Involvement of Endoplasmic Reticulum Stress in Insulin Resistance and Diabetes

Nakatani, Yoichiro; Kaneto, Hideaki; Kawamori, Dan; Yoshiuchi, Kazutomi; Hatazaki, Masahiro; Matsuoka, Taka‐aki; Ozawa, Kentaro; Ogawa, Satoshi; Hori, Masatsugu; Yamasaki, Yoshimitsu; Matsuhisa, Munehide

doi:10.1074/jbc.m411860200

Cited by 414 publications

(320 citation statements)

References 17 publications

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“…Both 4-PBA and UDCA have been successfully used to alleviate ER stress, restore glucose tolerance and improve insulin sensitivity. 20,45,46 However, the effect of 4-PBA or UDCA on ER stress in DN remains un-elucidated. Our findings have shown that both UDCA and 4-PBA could suppress the UPR in podocytes in vitro, as evidenced by the decreased protein expression of BiP, phospho-PERK, phospho-IRE1α and cleaved ATF-6, which were upregulated by HG, suggesting that UDCA and 4-PBA could inhibit HG-induced ER stress in podocytes.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Wang

Chen

et al. 2016

Laboratory Investigation

104

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Endoplasmic reticulum (ER) stress, resulting from the accumulation of misfolded and/or unfolded proteins in ER membranes, is involved in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the role of ER stress inhibitors ursodeoxycholic acid (UDCA) and 4-phenylbutyrate (4-PBA) in the treatment of DN in db/db mice. Findings have revealed that diabetic db/db mice were more hyperglycemic than their non-diabetic controls, and exhibited a marked increase in body weight, water intake, urine volume, fasting plasma glucose, systolic blood pressure, glucose and insulin tolerance. UDCA (40 mg/kg/day) or 4-PBA (100 mg/kg/day) treatment for 12 weeks resulted in an improvement in these biochemical and physical parameters. Moreover, UDCA or 4-PBA intervention markedly decreased urinary albuminuria and attenuated mesangial expansion in diabetic db/db mice, compared with db/db mice treated with vehicle. These beneficial effects of UDCA or 4-PBA on DN were associated with the inhibition of ER stress, as evidenced by the decreased expression of BiP, phospho-IRE1α, phospho-eIF2α, CHOP, ATF-6 and spliced X-box binding protein-1 in vitro and in vivo. UDCA or 4-PBA prevented hyperglycemia-induced or high glucose (HG)-induced apoptosis in podocytes in vivo and in vitro via the inhibition of caspase-3 and caspase-12 activation. Autophagy deficiency was also seen in glomeruli in diabetic mice and HG-incubated podocytes, exhibiting decreased expression of LC3B and Beclin-1, which could be restored by UDCA or 4-PBA treatment. Taken together, our results have revealed an important role of ER stress in the development of DN, and UDCA or 4-PBA treatment may be a potential novel therapeutic approach for the treatment of DN.

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Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Wang

Chen

et al. 2016

Laboratory Investigation

104

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“…The ER is a complicated and systemic network, and excessive ER stress may result in insulin resistance [3,41,42] and islet β-cell dysfunction [43] . Currently, increasing chaperones has been reported to help improve insulin resistance [6] . Here we focused on ATF6 for its potent service as a critical signal transducer in the ER stress system.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, there has been a special interest in ER stress because of its central role in the pathogenesis of type 2 diabetes, and valuable results have been discovered [3][4][5][6] . For example, it was found that molecular indicators of ER stress, such as PERK, eukaryotic initiation factor 2α (eIF2α) and glucoseregulated protein 78 (GRP78), increased in liver and adipose tissues of dietary and genetic murine obesity models.…”

Section: Introductionmentioning

confidence: 99%

“…Over-expression of X-box binding protein 1 (XBP-1), another important ER stress signal transducer, down-regulates JNK activity, enhances insulin receptor signaling pathway activity and restores glucose homeostasis [3] . The attenuation of ER stress by chemical chaperone [eg, 4-phenyl butyric acid (PBA) and taurine-conjugated derivative (TUDCA)] treatment or oxygen-regulated protein 150 kDa (Orp150) over-expression has been confirmed effective in increasing insulin sensitivity and ameliorating diabetes in vivo [4][5][6] . Although targeting ER stress has been hinted at as a promising therapeutic strategy for anti-diabetic agent discovery, further investigations should remain in consideration of the complexity of the ER stress network.…”

Section: Introductionmentioning

confidence: 99%

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Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

Tang¹,

Shen²,

Chen³

et al. 2011

Acta Pharmacol Sin

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Aim: Activating transcription factor 6 (ATF6) is a key signal transducer of endoplasmic reticulum stress (ER stress). This study was conducted to clarify the potential role of ATF6 in the insulin signaling pathway under chronic ER stress. Methods: ER stress of HEK293 cells was induced with tunicamycin (2 µg/mL). The cells were transfected with ATF6α or ATF6β. The phosphorylation level of insulin receptor (IR) was analyzed using Western blot. The changes in ER stress and ERK signaling pathways were explored using Western blot and quantitative real-time PCR. Results: Tunicamycin-induced chronic ER stress attenuated IR tyrosine phosphorylation in a time-dependent manner, whereas overexpression of ATF6 protected IR from desensitization. ATF6 modulation of IR suppression was associated with insulin-stimulated extracellular signal-regulated kinase (ERK) phosphorylation. The treatment of the cells with a specific ERK inhibitor U0126 (10 µmol/L) mimicked the effect of ATF6 over-expression and restored the insulin-stimulated IR phosphorylation. The treatment of the cells with the ERK activator epidermal growth factor (EGF, 200 ng/mL) decreased the protection effect of ATF6 on IR.Conclusion: Our results demonstrate that ATF6 may serve as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

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“…type 2 diabetes mellitus is a complex disease characterized by insulin resistance and insufficient insulin secretion [10,11]. Recently, various studies have shown that eR stress plays a crucial role in the development of insulin resistance and the pathogenesis of type 2 diabetes [12][13][14][15][16][17][18][19]. X-box-binding protein-1 (XBP-1) is a key transcription factor in the eR stress a frameshift of the fusion mRna, and translation of the spliced mRna continues up to the stop codon of venus.…”

mentioning

confidence: 99%

Pioglitazone Reduces ER Stress in the Liver: Direct Monitoring of in vivo ER Stress Using ER Stress-activated Indicator Transgenic Mice

et al. 2009

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Abstract. it is known that endoplasmic reticulum (eR) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. in this study, using eR stress-activated indicator (eRai) transgenic mice which express green fluorescent protein under ER stress conditions, we directly evaluated the effects of a diabetic agent pioglitazone on in vivo eR stress under diabetic conditions. in high fat and high sucrose diet-induced diabetic eRai transgenic mice, 8 weeks of pioglitazone treatment reduced the accumulation of fat droplets in the liver and attenuated the development of insulin resistance. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly reduced as early as after 4 weeks of pioglitazone treatment, preceding the improvement of insulin resistance. in addition, after the pioglitazone treatment, serum free fatty acid and triglyceride levels were decreased, and serum adiponectin levels were increased. these data indicate that pioglitazone treatment suppresses eR stress in the liver which may explain, at least in part, the pharmacological effects of pioglitazone to reduce insulin resistance.

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Involvement of Endoplasmic Reticulum Stress in Insulin Resistance and Diabetes

Cited by 414 publications

References 17 publications

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

Pioglitazone Reduces ER Stress in the Liver: Direct Monitoring of in vivo ER Stress Using ER Stress-activated Indicator Transgenic Mice

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