Elevated circulating free fatty acids levels causing pancreatic islet cell dysfunction through oxidative stress

Zhang, X.; Bao, Yige; Ke, Lin; Yu, Yerong

doi:10.1007/bf03346609

Cited by 17 publications

(14 citation statements)

References 28 publications

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“…We have demonstrated previously that 1) prolonged elevation of plasma FFA in rats impairs glucose-stimulated insulin secretion (GSIS) in vivo during hyperglycemic clamps and ex vivo in freshly isolated islets and 2) the treatment with the antioxidants N-acetylcysteine, taurine, or tempol, which decreases islet ROS measured with dihydrodichlorofluorescein diacetate (H 2 DCF-DA), prevents the impairing effects of FFA on ␤-cell function (51). Zhang et al (72) confirmed our findings in rats (51) in a different model of prolonged FFA elevation. Our group has also shown that the antioxidant taurine alleviates FFA-induced impairment in ␤-cell function in humans (68).…”

supporting

confidence: 81%

Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo

Koulajian

Ivovic

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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-We have shown that oxidative stress is a mechanism of free fatty acid (FFA)-induced ␤-cell dysfunction. Unsaturated fatty acids in membranes, including plasma and mitochondrial membranes, are substrates for lipid peroxidation, and lipid peroxidation products are known to cause impaired insulin secretion. Therefore, we hypothesized that mice overexpressing glutathione peroxidase-4 (GPx4), an enzyme that specifically reduces lipid peroxides, are protected from fat-induced ␤-cell dysfunction. GPx4-overexpressing mice and their wild-type littermate controls were infused intravenously with saline or oleate for 48 h, after which reactive oxygen species (ROS) were imaged, using dihydrodichlorofluorescein diacetate in isolated islets, and ␤-cell function was assessed ex vivo in isolated islets and in vivo during hyperglycemic clamps. Forty-eight-hour FFA elevation in wild-type mice increased ROS and the lipid peroxidation product malondialdehyde and impaired ␤-cell function ex vivo in isolated islets and in vivo, as assessed by decreased disposition index. Also, islets of wild-type mice exposed to oleate for 48 h had increased ROS and lipid peroxides and decreased ␤-cell function. In contrast, GPx4-overexpressing mice showed no FFA-induced increase in ROS and lipid peroxidation and were protected from the FFA-induced impairment of ␤-cell function assessed in vitro, ex vivo and in vivo. These results implicate lipid peroxidation in FFA-induced ␤-cell dysfunction. oxidative stress; lipid peroxide; glutathione peroxidase 4; lipotoxicity; ␤-cell dysfunction; in vivo CHRONIC EXPOSURE of pancreatic ␤-cells to free fatty acids (FFA) impairs ␤-cell function (21). Although not all studies are concordant (45), a growing body of evidence implicates oxidative stress as a mechanism of FFA-induced ␤-cell dysfunction (9,38,46,60,67). Pancreatic ␤-cells have low antioxidant defenses (34) and are thus susceptible to reactive oxygen species (ROS)-induced decrease in function and viability (37,47). We have demonstrated previously that 1) prolonged elevation of plasma FFA in rats impairs glucose-stimulated insulin secretion (GSIS) in vivo during hyperglycemic clamps and ex vivo in freshly isolated islets and 2) the treatment with the antioxidants N-acetylcysteine, taurine, or tempol, which decreases islet ROS measured with dihydrodichlorofluorescein diacetate (H 2 DCF-DA), prevents the impairing effects of FFA on ␤-cell function (51). Zhang et al. (72) confirmed our findings in rats (51) in a different model of prolonged FFA elevation. Our group has also shown that the antioxidant taurine alleviates FFA-induced impairment in ␤-cell function in humans (68).The type and cellular localization of ROS in FFA-induced ␤-cell dysfunction are still unclear. We have demonstrated that cytosolic superoxide plays a causal role in fat-induced ␤-cell dysfunction (32); however, since the antioxidants N-acetylcysteine and taurine, which do not decrease superoxide, were also effective in restoring ␤-cell function (51), other ROS are implicated in addition ...

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supporting

confidence: 81%

Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo

Koulajian

Ivovic

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Support for a role of PKC is from (38,76). Support for a role of oxidative stress is from (63,93,97) and for ER stress from our studies in humans (91). Support for a role of inflammation is from (29,65,75,88) and from our studies using salicylate in rats (unpublished observartions).…”

Section: Mechanisms Of Lipid-induced ␤-Cell Dysfunction and Death: Fomentioning

confidence: 68%

“…We found that the antioxidants taurine, N-acetylcysteine (NAC), and tempol prevented the impairment in ␤-cell function induced by prolonged exposure to FFA in vivo during hyperglycemic clamps and ex vivo in isolated islets of oleate-treated rats (63). Other authors have found NAC to prevent impairment of GSIS in vivo and in the perfused pancreas of 96-h Intralipid-infused rats (97).…”

Section: Mechanisms Of Lipid-induced ␤-Cell Dysfunction and Death: Fomentioning

confidence: 88%

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

Giacca

Xiao²,

Oprescu

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

185

133

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The phenomenon of lipid-induced pancreatic ␤-cell dysfunction ("lipotoxicity") has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of ␤-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on ␤-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs ␤-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of ␤-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of ␤-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined ␤-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced ␤-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic ␤-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic ␤-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.␤-cell function; insulin secretion OBESITY, IN PARTICULAR CENTRAL DISTRIBUTION of body fat, is a major predisposing factor for type 2 diabetes. Obesity is associated with insulin resistance, which is in part due to elevated circulating free fatty acids (FFA) and ectopic fat storage in nonadipose tissues. The mechanisms of lipid-induced insulin resistance have been discussed before and are beyond the scope of this review. Insulin resistance may be compensated for by increased insulin secretion, thereby maintaining normal glucose homeostasis. However, in individuals predisposed to developing type 2 diabetes, insulin secretion fails to fully compensate for insulin resistance, leading to impaired glucose tolerance and eventually type 2 diabetes. This review describes how chronically elevated FFA impair ␤-cell compensation, thus contributing to the pathogenesis of type 2 diabetes. A number of comprehensive reviews have outlined the mechanisms of the effects of FFA on the ␤-cell at the molecular level (62, 71). The present review instead focuses on findings from in vivo studies performed in animals and humans, in...

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“…9 Underlying mechanisms include lipid accumulation with subsequent inflammation, 10 oxidative stress, 11 lipid peroxidation, 12 and endoplasmic reticulum stress. 13 HDL may protect against β-cell dysfunction and increase glucose-stimulated insulin secretion (GSIS) via cellular cholesterol removal 2,4,[14][15][16] and direct signaling actions.…”

mentioning

confidence: 99%

Effects of High-Density Lipoprotein Elevation With Cholesteryl Ester Transfer Protein Inhibition on Insulin Secretion

Siebel

Natoli

Yap

et al. 2013

Circulation Research

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Previous cellular, animal, and human studies suggest that increasing plasma HDL cholesterol may modulate insulin secretion. 5,[20][21][22] Cholesteryl ester transfer protein (CETP) inhibition increases plasma HDL cholesterol via a reduction in the transfer of neutral lipids (triglycerides and cholesteryl esters) between HDL and triglyceride-rich lipoprotein particles. The efficacy of this strategy to improve cardiovascular outcomes has not yet been determined, and there is controversy regarding whether CETP inhibition might produce a dysfunctional form of HDL cholesterol, which is less efficient at promoting reverse cholesterol transport than native HDL. 23 This controversy has arisen, in part, because of the early termination of 2 CETP inhibitor trials resulting from adverse events in the case of torcetrapib 24

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Elevated circulating free fatty acids levels causing pancreatic islet cell dysfunction through oxidative stress

Cited by 17 publications

References 28 publications

Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo

Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

Effects of High-Density Lipoprotein Elevation With Cholesteryl Ester Transfer Protein Inhibition on Insulin Secretion

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