Fatty acid-induced toxicity and neutral lipid accumulation in insulin-producing RINm5F cells

Azevedo-Martins, Anna Karenina; Monteiro, Ariana Pereira; Lima, Camila Lopes; Lenzen, Sigurd; Curi, Rui

doi:10.1016/j.tiv.2006.02.007

Cited by 47 publications

(37 citation statements)

References 35 publications

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“…FFA has been proposed as a link between obesity and insulin resistance because there is an elevation of plasma FFA levels in obese animals and humans (15). Increased plasma concentrations of FFA lead to intramyocellular lipid accumulation in humans, suggesting that FFA may play a critical role in initiating and developing insulin resistance (16,17). Our study found increased levels of insulin, glucose, and glycohemoglobin in blood, accompanied by elevated FFA levels in db/db mice.…”

Section: Discussionsupporting

confidence: 51%

The Effects of Palmitate on Hepatic Insulin Resistance Are Mediated by NADPH Oxidase 3-derived Reactive Oxygen Species through JNK and p38MAPK Pathways

Gao

Nong

Huang

et al. 2010

Journal of Biological Chemistry

283

229

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Elevated plasma free fatty acid (FFA) levels in obesity may play a pathogenic role in the development of insulin resistance. However, molecular mechanisms linking FFA to insulin resistance remain poorly understood. Oxidative stress acts as a link between FFA and hepatic insulin resistance. NADPH oxidase 3 (NOX3)-derived reactive oxygen species (ROS) may mediate the effect of TNF-␣ on hepatocytes, in particular the drop in cellular glycogen content. In the present study, we define the critical role of NOX3-derived ROS in insulin resistance in db/db mice and HepG2 cells treated with palmitate. The db/db mice displayed increased serum FFA levels, excess generation of ROS, and upregulation of NOX3 expression, accompanied by increased lipid accumulation and impaired glycogen content in the liver. Similar results were obtained from palmitate-treated HepG2 cells. The exposure of palmitate elevated ROS production and NOX3 expression and, in turn, increased gluconeogenesis and reduced glycogen content in HepG2 cells. We found that palmitate induced hepatic insulin resistance through JNK and p38 MAPK pathways, which are rescued by siRNA-mediated NOX3 reduction. In conclusion, our data demonstrate a critical role of NOX3-derived ROS in palmitate-induced insulin resistance in hepatocytes, indicating that NOX3 is the predominant source of palmitate-induced ROS generation and that NOX3-derived ROS may drive palmitate-induced hepatic insulin resistance through JNK and p38 MAPK pathways.

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Section: Discussionsupporting

confidence: 51%

The Effects of Palmitate on Hepatic Insulin Resistance Are Mediated by NADPH Oxidase 3-derived Reactive Oxygen Species through JNK and p38MAPK Pathways

Gao

Nong

Huang

et al. 2010

Journal of Biological Chemistry

283

229

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“…Accumulating evidence suggests that chain length, spatial conformation and degree of saturation of FFAs profoundly influence the insulinotropic potency and the stimulation of KATP channel activity [7,16,[18][19][20]. Studies focussed on fatty acids chain length reported that the increase of the number of carbons has a negative effect on insulin release by increasing β-cell KATP channel activity and induces uncoupling of β-cell oxidative phosphorylation [7,16,18].…”

Section: Introductionmentioning

confidence: 99%

“…However, studies showing a positive association between saturated fatty acids and a higher risk of type 2 diabetes are more consistent [18,20,24]. It has been shown that palmitic acid (C16:0) is toxic to β-cells, even at moderate levels [19,25]. This fatty acid affects glucose-induced insulin gene expression, ceramide synthesis and activates mitochondrial apoptotic pathways [13,15,[26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Soybean oil treatment impairs glucose-stimulated insulin secretion and changes fatty acid composition of normal and diabetic islets

et al. 2007

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We investigated the effect of sub-chronic soybean oil (SO) treatment on the insulin secretion and fatty acid composition of islets of Langerhans obtained from Goto-Kakizaki (GK), a model of type 2 diabetes, and normal Wistar rats. We observed that soybean-treated Wistar rats present insulin resistance and defective islet insulin secretion when compared with untreated Wistar rats. The decrease in insulin secretion occurred at all concentrations of glucose and arginine tested. Furthermore we observed that soybean-treated normal islets present a significant decrease in two saturated fatty acids, myristic and heneicosanoic acids, and one monounsaturated eicosenoic acid, and the appearance of the monounsaturated erucic acid. Concerning diabetic animals, we observed that soybean-treated diabetic rats, when compared with untreated GK rats, present an increase in plasma non-fasting free fatty acids, an exacerbation of islet insulin secretion impairment in all conditions tested and a significant decrease in the monounsaturated palmitoleic acid. Altogether our results show that SO treatment results in a decrease of insulin secretion and alterations on fatty acid composition in normal and diabetic islets. Furthermore, the impairment of insulin secretion, islet erucic acid and fasting plasma insulin levels are similar in treated normal and untreated diabetic rats, suggesting that SO could have a deleterious effect on β-cell function and insulin sensitivity.

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“…Accumulating evidence suggests that palmitic acid, a saturated FA, plays an important role in beta cell death [31,32]. Prolonged exposure of beta cells to elevated palmitate concentrations has been shown to cause downstream JNK activation and increased p53 expression, events which are in part mediated by enhanced oxidative stress and typically linked to cellular damage [7, 24, 33, this study].…”

Section: Discussionmentioning

confidence: 77%

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

et al. 2015

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Aims/hypothesis The role of the redox adaptor protein p66 Shc as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. Methods The effects of the FA palmitate on p66 Shc expression were evaluated in human and murine islets and in rat insulinsecreting INS-1E cells. p66 Shc expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66 Shc was investigated using pancreatic islets from p66 Shc−/− mice and in INS-1E cells with knockdown of p66 Shc or overexpression of wildtype and phosphorylation-defective p66 Shc . Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. Results Palmitate induced a selective increase in p66 Shc protein expression and phosphorylation on Ser 36 and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66 Shc expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 Shc−/− mice and following p66 Shc knockdown in INS-1E cells; by contrast, overexpression of p66 Shc , but not that of the phosphorylation-defective p66 Shc mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66 Shc were dependent upon its c-Jun N-terminal kinasemediated phosphorylation on Ser 36 and associated with generation of ROS. p66 Shc protein expression and function were also elevated in islets from HFD-fed mice and from obese/ overweight cadaveric human donors. Conclusions/interpretation p53-dependent augmentation of p66 Shc expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.

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Fatty acid-induced toxicity and neutral lipid accumulation in insulin-producing RINm5F cells

Cited by 47 publications

References 35 publications

The Effects of Palmitate on Hepatic Insulin Resistance Are Mediated by NADPH Oxidase 3-derived Reactive Oxygen Species through JNK and p38MAPK Pathways

The Effects of Palmitate on Hepatic Insulin Resistance Are Mediated by NADPH Oxidase 3-derived Reactive Oxygen Species through JNK and p38MAPK Pathways

Soybean oil treatment impairs glucose-stimulated insulin secretion and changes fatty acid composition of normal and diabetic islets

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

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