Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function.

Eizirik, Décio L.; Korbutt, Gregory S.; Hellerström, Claes

doi:10.1172/jci115989

Cited by 301 publications

(253 citation statements)

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“…With our model of in-vitro human islets, we showed that beta-cell alterations characteristic of clinical Type 2 diabetes, including loss of GSIS and decrease in insulin content, can be reproduced with either increased glucose or NEFA concentrations. The deleterious effect of high glucose is well established [2,3], but increased NEFA at physiological glucose concentrations were also able to significantly alter GSIS and insulin content. These results are in accordance with previous studies [6,10,33], but argue against the hypothesis that increased glucose is a prerequisite for the deleterious effect of NEFA on betacell function [11,12,13,14].…”

Section: Discussionmentioning

confidence: 91%

“…However, whether glucose and NEFA alter beta-cell function synergistically or separately, remains controversial. Some authors have shown that beta-cell failure was induced by increased glucose alone [2,9] or increased NEFA alone [6,10], while others have suggested that excess glucose or NEFA are not deleterious separately, but synergize in causing glucolipotoxicity [11,12,13,14].…”

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confidence: 99%

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Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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Aims/hypothesis. Whether excess glucose (glucotoxicity) and excess non-esterified fatty acids (lipotoxicity) act synergistically or separately to alter beta-cell function on Type 2 diabetes remains controversial. We examined the influence of non-esterified fatty acids, with or without concomitant increased glucose concentrations, on human islet function and on the expression of genes involved in lipid metabolism. Methods. Human islets isolated from non-diabetic and non-obese donors were cultured with 5.5, 16 or 30 mmol/l glucose, and when appropriate with 1 or 2 mmol/l non-esterified fatty acids. After 48 h, glucose-stimulated insulin secretion, insulin content, triglyceride content and expression of different genes were evaluated. Results. Non-esterified fatty acids decreased glucosestimulated insulin secretion, insulin content and increased triglyceride content of human isolated islets, independently from the deleterious effect of glucose. Increased glucose concentrations also decreased glucosestimulated insulin secretion and insulin content, but had no influence on triglyceride content. Glucose-stimulated insulin secretion of islets appeared to be significantly correlated with their triglyceride content. Glucose and non-esterified fatty acids modified the gene expression of carnitine palmitoyltransferase-I, acetyl-CoA carboxylase, acyl-CoA oxidase and uncoupling protein 2. Conclusion/interpretation. In our model of isolated human islets, increased glucose and non-esterified fatty acids separately reproduced the two major beta-cell alterations observed in vivo, i.e. loss of glucose-stimulated insulin secretion and reduction in islet insulin content. Our results also suggest that this deleterious effect was, at least in part, mediated by modifications in lipid metabolism gene expression. [Diabetologia (2004) 47:463-469]

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Section: Discussionmentioning

confidence: 91%

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confidence: 99%

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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“…Other studies in human islets have shown that culture at high glucose for several days leads to downregulation of insulin biosynthesis, possibly secondary to decreased expression of the relevant transcription factors (12). Still other studies have reported decreased glucose metabolism (13). The role of overstimulation versus effects of glucose per se could not, however, be assessed in these experiments.…”

mentioning

confidence: 84%

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 isolation and culture conditions for human pancreatic islets have been described previously [15]. The islets were subsequently sent by air to Uppsala, where they were cultured in RPMI 1640 medium containing 10% FCS and 5.6 mM glucose.…”

Section: Islet Isolation Culture and Test Agent Treatmentmentioning

confidence: 99%

“…The islets were subsequently sent by air to Uppsala, where they were cultured in RPMI 1640 medium containing 10% FCS and 5.6 mM glucose. We have previously shown that functional preservation in RPMI 1640 medium is optimal at 5.6 mM glucose for human islets [15] and at 11 mM for rodent islets [10,14]. After 5-6 days in culture, groups of human islets were acutely exposed to peroxynitrite (0.2 or 1.0 mM) for 10 min and then functional and survival studies were performed either immediately after (acute) or following a subsequent period of 24 h in culture without the radical (see below).…”

Section: Islet Isolation Culture and Test Agent Treatmentmentioning

confidence: 99%

Sensitivity of human pancreatic islets to peroxynitrite‐induced cell dysfunction and death

et al. 1996

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Nitric oxide and peroxynitrite (generated by the reaction of nitric oxide with the superoxide anion) may both be mediators of [$-ceH damage in early insulin-dependent diabetes mellitus. We observed that acute exposure of primary cultured human pancreatic islets to peroxynitrite results in a significant decrease in glucose oxidation and islet retrieval. DNA strand breaks in single human and rat islet cells are detectable after acute peroxynitrite exposure, followed by a decrease in islet cell survival after 1 h and 24 h. Cell death appeared to occur via a toxic cell death mechanism (necrosis) rather than apoptosis, as suggested by vital staining and ultrastructural evidence of early membrane and organelle degradation, mitochondrial swelling and loss of matrix. This study demonstrates for the first time that cultured human pancreatic islets are susceptible to the noxious effects of peroxynitrite.

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Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function.

Cited by 301 publications

References 40 publications

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Overstimulation and beta-cell function.

Sensitivity of human pancreatic islets to peroxynitrite‐induced cell dysfunction and death

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