 0.5 mmol/l alloxan, 0.5 mmol/l, sodium nitroprusside or 12.5 or 25 U/ml of IL-1 β were added.…”

Section: Methodsmentioning

confidence: 99%

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Protection of rat pancreatic islets by potassium channel openers against alloxan, sodium nitroprusside and interleukin-1β mediated suppression—possible involvement of the mitochondrial membrane potential

Kullin

Hansen

et al. 2003

Diabetologia

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Aims/hypothesis. We aimed to study the effects of two K ATP channel openers (KCO), diazoxide and the more potent compound NNC 55-0118, on beta-cell suppression and/or toxicity induced by alloxan, sodium nitroprusside and IL-1β. Methods. Islets from rats were exposed to 0.3 mmol/l diazoxide or NNC 55-0118 for 30 min and either alloxan (0.5 mmol/l), sodium nitroprusside (0.5 mmol/l) or IL-1β (12.5 or 25 U/ml) were added and the incubation continued for 30 min. Islets were then washed and incubated for 24 h before examination. Results. After exposure to alloxan, islets showed reduced glucose oxidation rate and impaired glucosestimulated insulin release. NNC 55-0118 counteracted the effects of alloxan, while diazoxide was less effective. After treatment with sodium nitroprusside, islet glucose oxidation rates were reduced and this was prevented by pretreatment with NNC 55-0118. In shortterm experiments the potassium channel openers (KCOs) did not influence the IL-1β effect on insulin secretion. However, long-term addition (24 h) of NNC 55-0118 counteracted IL-1β induced inhibition of the glucose oxidation rate. It was shown, using the fluorescent probe JC-1, that the mitochondrial membrane potential was reduced by the potassium channel openers (KCOs), most strongly by NNC 55-0118. Nevertheless culture with KCOs for 72 h did not cause irreversible damage to the islets. Conclusion/interpretation. Potassium channel openers (KCOs), in particular NNC 55-0118, prevented the toxic effects of alloxan and sodium nitroprusside. IL-1β mediated suppression was reduced by NNC 55-0118 provided the long-term addition of the potassium channel opener (KCO). The protective mechanism of potassium channel openers (KCOs) might involve a decrease of the mitochondrial membrane potential. [Diabetologia (2003) 46:80-88] Keywords Alloxan, interleukin-1β, mitochondria, nitric oxide, pancreatic islets, potassium channel opener, sodium nitroprusside. Environmental as well as immunological events are thought to be of importance for the destruction of the insulin-producing beta-cells in the islets of Langerhans in Type 1 diabetes [1]. The mechanisms and mediators of this process are not fully understood. There is evidence suggesting that a period of reduced activity following the start of insulin treatment is beneficial in new onset diabetes [2,3] and that the cellular activity affects the susceptibility to damage in vitro [4,5,6]. Inhibition of insulin secretion by the use of potassium channel openers (KCOs) provides a means of inducing 'beta-cell rest'. The drugs open the ATP-sensitive potassium channel (K ATP channel) and hyperpol-

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K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

Cited by 42 publications

References 31 publications

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

KATP Channels and Pancreatic Islet Blood Flow in Anesthetized Rats

Protection of rat pancreatic islets by potassium channel openers against alloxan, sodium nitroprusside and interleukin-1β mediated suppression—possible involvement of the mitochondrial membrane potential

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