Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Özcan, Umut; Cao, Qiong; Yılmaz, Erkan; Lee, Ann–Hwee; Iwakoshi, Neal N.; Özdelen, Esra; Tuncman, Gürol; Görgün, Cem Z.; Glimcher, Laurie H.; Hotamışlıgil, Gökhan S.

doi:10.1126/science.1103160

Cited by 3,287 publications

(3,132 citation statements)

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“…Experimental studies in cultured endothelial cells have demonstrated that chemically induced ER stress causes endothelial dysfunction and insulin resistance 37, 38. Further, a number of studies in animal models have provided additional insights into the molecular mechanisms linking ER stress induction and endothelial dysfunction 39, 40. Nevertheless, limited translational research has addressed the impact of ER stress in the vasculature,41, 42 and the contribution of ER stress to endothelial dysfunction in human DM is not known.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

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BackgroundPrior studies have shown that nutrient excess induces endoplasmic reticulum (ER) stress in nonvascular tissues from patients with diabetes mellitus (DM). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown.Methods and ResultsTo characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase–like ER eukaryotic initiation factor‐2a kinase and inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/EBPα‐homologous protein (P=0.02), were activated in patients with DM. Higher inositol‐requiring ER‐to‐nucleus signaling protein 1 activation was associated with lower flow–mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, reduced p‐inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.01), and the activation of its downstream target c‐jun N‐terminal kinase (P=0.025) in endothelial cells from patients with DM. Furthermore, liraglutide restored insulin‐stimulated endothelial nitric oxide synthase activation in patients with DM (P=0.019).ConclusionsIn summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM. Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c‐jun N‐terminal kinase activation and restores insulin‐mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM.

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Section: Discussionmentioning

confidence: 99%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

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“…This may explain the observation that patients with NAFLD and type 2 diabetes mellitus have a very poor prognosis [127][128][129]. Evidence [130] indicates that insulin may be directly involved in causing endoplasmic reticulum stress along with the unfolding protein response and apoptosis. This may exacerbate insulin resistance [131].…”

Section: Insulinmentioning

confidence: 99%

Role of free radicals in liver diseases

2009

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Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B 1 consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-pbenzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

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“…Restoration to the nontransgenic level by BiP mRNA in B27 rats with additional Hu␤ 2 m. To assess whether the 283-2 transgene locus affects triggering of the UPR by B27, portions of the Con A blast populations described above were subjected to Northern blot analysis of BiP mRNA, a marker of UPR triggering (31,32). As shown in Figures 5A and B, BiP mRNA levels were elevated in all of the HLA-B27 lines, but were reduced in the additional presence of the 283-2 Hu␤ 2 m transgene locus.…”

Section: Production Of An Hu␤ 2 M-transgenic Linementioning

confidence: 99%

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

Tran¹,

Dorris²,

Satumtira³

et al. 2006

Arthritis & Rheumatism

156

150

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Objective. Ankylosing spondylitis and related spondylarthritides are associated with HLA-B27, and also with intestinal inflammation, by unknown mechanisms. The folded HLA-B27 molecule is a trimer of heavy chain, ␤ 2 -microglobulin (␤ 2 m), and short peptide. However, B27 heavy chain has an unusual propensity to misfold and trigger the unfolded protein response (UPR). This study was initiated to test the hypothesis that B27 misfolding plays a role in the pathogenesis of spondylarthritis.Methods. Rats with high transgene copy numbers of HLA-B27 heavy chain together with human ␤ 2 m (Hu␤ 2 m) spontaneously develop colitis, peripheral arthritis, and occasional spondylitis, and those with lower transgene copy numbers remain healthy. We crossed disease-prone and healthy HLA-B27/Hu␤ 2 mtransgenic rat lines with a healthy line, 283-2, carrying only the Hu␤ 2 m transgene. HLA-B27 assembly was assessed by pulse-chase analysis of B27 molecules, and UPR triggering was assessed by measuring BiP/Grp78 messenger RNA (mRNA) in splenic concanavalin A blasts. Surface expression of B27 and Hu␤ 2 m was determined by flow cytometry. Disease manifestations were identified by clinical observation, histology, and measurement of cytokine mRNA.Results. The extra Hu␤ 2 m from the 283-2 line significantly reduced B27 misfolding and UPR triggering. Unexpectedly, however, F 1 male offspring of the healthy 21-3 line crossed with the 283-2 line showed a high prevalence, severity, and duration of arthritis and spondylitis, in the absence of colitis. The arthropathy showed many features characteristic of human spondylarthritis.Conclusion. These results suggest that B27 misfolding is associated with intestinal inflammation, but that neither B27 misfolding nor intestinal inflammation is critical to the development of B27-associated arthropathy.The spondylarthritides are a group of inflammatory rheumatic diseases characterized by axial and peripheral arthropathy and a variety of extraarticular lesions (1). In the prototype of these disorders, ankylosing spondylitis (AS), there is inflammation in the spinal and sacroiliac joints and in ligamentous attachments that, in severe cases, leads to bony fusion. The pathogenesis of spondylarthritis is poorly understood. Two factors strongly associated with these conditions are intestinal inflammation and the major histocompatibility complex (MHC) class I gene HLA-B27.With regard to the association with intestinal inflammation, the prevalence of inflammatory bowel disease (IBD) (both Crohn's disease and ulcerative colitis) is increased in individuals with AS. An even higher prevalence of IBD is found in individuals with other forms of spondylarthritis (2), and endoscopic studies with biopsy have shown a prevalence of microscopic inflammatory bowel lesions in 60-70% of patients

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Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Cited by 3,287 publications

References 25 publications

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Role of free radicals in liver diseases

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

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Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Cited by 3,287 publications

References 25 publications

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Role of free radicals in liver diseases

Additional human β2‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

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Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats