Exendin-4 protects murine pancreatic β-cells from dexamethasone-induced apoptosis through PKA and PI-3K signaling

Wang, Lin-Xi; Wang, Yanping; Zhou, Chuanpeng; Liu, Xiaoying; Liu, Xiaohong; Liu, Liang; Chen, Wen-Jia; Liu, Libin

doi:10.1016/j.diabres.2010.09.004

Cited by 15 publications

(8 citation statements)

References 30 publications

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“…In vitro studies show that glucocorticoids can reduce β cell glucose uptake and phosphorylation, thereby reducing ATP synthesis and Ca + influx, leading to reduced insulin biosynthesis and release [6,27]. In addition, glucocorticoids can reduce β cell mass by inducing apoptosis [28,29]. In contrast, a study by Rafacho et al [30] showed that with high-dose dexamethasone treatment, rat pancreatic islet β cells underwent adaptive changes, the ability of the islets to respond to glucose increased, and insulin compensated secretion increased.…”

Section: Discussionmentioning

confidence: 99%

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: a whole-body 18F-FDG PET/CT study

et al. 2020

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Aims Steroid diabetes mellitus (SDM) is a metabolic syndrome caused by an increase in glucocorticoids, and its pathogenesis is unclear. 18F-FDG PET/CT can reflect the glucose metabolism of tissues and organs under living conditions. Here, PET/CT imaging of SDM and type 2 diabetes mellitus (T2DM) rats was used to visualize changes in glucose metabolism in the main glucose metabolizing organs and investigate the pathogenesis of SDM. Methods SDM and T2DM rat models were established. During this time, PET/CT imaging was used to measure the %ID/g value of skeletal muscle and liver to evaluate glucose uptake. The pancreatic, skeletal muscle and liver were analyzed by immunohistochemistry. Results SDM rats showed increased fasting blood glucose and insulin levels, hyperplasia of islet α and β cells, increased FDG uptake in skeletal muscle accompanied by an up-regulation of PI3Kp85α, IRS-1, and GLUT4, no significant changes in liver uptake, and that glycogen storage in the liver and skeletal muscle increased. T2DM rats showed atrophy of pancreatic islet β cells and decreased insulin levels, significantly reduced FDG uptake and glycogen storage in skeletal muscle and liver. Conclusions The pathogenesis of SDM is different from that of T2DM. The increased glucose metabolism of skeletal muscle may be related to the increased compensatory secretion of insulin. Glucocorticoids promote the proliferation of islet α cells and cause an increase in gluconeogenesis in the liver, which may cause increased blood glucose.

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Section: Discussionmentioning

confidence: 99%

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: a whole-body 18F-FDG PET/CT study

et al. 2020

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“…The acute effects of GCs have also been associated with decreased insulin secretion both in the pancreatic β-cell lines and mouse pancreatic islets (Hult et al 2009). GCs reduce insulin secretion through several mechanisms, including decreased glucose uptake and oxidation, membrane depolarization, and calcium-induced insulin exocytosis (Wang et al 2010, Fransson et al 2013. On the other hand, the chronic effects of GCs cause a defect of insulin biosynthesis and induce pancreatic β-cell death through endoplasmic reticulum (ER) stress (Linssen et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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

Suksri

Semprasert

Junking

et al. 2021

Journal of Molecular Endocrinology

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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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“…In vitro studies show that glucocorticoids can reduce β cell glucose uptake and phosphorylation, thereby reducing ATP synthesis and Ca + influx, leading to reduced insulin biosynthesis and release (11,34). In addition, glucocorticoids can reduce β cell mass by inducing apoptosis (35,36). To the opposite, studies by Rafacho et al showed that with high-dose dexamethasone treatment, rat pancreatic islet β cells underwent adaptive changes, the ability of the islets to respond to glucose increased, and insulin compensated secretion increased (37,38) (40,41).…”

Section: Discussionmentioning

confidence: 99%

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: A whole-body 18F-FDG PET/CT study

Zhao

Zhou

Pan

et al. 2020

Preprint

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Background Steroid diabetes mellitus (SDM) is a metabolic syndrome caused by an increase in glucocorticoids, and its pathogenesis is unclear. 18F-FDG PET/CT can reflect the glucose metabolism of tissues and organs under living conditions, and plays an important role in diabetes research. Here, PET/CT imaging of SDM and type 2 diabetes mellitus (T2DM) rats was used to observe the changes of glucose metabolism in major glucose metabolism organs and immunohistochemical analysis to explore the possible pathogenesis of SDM. Results The SDM rat model was successfully established, which showed increased FBG and insulin levels; 18F-FDG PET/CT imaging showed increased FDG uptake in skeletal muscle, but no significant increase in liver uptake (15d);Immunohistochemistry showed that islet α-cell and β-cell proliferation, GLUT-4 and IRS-1, PI3Kp85α expression in skeletal muscle increased, and glycogen storage in liver and skeletal muscle increased.T2DM rats showed atrophy of pancreatic islet β cells and decreased insulin levels; Significantly reduced FDG uptake and glycogen storage in skeletal muscle and liver; IRS-1 expression in skeletal muscle decreased, and GLUT-4 and PI3Kp85α did not change significantly. Conclusion The pathogenesis of SDM is different from that of T2DM. The increased glucose metabolism of skeletal muscle may be related to the increased compensatory secretion of insulin; glucocorticoids promote the proliferation of islet α cells and cause the increase of gluconeogenesis in the liver may be the cause of its increased blood glucose.

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Exendin-4 protects murine pancreatic β-cells from dexamethasone-induced apoptosis through PKA and PI-3K signaling

Cited by 15 publications

References 30 publications

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: a whole-body 18F-FDG PET/CT study

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: a whole-body 18F-FDG PET/CT study

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

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: A whole-body 18F-FDG PET/CT study

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