Prolonged Exposure to Insulin Inactivates Akt and Erk1/2 and Increases Pancreatic Islet and INS1E β-Cell Apoptosis

Abstract Aims Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets. Methods Streptozotocin-treated diabetic mice expressing a fluorescent reporter specifically in pancreatic islet α-cells were administered the biguanide metformin (100 mg/kg), thiazolidinedione rosiglitazone (10 mg/kg), or sulfonylurea tolbutamide (20 mg/kg) for 10 days. We assessed the impact of the treatment on metabolic status of the animals as well as on the morphology, proliferative potential and transdifferentiation of pancreatic islet cells, using immunofluorescence. Results The effect of the therapy on the islet cells varied depending on the drug and included enhanced pancreatic islet β-cell proliferation, in case of metformin and rosiglitazone; de-differentiation of α-cells and β-cell apoptosis with tolbutamide; increased relative number of β-cells and bi-hormonal insulin + glucagon + cells with metformin. These effects were accompanied by normalisation of food and fluid intake with only minor effects on glycaemia at the low doses of the agents employed. Conclusions Our data suggest that metformin and rosiglitazone attenuate the depletion of the β-cell pool in the streptozotocin-induced diabetes, whereas tolbutamide exacerbates the β-cell apoptosis, but is likely to protect β-cells from chronic hyperglycaemia by directly elevating insulin secretion.

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Role of nucleolar protein NOM1 in pancreatic islet β cell apoptosis in diabetes

Experimental and Therapeutic Medicine ◽

10.3892/etm.2016.3576 ◽

2016 ◽

Vol 12 (4) ◽

pp. 2275-2280 ◽

Cited By ~ 1

Author(s):

Leilei Yu ◽

Huifeng Wang ◽

Zhongxiu Guo ◽

Fenghua Li ◽

Hong Cui

Keyword(s):

Pancreatic Islet ◽

Cell Apoptosis ◽

Nucleolar Protein ◽

Β Cell

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Protease inhibitors used in the treatment of HIV+ induce β-cell apoptosis via the mitochondrial pathway and compromise insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90445.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. E925-E935 ◽

Cited By ~ 16

Author(s):

Sheng Zhang ◽

Michael J. Carper ◽

Xiaoyong Lei ◽

W. Todd Cade ◽

Kevin E. Yarasheski ◽

...

Keyword(s):

Cell Death ◽

Protease Inhibitors ◽

Pancreatic Islet ◽

Cell Apoptosis ◽

Cell Function ◽

People Living With Hiv ◽

Β Cell ◽

Apoptotic Pathway ◽

Insulinoma Cells ◽

Factor C

Inclusion of HIV protease inhibitors (PIs) in the treatment of people living with HIV+ has markedly decreased mortality but also increased the incidence of metabolic abnormalities, causes of which are not well understood. Here, we report that insulinopenia is exacerbated when Zucker fa/fa rats are exposed to a PI for 7 wk, suggesting that chronic PI exposure adversely affects pancreatic islet β-cell function. In support of this possibility, we find increased apoptosis, as reflected by TUNEL fluorescence analyses, and reduced insulin-secretory capacity in insulinoma cells and human pancreatic islet cells after in vitro exposures (48–96 h) to clinically relevant PIs (ritonavir, lopinavir, atazanavir, or tipranavir). Furthermore, pancreatic islets isolated from rats administered an HIV-PI for 3 wk exhibit greater cell death than islets isolated from vehicle-administered rats. The higher incidence of HIV-PI-induced cell death was associated with cleavage and, hence, activation of caspase-3 and poly(ADP)-ribose polymerase but not with activation of phospho-pancreatic endoplasmic reticulum (ER) kinase or induction of ER stress apoptotic factor C/EBP homologous protein. Exposure to the HIV-PIs, however, led to activation of mitochondria-associated caspase-9, caused a loss in mitochondrial membrane potential, and promoted the release of cytochrome c, suggesting that HIV-PIs currently in clinically use can induce β-cell apoptosis by activating the mitochondrial apoptotic pathway. These findings therefore highlight the importance of considering β-cell viability and function when assessing loss of glycemic control and the course of development of diabetes in HIV+ subjects receiving a protease inhibitor.

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Exendin-4 inhibits glucolipotoxic ER stress in pancreatic β cells via regulation of SREBP1c and C/EBPβ transcription factors

Journal of Endocrinology ◽

10.1530/joe-12-0311 ◽

2012 ◽

Vol 216 (3) ◽

pp. 343-352 ◽

Cited By ~ 28

Author(s):

Yoon Sin Oh ◽

Youn-Jung Lee ◽

Yup Kang ◽

Jaeseok Han ◽

Oh-Kyung Lim ◽

...

Keyword(s):

Er Stress ◽

Cell Apoptosis ◽

Molecular Mechanisms ◽

Prolonged Exposure ◽

Nuclear Translocation ◽

Β Cells ◽

Β Cell ◽

Stress Markers ◽

Glucagon Like Peptide 1

Prolonged exposure to high glucose (HG) and palmitate (PA) results in increased ER stress and subsequently induces β-cell apoptosis. Exendin-4, a glucagon-like peptide-1 agonist, is known to protect β cells from toxicity induced by cytokines, HG, or fatty acids by reducing ER stress. However, the detailed molecular mechanisms for this protective effect are still not known. In this study, we investigated the role of exendin-4 in the inhibition of glucolipotoxicity-induced ER stress and β-cell apoptosis. Exendin-4 treatment protected INS-1 β cells from apoptosis in response to HG/PA (25 mM glucose+400 μM PA). HG/PA treatment increased cleaved caspase-3 and induced ER stress maker proteins such as PERK (EIF2AK3), ATF6, and phosphorylated forms of PERK, eIF2α, IRE1α (ERN1), and JNK (MAPK8), and these increases were significantly inhibited by exendin-4 treatment. HG/PA treatment of INS-1 cells increased SREBP1 (SREBF1) protein and induced its nuclear translocation and subsequently increased C/EBPβ (CEBPB) protein and its nuclear translocation. Exendin-4 treatment attenuated this increase. Knockdown ofSREBP1creduced the activation ofC/EBPβand also blocked the expression of ER stress markers induced by HG/PA treatment. Our results indicate that exendin-4 inhibits the activation of SREBP1c and C/EBPβ, which, in turn, may reduce glucolipotoxicity-induced ER stress and β-cell apoptosis.

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ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.0c06456 ◽

2020 ◽

Author(s):

Yanqi Li ◽

Yanchao Wang ◽

Lei Zhang ◽

Ziyi Yan ◽

Jingjing Shen ◽

...

Keyword(s):

Cell Apoptosis ◽

Mitochondrial Apoptosis ◽

Β Cell ◽

Apoptosis Pathway ◽

Mitochondrial Apoptosis Pathway

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Dihydroartemisinin prevents palmitate-induced β-cell apoptosis

APOPTOSIS ◽

10.1007/s10495-021-01660-6 ◽

2021 ◽

Author(s):

Zhiyong Wang ◽

·Yan Hao ◽

·Haibing Yu ◽

Pei Wei

Keyword(s):

Cell Apoptosis ◽

Β Cell

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PanK4 inhibits pancreatic β-cell apoptosis by decreasing the transcriptional level of pro-caspase-9

Cell Research ◽

10.1038/cr.2007.93 ◽

2007 ◽

Vol 17 (11) ◽

pp. 966-968 ◽

Cited By ~ 4

Author(s):

Ruo Lan Xiang ◽

Yan Li Yang ◽

Jin Zuo ◽

Xin Hua Xiao ◽

Yong Sheng Chang ◽

...

Keyword(s):

Cell Apoptosis ◽

Transcriptional Level ◽

Pancreatic Β Cell ◽

Caspase 9 ◽

Β Cell

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Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0238 ◽

2021 ◽

Author(s):

Kanchana Suksri ◽

Namoiy Semprasert ◽

Mutita Junking ◽

Suchanoot Kutpruek ◽

Thawornchai Limjindaporn ◽

...

Keyword(s):

Cell Apoptosis ◽

Molecular Mechanisms ◽

Cultured Cells ◽

Death Receptor ◽

Caspase 8 ◽

Pancreatic Β Cell ◽

Β Cell ◽

Apoptotic Protein ◽

Induced Apoptosis ◽

Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

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Intermittent-Hypoxia-Induced Autophagy Activation Through the ER-Stress-Related PERK/eIF2α/ATF4 Pathway is a Protective Response to Pancreatic β-Cell Apoptosis

Cellular Physiology and Biochemistry ◽

10.1159/000496047 ◽

2018 ◽

Vol 51 (6) ◽

pp. 2955-2971 ◽

Cited By ~ 16

Author(s):

Shuling Song ◽

Jin Tan ◽

Yuyang Miao ◽

Zuoming Sun ◽

Qiang Zhang

Keyword(s):

Er Stress ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Intermittent Hypoxia ◽

Autophagic Vacuole ◽

Pancreatic Β Cell ◽

Β Cell ◽

Protective Response

Background/Aims: Intermittent hypoxia (IH) causes apoptosis in pancreatic β-cells, but the potential mechanisms remain unclear. Endoplasmic reticulum (ER) stress, autophagy, and apoptosis are interlocked in an extensive crosstalk. Thus, this study aimed to investigate the contributions of ER stress and autophagy to IH-induced pancreatic β-cell apoptosis. Methods: We established animal and cell models of IH, and then inhibited autophagy and ER stress by pharmacology and small interfering RNA (siRNA) in INS-1 cells and rats. The levels of biomarkers for autophagy, ER stress, and apoptosis were evaluated by immunoblotting and immunofluorescence. The number of autophagic vacuoles was observed by transmission electron microscopy. Results: IH induced autophagy activation both in vivo and in vitro, as evidenced by increased autophagic vacuole formation and LC3 turnover, and decreased SQSTM1 level. The levels of ER-stress-related proteins, including GRP78, CHOP, caspase 12, phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-eIF2α, and activating transcription factor 4 (ATF4) were increased under IH conditions. Inhibition of ER stress with tauroursodeoxycholic acid or 4-phenylbutyrate partially blocked IH-induced autophagy in INS-1 cells. Furthermore, inhibition of PERK with GSK2606414 or siRNA blocked the ERstress-related PERK/eIF2α/ATF4 signaling pathway and inhibited autophagy induced by IH, which indicates that IH-induced autophagy activation is dependent on this signaling pathway. Promoting autophagy with rapamycin alleviated IH-induced apoptosis, whereas inhibition of autophagy with chloroquine or autophagy-related gene (Atg5 and Atg7) siRNA aggravated pancreatic β-cell apoptosis caused by IH. Conclusion: IH induces autophagy activation through the ER-stress-related PERK/eIF2α/ATF4 signaling pathway, which is a protective response to pancreatic β-cell apoptosis caused by IH.

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