Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose.

Marshak, Sonya; Leibowitz, Gil; Bertuzzi, Federico; Socci, C.; Kaiser, Nurit; Gross, David J.; Cerasi, Erol; Melloul, Danielle

doi:10.2337/diabetes.48.6.1230

Cited by 160 publications

(133 citation statements)

References 26 publications

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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: 89%

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: 89%

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

et al. 2004

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“…Moreover, Fas and FLIP up-regulation increased insulin and PDX-1 expression. Interestingly, mutations in PDX-1 have been associated with type 2 diabetes (31, 32), and high glucose dramatically lowers DNA-binding activity of PDX-1 (33).…”

Section: Discussionmentioning

confidence: 99%

The Fas pathway is involved in pancreatic β cell secretory function

Schumann

Maedler

Franklin³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ␤ cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in ␤ cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates ␤ cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a ␤ cell-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fasdeficient ␤ cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased ␤ cell mass. Up-regulation of FLIP enhanced NF-B activity via NF-B-inducing kinase and RelB. This led to increased PDX-1 and insulin production independent of changes in cell turnover. The results support a previously undescribed role for the Fas pathway in regulating insulin production and release.diabetes ͉ IL-1 ͉ insulin

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“…Short-term exposure of the beta cell to elevated concentrations of glucose promotes insulin release and enhances insulin biosynthesis [1,5]. However, chronic hyperglycaemia causes beta cell dysfunction characterised by reduced insulin biosynthesis [6] and increased levels of apoptosis (glucotoxicity) [7,8,9,10,11]. Similarly, acute exposure to NEFA potentiates glucose-induced insulin secretion by beta cells [12], whereas prolonged exposure to high concentrations of NEFA triggers beta cell apoptosis (lipotoxicity) [13,14,15,16,17].…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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Aims/hypothesis. We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. Methods. Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay. Results. In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagonlike peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two antiapoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. Conclusions/interpretation. The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo-and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.

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Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose.

Cited by 160 publications

References 26 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

The Fas pathway is involved in pancreatic β cell secretory function

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

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