Pioglitazone attenuates fatty acid–induced oxidative stress and apoptosis in pancreatic β‐cells

Saitoh, Yoshiko; Chu, Chun-Ping; Noma, K.; Ueno, Hiroaki; Mizuta, Masanari; Nakazato, Masamitsu

doi:10.1111/j.1463-1326.2007.00749.x

Cited by 38 publications

(23 citation statements)

References 54 publications

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“…Another mechanism involves direct actions on pancreatic beta cells [44]. Recent reports have demonstrated that thiazolidinediones directly improve beta cell function [45], ameliorate lipotoxicity [46] and prevent beta cell apoptosis [47,48]. In Wfs1 −/− A y /a mice, direct protective effects, as well as indirect effects, are likely to be exerted.…”

Section: Discussionmentioning

confidence: 99%

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

et al. 2009

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Aims/hypothesis The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. Methods We studied the effect of breeding Wfs1 −/− mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A y /a). We also treated the mice with pioglitazone.

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Section: Discussionmentioning

confidence: 99%

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

et al. 2009

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“…Partial recovery from palmitate and HG-induced inflammation via TLR2 and TLR4 inhibition suggests the presence of alternate NF-B inflammatory pathways. Recent data indicate that peroxisome proliferator-activated receptor (PPAR)␥ activation may be related to TLR activation supporting this process (30).…”

Section: Ajp-endocrinol Metabmentioning

confidence: 99%

Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors

Dasu

Jialal

2011

American Journal of Physiology-Endocrinology and Metabolism

182

116

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Type 2 diabetes (T2DM) is characterized by hyperglycemia, dyslipidemia, and increased inflammation. Previously, we showed that high glucose (HG) induces Toll-like receptor (TLR) expression, activity, and inflammation via NF-B followed by cytokine release in vitro and in vivo. Here, we determined how HG-induced inflammation is affected by free fatty acids (FFA) in human monocytes. THP-1 monocytic cells, CD14 ϩ human monocytes, and transiently transfected HEK293 cells were exposed to various FFA (0 -500 M) and glucose (5-20 mM) for evaluation of TLR2, TLR4, NF-B, IL-1␤, monocyte chemoattractant protein-1 (MCP-1), and superoxide release. In THP-1 cells, palmitate increased cellular TLR2 and TLR4 expression, generated reactive oxygen species (ROS), and increased NF-B activity, IL-1␤, and MCP-1 release in a dose-and time-dependent manner. Similar data were observed with stearate and FFA mixture but not with oleate. Conversely, NADPH oxidase inhibitor treatment repressed glucoseand palmitate-stimulated ROS generation and NF-B activity and decreased IL-1␤ and MCP-1 expression. Silencing TLR2, TLR4, and p47phox with small inhibitory RNAs (siRNAs) significantly reduced superoxide release, NF-B activity, IL-1␤, and MCP-1 secretion in HG and palmitate-treated THP-1 cells. Moreover, data from transient transfection experiments suggest that TLR6 is required for TLR2 and MD2 for TLR4 to augment inflammation in FFA-and glucoseexposed cells. These findings were confirmed with human monocytes. We conclude that FFA exacerbates HG-induced TLR expression and activity in monocytic cells with excess superoxide release, enhanced NF-B activity, and induced proinflammatory factor release.palmitate; hyperglycemia; Toll-like receptor 2; Toll-like receptor 4 THE LEVELS OF PLASMA free fatty acids (FFA) and glucose are elevated in obesity and type 2 diabetes (T2DM) and are implicated in the excess cardiovascular disease (CVD) risk associated with diabetes (15). Cell culture and animal studies have established chronic inflammation in the development and progression of insulin resistance (IR) and T2DM (29). In parallel, epidemiologic studies showed elevated plasma levels of C-reactive protein (CRP), serum amyloid A, cytokines, and chemokines as potential mediators of inflammation and predictors of CVD in T2DM patients (28). Monocytes and macrophages are pivotal cells orchestrating the development of IR and CVD (4). They are closely linked to the chronic inflammatory processes that underline IR, T2DM, and atherosclerosis (27). Proinflammatory factors derived from them have deleterious effects in the development and progression of IR and diabetes (27). Thus the mechanisms by which these metabolic abnormalities (dyslipidemia and hyperglycemia) contribute to systemic inflammation are essential for understanding of the pathophysiology of IR, T2DM, and CVD.Activation of the innate immune system via Toll-like receptors (TLRs) is implicated in a plethora of inflammatory diseases (8,33,36,41). TLRs are evolutionarily conserved pattern recognition recep...

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“…Therefore, oxidative stress may be the central mechanism mediating glucotoxicity or lipotoxicity in pancreatic ␤-cells (31). Interestingly, TZDs also inhibit ␤-cell dysfunction induced by high levels of glucose or lipids (35,41,43). In this study, we found that Fig.…”

Section: E917 Antioxidative Effects Of Tzds In Pancreatic ␤-Cellsmentioning

confidence: 49%

“…In addition, TZDs improve islet ␤-cell function and reduce oxidative stress in islets of db/db mice (15-17). Although the expression level of PPAR␥ is quite low in islets, several reports have shown protective effects of TZDs against glucose-or lipid-induced toxicity in islets (27,35,41). These reports suggest that TZDs directly provide beneficial effects on islet ␤-cells, and the reduction of oxidative stress may play an important role in this process.…”

mentioning

confidence: 98%

Mechanism for antioxidative effects of thiazolidinediones in pancreatic β-cells

Chung

Kim

Lee

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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dinediones (TZDs) are synthetic ligands of peroxisome proliferatoractivated receptor-␥ (PPAR␥), a member of the nuclear receptor superfamily. TZDs are known to increase insulin sensitivity and also to have an antioxidative effect. In this study, we tested whether TZDs protect pancreatic ␤-cells from oxidative stress, and we investigated the mechanism involved in this process. To generate oxidative stress in pancreatic ␤-cells (INS-1 and ␤TC3) or isolated islets, glucose oxidase was added to the media. The extracellular and intracellular reactive oxygen species (ROS) were measured to directly determine the antioxidant effect of TZDs. The phosphorylation of JNK/MAPK after oxidative stress was detected by Western blot analysis, and glucose-stimulated insulin secretion and cell viability were also measured. TZDs significantly reduced the ROS levels that were increased by glucose oxidase, and they effectively prevented ␤-cell dysfunction. The antioxidative effect of TZDs was abolished in the presence of a PPAR␥ antagonist, GW9662. Real-time PCR was used to investigate the expression levels of antioxidant genes. The expression of catalase, an antioxidant enzyme, was increased by TZDs in pancreatic ␤-cells, and the knockdown of catalase significantly inhibited the antioxidant effect of TZDs. These results suggest that TZDs effectively protect pancreatic ␤-cells from oxidative stress, and this effect is dependent largely on PPAR␥. In addition, the expression of catalase is increased by TZDs, and catalase, at least in part, mediates the antioxidant effect of TZDs in pancreatic ␤-cells.peroxisome proliferator-activated receptor-␥; reactive oxygen species; catalase OXIDATIVE STRESS HAS BEEN IMPLICATED in the pathogenesis of type 2 diabetes and its vascular complications. Oxidative stress plays an important role in the development of ␤-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. It is well known that excessive reactive oxygen species (ROS) cause ␤-cell dysfunction, such as defects in insulin synthesis and secretion, and apoptosis (9, 23, 32). Pancreatic ␤-cells are very susceptible to oxidative stress because the expression levels of antioxidant enzymes, including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), are relatively low in ␤-cells (12, 39). There are several reports showing that the overexpression of antioxidant enzymes protects pancreatic ␤-cells from oxidative stress-induced dysfunction (1). Exposure to a high level of glucose and/or free fatty acid (FFA) results in the dysfunction of isolated islet or ␤-cells, such as a decrease in insulin release and apoptosis (33,36). An antioxidant N-acetyl-cysteine (NAC) protects ␤-cells from the high-glucose-or high-fatinduced impairments (37). These results suggest that ROS are involved in the glucose/FFA-induced ␤-cell dysfunction.Peroxisome proliferator-activated receptor-␥ (PPAR␥), a member of the nuclear receptor superfamily, is expressed predominantly in adipose tissue and plays an im...

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Pioglitazone attenuates fatty acid–induced oxidative stress and apoptosis in pancreatic β‐cells

Abstract: Pioglitazone attenuated fatty acid-induced oxidative stress and apoptosis in pancreatic beta-cells. TZDs might be used as a mean for maintaining beta-cell survival and preserving capacity of insulin secretion in patients with diabetes mellitus.

Cited by 38 publications

References 54 publications

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors

Mechanism for antioxidative effects of thiazolidinediones in pancreatic β-cells

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