Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells

Segall, Laura; Lameloise, Nathalie; Assimacopoulos-Jeannet, F.; Roche, Enrique; Corkey, Pamela; Thumelin, Stéphane; Corkey, Barbara E.; Prentki, Marc

doi:10.1152/ajpendo.1999.277.3.e521

Cited by 69 publications

(83 citation statements)

References 46 publications

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“…Long-term exposure of the beta cell to high glucose induces glucose desensitisation, depletion of the readily releasable pool of insulin and may cause apoptosis [55]. Long-term exposure of beta cells to NEFA increases basal insulin release but inhibits glucose-induced insulin secretion [56]. NEFA also reduces glucose-induced insulin gene expression [57] and induces beta cell apoptosis [58].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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“…Sustained elevated lipid concentrations result in impaired insulin action and secretion in vivo and in vitro; this has implications for obesity-related diabetes [1][2][3]. It is known that increased plasma NEFA concentrations reduce insulinmediated glucose uptake and metabolism in muscles-the Randle effect [4]-but the exact mechanism of action of NEFA on the beta cell to modulate glucose-stimulated insulin secretion (GSIS) [5,6] is not known.…”

Section: Introductionmentioning

confidence: 99%

Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro

et al. 2005

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Aims/hypothesis: Long-term exposure of beta cells to lipids, particularly saturated fatty acids in vitro, results in cellular dysfunction and apoptosis (lipotoxicity); this could contribute to obesity-related diabetes. Our aims were to relate cell death to intracellular triglyceride concentration, composition and localisation following incubation of INS1 cells in saturated and unsaturated NEFA in high and low glucose concentrations. Materials and methods: In sulin-producing INS1 cells were cultured (24 h; 3 and 20 mmol/l glucose) with palmitic, oleic or linoleic acids and the resulting intracellular lipids were analysed by gas chromatography and microscopy. Cell death was determined by quantitative microscopy and 3-(4,5-dimethlthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and glucose-stimulated insulin secretion by ELISA. Results: All NEFA (0.5 mmol/l, 0.5% albumin) inhibited glucose-stimulated (20 mmol/l) insulin secretion. Cytotoxicity was evident only with palmitic acid (p<0.05), in which case intracellular triglyceride consisted largely of tripalmitin in angular-shaped dilated endoplasmic reticulum. Cytotoxicity and morphological disruption were reduced by addition of unsaturated NEFA. Triglyceridecontent (control cells; 14.5 ng/μg protein) increased up to 10-fold following incubation in NEFA (oleic acid 153.2 ng/μg protein; p<0.05) and triglyceride and phospholipid fractions were both enriched with the specific fatty acid added to the medium (p<0.05). Conclusions/ interpretation: In INS1 cells, palmitic acid is converted in the endoplasmic reticulum to solid tripalmitin (melting point >65C), which could induce endoplasmic reticulum stress proteins and signal apoptosis; lipid-induced apoptosis would therefore be a consequence of the physicochemical properties of these triglycerides. Since cellular triglycerides composed of single species of fatty acid are not likely to occur in vivo, destruction of beta cells by saturated fatty acids could be predominantly an in vitro scenario.

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“…To a large part at least, the effects of activated AMPK can be attributed to a suppression of glucose oxidation [52,56,57] and consequently Ca 2+ influx. The mechanisms through which AMPK inhibits glucose metabolism have yet to be fully elucidated, but the activation of fatty acid oxidation and also a Randle effect [66] may be involved (though see [67] for a contrary view).…”

Section: Introductionmentioning

confidence: 99%

Visualising insulin secretion. The Minkowski Lecture 2004

Rutter

2004

Diabetologia

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Insulin secretion from pancreatic islet beta cells is a tightly regulated process, under the close control of blood glucose concentrations, neural inputs and circulating hormones. Defects in glucose-triggered insulin secretion, possibly exacerbated by a decrease in beta cell mass, are ultimately responsible for the development of type 2 diabetes. A full understanding of the mechanisms by which glucose and other nutrients trigger insulin secretion will probably be essential to allow for the development of new therapies of type 2 diabetes and for the derivation of "artificial" beta cells from embryonic stem cells as a treatment for type 1 diabetes. I focus here on recent developments in our understanding of beta cell glucose sensing, achieved in part through the development of recombinant targeted probes (luciferase, green fluorescent protein) that allow islet beta cell metabolism and Ca 2+ handling to be imaged in situ in the intact islet with single cell resolution. Combined with classical biochemistry, these techniques show that the beta cell is uniquely poised, thanks to the expression of low levels of lactate dehydrogenase and plasma membrane lactate/monocarboxylate transporters, to channel glucose carbons towards oxidative metabolism, ATP synthesis and inhibition of AMP-activated protein kinase, a newly defined regulator of insulin release. I also discuss the molecular basis of the recruitment of secretory vesicles to the cell surface, analysed by the use of new imaging techniques including total internal reflection of fluorescence, as well as the "nanomechanics" of the exocytotic event itself.

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Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells

Cited by 69 publications

References 46 publications

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro

Visualising insulin secretion. The Minkowski Lecture 2004

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