Fatty acid metabolism and insulin secretion in pancreatic beta cells

Yaney, Gordon C.; Corkey, Barbara E.

doi:10.1007/s00125-003-1207-4

Cited by 215 publications

(179 citation statements)

References 186 publications

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“…As shown previously [38], a chronic increase in fatty acids, enhances insulin basal secretion (hence diminushing GSIS) by stimulating fatty acyl-CoA that acts distally and in turn stimulates the exocytic machinery. In accordance with previous studies, NEFA concentrations appeared also linked to CPT-I expression in human islets, [22,35].…”

Section: Discussionsupporting

confidence: 53%

“…ACC induces the inhibitor of CPT-I, malonyl-CoA, and is also critical for the regulation of fatty-acid balance between oxidation and cytoplasmic accumulation. At this time, the effect of NEFA on ACC expression is still controversial [20,35,38,41]. So, complementary studies exploring enzymatic activity of CPT-I and NEFA oxidation are necessary to determine the precise interaction between CPT-I and ACC and their regulation by glucose and NEFA.…”

Section: Discussionmentioning

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: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…The hypothesis that lipidinduced beta-cell death (lipoapoptosis) is a major aetiological factor in type 2 diabetes has evolved partly from such in vitro investigations. Our data would suggest that decreased GSIS derives from an imbalance in the sensitive interaction between glucose and lipid metabolism [51] coupled with important changes in phospholipids in beta cells. We believe that 'lipotoxicity' describes a metabolic dysregulation rather than a cellular insult and should therefore not be studied in cell models supplying a single species of saturated fatty acid.…”

Section: Discussionmentioning

confidence: 76%

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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“…In this regard, the activity of the anaplerotic pathway depends on acetyl-CoA, a positive allosteric modulator of PC. As fatty acids represent a major endogenous energy source for islets (Yaney and Corkey 2003), we propose that fatty acid oxidation is a likely source for acetyl-CoA production in Vhlh −/− islets. The prediction that HIF1␣-mediated PDK1 and LDHA up-regulation plays a role in attenuating full mitochondrial activity and thus the efficient generation of key mitochondrial signals is consistent with our observation that glucose-stimulated secretion is less efficient in Vhlh −/− islets than in control islets (Fig.…”

Section: Pvhl-hif Regulates Insulin Secretion Genes and Development 3141mentioning

confidence: 92%

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

108

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Insulin secretion from pancreatic ␤ cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1␣, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1␣ pathway in the control of ␤-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in ␤ cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca 2+ concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1␣ rescued these phenotypes, implying that they are the result of HIF1␣ activation. Together, these results identify pVHL and HIF1␣ as key regulators of insulin secretion from pancreatic ␤ cells. They further suggest that changes in the metabolic strategy of glucose metabolism in ␤ cells have profound effects on whole-body glucose homeostasis.[Keywords: HIF; VHL; glucose intolerance; islet; pancreas] Supplemental material is available at http://www.genesdev.org. Received July 14, 2008; revised version accepted September 5, 2008. During adulthood, cell type-specific growth that exceeds the normal physiological constraints is a common feature of adaptive processes of tissues to changes in metabolic homeostasis and underlies the development of many human diseases, including cancer, heart disease, and diabetes (De Boer et al. 2003;Bouwens and Rooman 2005). Adaptive cell mass expansion, whether neoplastic or nonneoplastic, creates a requirement for compensatory neovascularization to supply oxygen, metabolic substances, and growth/survival factors to the growing tissue (Marti 2005). Therefore, adaptive cell growth responses are generally accompanied, at least initially, by relative states of hypoxia as a result of a mismatch between oxygen demand caused by tissue expansion and oxygen supply provided by the vasculature. An immediate consequence of decreased tissue oxygen availability is that cells shift cellular fuel metabolism from mitochondrial respiration to glycolysis and activate an angiogenic program to increase oxygen delivery in order to overcome the imbalance between tissue mass and vascularization (Semenza 2001;Brahimi-Horn et al. 2007). In this way, tissue function is supported and further mass expansion can occur.At the molecular level, the central regulators of the cellular response to low-oxygen availability are the hypoxia-inducible transcription factors (HIF). HIF are heterodimeric transcription factors composed of HIF1␣, HIF2␣, or HI...

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Fatty acid metabolism and insulin secretion in pancreatic beta cells

Cited by 215 publications

References 186 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

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

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

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