Sphingosine 1-Phosphate Affects Cytokine-Induced Apoptosis in Rat Pancreatic Islet β-Cells

Cytokines mediate pancreatic islet β-cell apoptosis and necrosis, leading to loss of insulin secretory capacity and type 1 diabetes mellitus. The cytokines, IL-1β and interferon-γ, induced terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining of rat islet cells within 48 h by about 25–30%, indicative of apoptosis and/or necrosis. Sphingosine 1-phosphate (S1P) at nanomolar concentrations significantly reduced islet cell cytokine-induced TUNEL staining. Similar effects were observed in INS-1 cells. The dihydro analog of S1P also reduced the percentage of TUNEL stained islet and INS-1 cells, whereas the S1P receptor antagonist BML-241 blocked the protective effects. Pertussis toxin did not affect the S1P protective response. In the presence of a phospholipase C antagonist, U73122, there was significant inhibition of the S1P protective effects against apoptosis/necrosis. S1P stimulated INS-1 cell protein kinase C activity. Carbamylcholine chloride acting through muscarinic receptors also inhibited cytokine-induced TUNEL staining in pancreatic islet cells. S1P and/or dihydro-S1P also antagonized cytokine-induced increases in cytochrome c release from mitochondria and caspase-3 activity in INS-1 cells, which are indicative of cell apoptosis vs. necrosis. S1P failed to affect nitric oxide synthase activity after 48 h. Thus, the evidence suggests that S1P acting on S1P receptors coupled to Gq mediates protective effects on islet β-cells against cytokine-induced apoptosis.

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Banxia Xiexin Decoction Ameliorates t-BHP-Induced Apoptosis in Pancreatic Beta Cells by Activating the PI3K/AKT/FOXO1 Signaling Pathway

Journal of Diabetes Research ◽

10.1155/2020/3695689 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Li-juan Du ◽

Bing Pang ◽

Yu-meng Tan ◽

Ya-nan Yang ◽

Mei-zhen Zhang ◽

...

Keyword(s):

Signaling Pathway ◽

Cell Apoptosis ◽

Pancreatic Beta Cells ◽

Caspase 3 ◽

Terminal Deoxynucleotidyl Transferase ◽

Signal Molecules ◽

Protective Effects ◽

Min6 Cells ◽

Banxia Xiexin Decoction ◽

Induced Apoptosis

Background. Banxia Xiexin Decoction (BXXD) reportedly regulates glycolipid metabolism and inhibits pancreatic β-cell apoptosis. This study is aimed at investigating the protective effect of BXXD on tert-butyl hydroperoxide- (t-BHP-) induced apoptosis in MIN6 cells and the underlying mechanisms. Methods. MIN6 cells were preincubated with BXXD or liraglutide (Li) with or without PI3K inhibitor LY294002 (LY) for 12 h, following which t-BHP was added to induce MIN6 cell apoptosis. The protective effects of BXXD on MIN6 cells were evaluated by detecting cell viability and proliferation and glucose-stimulated insulin secretion (GSIS). The antiapoptotic effects were evaluated by Hoechst 33342 staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay (TUNEL). Malondialdehyde and glutathione peroxidase content and superoxide dismutase activity were measured using commercial kits. The expression of PI3K/AKT/FOXO1 signaling pathway-related signal molecules, and that of apoptotic indicators Bax, P27, and Caspase-3, was quantified using western blotting. Results. Preincubation with BXXD significantly improved t-BHP-induced proliferation inhibition and apoptosis and enhanced GSIS. t-BHP induced the generation of reactive oxygen species and inhibited the activities of antioxidant enzymes, which could be neutralized by pretreatment with BXXD. BXXD promoted the phosphorylation of AKT and FOXO1 in t-BHP-induced MIN6 cells. Moreover, BXXD attenuated the expression of related apoptotic indicators Bax, P27, and Caspase-3. LY abolished these effects of BXXD. Conclusion. BXXD protected MIN6 cells against t-BHP-induced apoptosis and improved insulin secretory function through modulation of the PI3K/AKT pathway and the downstream FOXO1, thus suggesting a novel therapeutic approach for type 2 diabetes mellitus (T2DM).

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Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

Journal of Endocrinological Investigation ◽

10.1007/s40618-021-01620-6 ◽

2021 ◽

Author(s):

D. Sarnobat ◽

R. C. Moffett ◽

P. R. Flatt ◽

A. I. Tarasov

Keyword(s):

Pancreatic Islet ◽

Cell Apoptosis ◽

Islet Cells ◽

Early Stage ◽

Proliferative Potential ◽

Low Doses ◽

Β Cells ◽

Β Cell ◽

Oral Hypoglycaemic Agents ◽

The Impact

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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Compound K protects pancreatic islet cells against apoptosis through inhibition of the AMPK/JNK pathway in type 2 diabetic mice and in MIN6 β-cells

Life Sciences ◽

10.1016/j.lfs.2014.04.034 ◽

2014 ◽

Vol 107 (1-2) ◽

pp. 42-49 ◽

Cited By ~ 22

Author(s):

Feng Ying Guan ◽

Jian Gu ◽

Wei Li ◽

Ming Zhang ◽

Yingshi Ji ◽

...

Keyword(s):

Pancreatic Islet ◽

Islet Cells ◽

Pancreatic Islet Cells ◽

Diabetic Mice ◽

Compound K ◽

Β Cells ◽

Jnk Pathway ◽

Type 2 Diabetic

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Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00074.2012 ◽

2012 ◽

Vol 303 (1) ◽

pp. E132-E143 ◽

Cited By ~ 16

Author(s):

Fang Zhao ◽

Fengjie Huang ◽

Mengxiong Tang ◽

Xiaoming Li ◽

Nina Zhang ◽

...

Keyword(s):

Signaling Pathway ◽

Cell Apoptosis ◽

Caspase 3 ◽

Biological Effects ◽

Cell Mass ◽

Type I ◽

Β Cells ◽

Β Cell ◽

Akt Phosphorylation ◽

Induced Apoptosis

We demonstrated previously that the activation of ALK7 (activin receptor-like kinase-7), a member of the type I receptor serine/threonine kinases of the TGF-β superfamily, resulted in increased apoptosis and reduced proliferation through suppression of Akt signaling and the activation of Smad2-dependent signaling pathway in pancreatic β-cells. Here, we show that Nodal activates ALK7 signaling and regulates β-cell apoptosis. We detected Nodal expression in the clonal β-cell lines and rodent islet β-cells. Induction of β-cell apoptosis by treatment with high glucose, palmitate, or cytokines significantly increased Nodal expression in clonal INS-1 β-cells and isolated rat islets. The stimuli induced upregulation of Nodal expression levels were associated with elevation of ALK7 protein and enhanced phosphorylated Smad3 protein. Nodal treatment or overexpression of Nodal dose- or time-dependently increased active caspase-3 levels in INS-1 cells. Nodal-induced apoptosis was associated with decreased Akt phosphorylation and reduced expression level of X-linked inhibitor of apoptosis (XIAP). Remarkably, overexpression of XIAP or constitutively active Akt, or ablation of Smad2/3 activity partially blocked Nodal-induced apoptosis. Furthermore, siRNA-mediated ALK7 knockdown significantly attenuated Nodal-induced apoptosis of INS-1 cells. We suggest that Nodal-induced apoptosis in β-cells is mediated through ALK7 signaling involving the activation of Smad2/3-caspase-3 and the suppression of Akt and XIAP pathways and that Nodal may exert its biological effects on the modulation of β-cell survival and β-cell mass in an autocrine fashion.

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Protective effects of an herbal formulation of Radix Astragali , Radix Codonopsis and Cortex Lycii on streptozotocin-induced apoptosis in pancreatic β -cells: an implication for its treatment of diabetes mellitus

Phytotherapy Research ◽

10.1002/ptr.2285 ◽

2007 ◽

Vol 22 (2) ◽

pp. 190-196 ◽

Cited By ~ 23

Author(s):

Judy Yuet-Wa Chan ◽

Ping-Chung Leung ◽

Chun-Tao Che ◽

Kwok-Pui Fung

Keyword(s):

Diabetes Mellitus ◽

Protective Effects ◽

Radix Astragali ◽

Β Cells ◽

Pancreatic Β Cells ◽

Astragali Radix ◽

Herbal Formulation ◽

Treatment Of Diabetes ◽

Induced Apoptosis ◽

Cortex Lycii

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High sensitivity of β-cell replication to the inhibitory effects of interleukin-1β: modulation by adenoviral overexpression of IGF2 in rat islets

Journal of Endocrinology ◽

10.1677/joe-09-0047 ◽

2009 ◽

Vol 203 (1) ◽

pp. 55-63 ◽

Cited By ~ 13

Author(s):

Elisabet Estil.les ◽

Noèlia Téllez ◽

Joan Soler ◽

Eduard Montanya

Keyword(s):

Cell Proliferation ◽

Cell Apoptosis ◽

Interleukin 1Β ◽

Complete Suppression ◽

Cell Replication ◽

Inhibitory Effects ◽

Β Cells ◽

Β Cell ◽

Rat Islets ◽

Induced Apoptosis

Interleukin-1β (IL1B) is an important contributor to the autoimmune destruction of β-cells in type 1 diabetes, and it has been recently related to the development of type 2 diabetes. IGF2 stimulates β-cell proliferation and survival. We have determined the effect of IL1B on β-cell replication, and the potential modulation by IGF2 and glucose. Control-uninfected and adenovirus encoding for IGF2 (Ad-IGF2)-infected rat islets were cultured at 5.5 or 22.2 mmol/l glucose with or without 1, 10, 30, and 50 U/ml of IL1B. β-Cell replication was markedly reduced by 10 U/ml of IL1B and was almost nullified with 30 or 50 U/ml of IL1B. Higher concentrations of IL1B were required to increase β-cell apoptosis. Although IGF2 overexpression had a strong mitogenic effect on β-cells, IGF2 could preserve β-cell proliferation only in islets cultured with 10 U/ml IL1B, and had no effect with 30 and 50 U/ml of IL1B. In contrast, IGF2 overexpression induced a clear protection against IL1B-induced apoptosis, and higher concentrations of the cytokine were needed to increase β-cell apoptosis in Ad-IGF2-infected islets. These results indicate that β-cell replication is highly sensitive to the deleterious effects of the IL1B as shown by the inhibition of replication by relatively low IL1B concentrations, and the almost complete suppression of β-cell replication with high IL1B concentrations. Likewise, the inhibitory effects of IL-β on β-cell replication were not modified by glucose, and were only modestly prevented by IGF2 overexpression, in contrast with the higher protection against IL1B-induced apoptosis afforded by glucose and by IGF2 overexpression.

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Adiponectin Protects against Glutamate-Induced Excitotoxicity via Activating SIRT1-Dependent PGC-1αExpression in HT22 Hippocampal Neurons

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/2957354 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 19

Author(s):

Liang Yue ◽

Lei Zhao ◽

Haixiao Liu ◽

Xia Li ◽

Bodong Wang ◽

...

Keyword(s):

Western Blot ◽

Cell Viability ◽

Cell Apoptosis ◽

Hippocampal Neurons ◽

Caspase 3 ◽

Critical Role ◽

Tunel Staining ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Expression Levels

Glutamate- (Glu-) induced excitotoxicity plays a critical role in stroke. This study aimed to investigate the effects of APN on Glu-induced injury in HT22 neurons. HT22 neurons were treated with Glu in the absence or the presence of an APN peptide. Cell viability was assessed using the MTT assay, while cell apoptosis was evaluated using TUNEL staining. Levels of LDH, MDA, SOD, and GSH-Px were detected using the respective kits, and ROS levels were detected using dichlorofluorescein diacetate. Western blot was used to detect the expression levels of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), cleaved caspase-3, Bax, and Bcl-2. In addition to the western blot, immunofluorescence was used to investigate the expression levels of SIRT1 and PGC-1α. Our results suggest that APN peptide increased cell viability, SOD, and GSH-Px levels and decreased LDH release, ROS and MDA levels, and cell apoptosis. APN peptide upregulated the expression of SIRT1, PGC-1α, and Bcl-2 and downregulated the expression of cleaved caspase-3 and Bax. Furthermore, the protective effects of the APN peptide were abolished by SIRT1 siRNA. Our findings suggest that APN peptide protects HT22 neurons against Glu-induced injury by inhibiting neuronal apoptosis and activating SIRT1-dependent PGC-1αsignaling.

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Carbamoylcholine regulation of polyphosphoinositide synthesis and hydrolysis in cultured, dispersed, digitonin-permeabilized mouse pancreatic islet cells

Acta Endocrinologica ◽

10.1530/eje.0.1360539 ◽

1997 ◽

Vol 136 (5) ◽

pp. 539-545 ◽

Cited By ~ 4

Author(s):

Andrew M Kardasz ◽

Peter Thams ◽

Kirsten Capito ◽

Carl J Hedeskov

Keyword(s):

Pancreatic Islet ◽

Kinase Activity ◽

Inositol Phosphates ◽

Islet Cells ◽

Pancreatic Islet Cells ◽

Β Cells ◽

Pancreatic Β Cells ◽

Mouse Pancreatic Islet ◽

Phosphatidylinositol 4 ◽

Stimulation Of

Abstract Continuing formation of inositol phosphates during stimulation of pancreatic β-cells by hormones and neurotransmitters requires the continued synthesis of the polyphosphoinositides phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5 bisphosphate (PIP2) from phosphatidylinositol (PI). In the present study we have investigated how this pathway and the activity of phosphoinositide-specific phospholipase C (PI-PLC) are regulated by carbamoylcholine (CCh), Ca2+, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), GTPγS and NaF in 44-h [3H]inositol-labelled, dispersed and digitonin-permeabilized mouse pancreatic islet cells. CCh stimulated not only PI-PLC (G-protein-mediated) but also, by an as yet unknown mechanism, significantly enhanced PI 4-kinase activity, estimated as the PIP:PI ratio, by 100%, and further increased the flux from PI to PIP and PIP2. GTPγS and NaF mimicked the effects of CCh on PI-PLC but had no effect on the levels of PIP and PIP2. TPA raised the PIP:PI ratio by 75%. In addition TPA counteracted the CCh stimulation of PI-PLC. There was no effect of 10−6 mol/l Ca2+ on the levels of PIP and PIP2. Experiments with quinacrine and adenosine confirmed that PI-PLC and PI 4-kinase could be regulated independently of each other. In conclusion, these data point to differential regulation of polyphosphoinositide synthesis and breakdown. European Journal of Endocrinology 136 539–545

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SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells

10.1101/2020.08.31.275719 ◽

2020 ◽

Cited By ~ 4

Author(s):

Katie C. Coate ◽

Jeeyeon Cha ◽

Shristi Shrestha ◽

Wenliang Wang ◽

Luciana Mateus Gonçalves ◽

...

Keyword(s):

Pancreatic Islet ◽

Endocrine Cells ◽

Islet Cells ◽

Cell Entry ◽

Pancreatic Ducts ◽

Human Pancreas ◽

Β Cells ◽

Ductal Cells ◽

Putative Receptor ◽

New Onset

Summary/AbstractReports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.

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