Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation.

Björklund, Anneli; Lansner, Anders; Grill, Valdemar

doi:10.2337/diabetes.49.11.1840

Cited by 65 publications

(58 citation statements)

References 54 publications

(49 reference statements)

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“…3c, d). Human islets cultured under highglucose conditions for 48 h have previously been described to be desensitised due to increased basal Ca 2+ levels and diminished slow [Ca 2+ ] i oscillations, and thus to respond poorly to glucose stimulation [49]. Interestingly, after 24 h we also found diminished Ca 2+ oscillations but hypersensitisation rather than desensitisation (Fig.…”

Section: Discussionsupporting

confidence: 58%

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

et al. 2012

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Section: Discussionsupporting

confidence: 58%

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

et al. 2012

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“…As to possible mechanisms for such an effect, one should consider the possibility of "Ca 2+ toxicity," i.e., negative effects of continuous inflow of Ca 2+ that may activate Ca 2+ -dependent intracellular proteases, thereby triggering apoptosis (20,21). Such a notion would be in line with our findings that culture of human islets for 48 h at high glucose leads to persistent elevation of cytoplasmic Ca 2+ and that diazoxide partly restores the Ca 2+ levels (11).…”

supporting

confidence: 55%

“…As further support, we found that culturing human islets for 48 h at a high glucose concentration completely desensitizes glucose-induced insulin secretion and that this is accompanied by profound alterations in Ca 2+ fluxes (11). Prominent abnormalities were 1) absence of a Ca 2+ response to glucose, 2) doubling of the postculture "resting" level of cyto-plasmic Ca 2+ , and 3) reduction of slow (0.2-0.5 min) Ca 2+ oscillations.…”

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confidence: 53%

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 enhanced release of [Ca 2+ ] i , possibly during ER stress induction, can increase basal secretion of insulin, but reduce GSIS. Since the enhanced basal [Ca 2+ ] i levels and the reduction of glucose-stimulated Ca 2+ influx was a typical characteristic of islet beta cells isolated from type 2 diabetic patients and since loss of GSIS was associated with enhanced basal [Ca 2+ ] i levels [35], the increase of basal [Ca 2+ ] i levels during ER stress may explain the role of ER stress in GSIS-inhibition in type 2 diabetes. Furthermore, stress kinase JNK, which was activated during the ER stress response may affect insulin secretion since JNK is known to suppress insulin biosynthesis [36].…”

Section: Discussionmentioning

confidence: 99%

A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucose-stimulated insulin secretion (GSIS)

Choi¹,

Lee²,

Jang³

et al. 2008

Archives of Biochemistry and Biophysics

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Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation.

Abstract: Chronic hyperglycemia desensitizes

Cited by 65 publications

References 54 publications

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

Overstimulation and beta-cell function.

A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucose-stimulated insulin secretion (GSIS)

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