Treatment with diazoxide causes prolonged improvement of β-cell function in rat islets transplanted to a diabetic environment

Hiramatsu, Shinsuke; Höög, Anders; Möller, Christer; Grill, V.

doi:10.1016/s0026-0495(00)80044-x

Cited by 20 publications

(16 citation statements)

References 27 publications

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“…The lack of association between the beneficial effects on insulin secretion and the number of beta cells and insulin content differs from our findings in a previous transplantation study [8]. There, diazoxide treatment enhanced arginine-induced insulin secretion in parallel with an increase in islet insulin content and preproinsulin mRNA in the transplants.…”

Section: Discussioncontrasting

confidence: 99%

“…Islets were cultured overnight in RPMI 1640 (SVA, Uppsala, Sweden). Then, two islet grafts with 150-220 and 20-50 islets respectively were transplanted under the left kidney capsule as previously described [8]. To minimise inter-individual variations between donors, islets isolated from two to three donor rats were mixed and then divided into three equal portions, one-third being transplanted to a rat belonging to the vehicle-treated, one-third to the diazoxidetreated and one-third to the NN414-treated group.…”

Section: Isolation and Transplantation Of Isletsmentioning

confidence: 99%

“…To answer this question, transplantation studies, although technically difficult and labourintensive, are needed. To test "proof of principle", we transplanted islets to rats that had been made severely diabetic by streptozotocin at adulthood (blood glucose >22 mmol/l) [8]. Eight weeks of diazoxide treatment followed by 1 week of no treatment improved insulin secretion in response to arginine but not to glucose, and in parallel increased insulin content and preproinsulin of the grafts.…”

Section: Introductionmentioning

confidence: 99%

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Openers of ATP-dependent K + -channels protect against a signal-transduction-linked and not freely reversible defect of insulin secretion in a rat islet transplantation model of Type 2 diabetes

Björklund

Hansen²,

Falkmer

et al. 2004

Diabetologia

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Aims/hypothesis. We tested whether chronic overstimulation by levels of hyperglycaemia commonly found in Type 2 diabetes can irreversibly desensitise beta cells and, if so, whether desensitisation relates to the reduction of insulin content and/or the number of beta cells. Methods. We transplanted islets from Wistar-Furth rats under the kidney capsule to neonatally streptozotocinised recipients. Recipients received daily vehicle, diazoxide (100 mg/kg) or the selective activator of beta cell type K + -ATP channels 6-chloro-3-(1-methylcyclopropyl) amino-4H-thienol [3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414) (3 mg/kg) intragastrically for at least 9 weeks. Endpoint measurements were made exactly 7 days after cessation of treatment.Results. Blood glucose did not differ between groups (mean of total: 13.2±1.4 mmol/l). C-peptide levels were significantly depressed in drug-versus vehicle-treated rats 3 to 4 hours after the last gastric tubing event, but not at endpoint. Insulin responses to 27 mmol/l glucose from perifused grafts were not significant after vehicle (median increment 18×10 −3 µU·islet −1 ·min −1 ) but were significant per se and versus vehicle in the diazoxide and NN414 groups (median 107 and 83×10 −3 respectively). Rising second-phase secretion was seen only in the drug-treated groups. Stimulation by 25 mmol/l KCl, together with 0.5 mmol/l 3-isobutyl-1-methylxanthine and 3.3 mmol/l glucose, was enhanced in the drug-treated groups (p<0.05 versus vehicle). Graft insulin content did not differ between groups, nor did percentage of beta cells (between 67 and 68% of endocrine cells). Conclusions/interpretation. Chronic overstimulation by moderate hyperglycaemia damages signalling events including those required for glucose-induced insulin secretion. This signal transduction defect occurs in the absence of any effect on islet macro-morphometry or insulin stores.

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Section: Discussioncontrasting

confidence: 99%

Section: Isolation and Transplantation Of Isletsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Openers of ATP-dependent K + -channels protect against a signal-transduction-linked and not freely reversible defect of insulin secretion in a rat islet transplantation model of Type 2 diabetes

Björklund

Hansen²,

Falkmer

et al. 2004

Diabetologia

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“…The question remains whether chronic overstimulation over months and years may produce irreversible damage to ␤-cells. In support of this, we have obtained evidence for a lasting effect of diazoxide treatment on ␤-cell function in a rat transplantation model (19). Islets from normal rats were transplanted under the kidney capsule in streptozotocin-induced diabetic syngeneic recipients.…”

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confidence: 74%

Overstimulation and beta-cell function.

Grill¹,

Björklund²

2001

Diabetes

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Previous and present evidence ascribes an important role to overstimulation of ␤-cells for the secretory abnormalities associated with type 2 diabetes. The abnormality most clearly linked to overstimulation is the elevated ratio of circulating proinsulin to insulin. Evidence obtained in human pancreatic islets suggests that aberrations in insulin oscillations that occur in type 2 diabetes could at least in part be linked to abnormalities in cytoplasmic Ca 2+ oscillations induced by overstimulation. Furthermore, in a transplantation model, we have obtained evidence for long-lasting, perhaps irreversible, effects of overstimulation, implying that this is a causative factor for the well-recognized deterioration of insulin secretion with increasing duration of type 2 diabetes. The mechanisms behind the effects of overstimulation are only partly clarified, but it is clear that reduced insulin secretion after overstimulation is only partly explained by decreased insulin stores. In cultured human pancreatic islets, overstimulation by high glucose leads to a rise in cytoplasmic Ca 2+ levels, which persists after normalization of the glucose levels. Persistent elevation of cytoplasmic Ca 2+ may trigger apoptosis, thus participating in long-term irreversible deterioration of ␤-cell function. These data provide sufficient rationale for clinical studies to test the beneficial effects of relative ␤-cell rest in type 2 diabetic patients. Diabetes 50 (Suppl. 1): S122-S124, 2001I n 1986, Leahy et al. (1) reported that 48 h of marked hyperglycemia in normal rats, achieved by massive glucose infusions, produced almost total insensitivity to glucose when insulin release was subsequently measured from the perfused pancreas. This desensitizing effect was specific for glucose and other secretagogues, such as arginine, eliciting normal or even exaggerated responses. Desensitization was reversible within 24 h. One of us (V.G.) later showed that if glucose-induced insulin secretion during glucose infusion was blocked by the simultaneous infusion of diazoxide, no later desensitization occurred; if anything, insulin responses to glucose were enhanced (2) (Fig. 1). Because the levels of hyperglycemia were kept similar with or without diazoxide, it was concluded that the desensitizing effect was due to overstimulation of the ␤-cells rather than to effects of hyperglycemia per se.We studied the desensitizing effect of overstimulation further in vitro (3). It was found to be induced in perifused islets by only a few hours of glucose stimulation. The decline of insulin secretion during prolonged in vitro stimulation mimicked that first described by Bolaffi et al. (4) as the third phase of insulin secretion, was proportionate to the degree of stimulation, and could be totally prevented by blocking glucose-induced insulin secretion with diazoxide.Which mechanisms explain desensitization by overstimulation and its prevention by diazoxide? Diazoxide blocks glucose-induced insulin secretion by opening K + -ATP channels (5). An effect of overstimula...

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“…The opening of K ATP channels leads to membrane hyperpolarization sufficient to induce ␤-cell rest. The nonselective K ATP channel opener diazoxide can protect ␤-cells of humans and rodents against hyperglycemiainduced desensitization in vitro (16,17), restoring firstphase and pulsatile insulin release (18), and can protect against streptozotocin-induced injury (18,19). Remarkably, diazoxide treatment also preserves residual insulin secretion in patients with type 1 (20,21) and type 2 (22) diabetes.…”

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confidence: 99%

The Actions of a Novel Potent Islet β-Cell–Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1

Kang

Elias

et al. 2007

Diabetes

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Islet ␤-cell-specific ATP-sensitive K ؉ (K ATP ) channel openers thiadiazine dioxides induce islet rest to improve insulin secretion, but their molecular basis of action remains unclear. We reported that syntaxin-1A binds nucleotide binding folds of sulfonylurea receptor 1 (SUR1) in ␤-cells to inhibit K ATP channels. As a strategy to elucidate the molecular mechanism of action of these K ATP channel openers, we explored the possibility that 6-chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC55-0462) might influence syntaxin-1A-SUR1 interactions or vice versa. Whole-cell and inside-out patch-clamp electrophysiology was used to examine the effects of glutathione S-transferase (GST)-syntaxin-1A dialysis or green fluorescence protein/syntaxin-1A cotransfection on NNC55-0462 actions. In vitro pull-down binding studies were used to examine NNC55-0462 influence on syntaxin-1A-SUR1 interactions. Dialysis of GST-syntaxin-1A into the cell cytoplasm reduced both potency and efficacy of extracellularly perfused NNC55-0462 in a HEK cell line stably expressing Kir6.2/SUR1 (BA8 cells) and in rat islet ␤-cells. Moreover, inside-out membrane patches excised from BA8 cells showed that both GST-syntaxin-1A and its H3 domain inhibited K ATP channels previously activated by NNC55-0462. This action on K ATP channels is isoform-specific to syntaxin-1A because syntaxin-2 was without effect. Furthermore, the parent compound diazoxide showed similar sensitivity to GST-syntaxin-1A inhibition. NNC55-0462, however, did not influence syntaxin-1A-SUR1 binding interaction. Our results demonstrated that syntaxin-1A interactions with SUR1 at its cytoplasmic domains can modulate the actions of the K ATP channel openers NNC55-0462 and diazoxide on K ATP channels. The reduced levels of islet syntaxin-1A in diabetes would thus be expected to exert a positive influence on the therapeutic effects of this class of K ATP channel openers. Diabetes

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Treatment with diazoxide causes prolonged improvement of β-cell function in rat islets transplanted to a diabetic environment

Cited by 20 publications

References 27 publications

Openers of ATP-dependent K + -channels protect against a signal-transduction-linked and not freely reversible defect of insulin secretion in a rat islet transplantation model of Type 2 diabetes

Openers of ATP-dependent K + -channels protect against a signal-transduction-linked and not freely reversible defect of insulin secretion in a rat islet transplantation model of Type 2 diabetes

Overstimulation and beta-cell function.

The Actions of a Novel Potent Islet β-Cell–Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1

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