Tungstate promotes β-cell survival in Irs2−/− mice

Pancreatic β-cells play a central role in type 2 diabetes (T2D) development, which is characterized by the progressive decline of the functional β-cell mass that is associated mainly with increased β-cell apoptosis. Thus, understanding how to enhance survival of β-cells is key for the management of T2D. The insulin receptor substrate-2 (IRS-2) protein is pivotal in mediating the insulin/IGF signaling pathway in β-cells. In fact, IRS-2 is critically required for β-cell compensation in conditions of increased insulin demand and for β-cell survival. Tungstate is a powerful antidiabetic agent that has been shown to promote β-cell recovery in toxin-induced diabetic rodent models. In this study, we investigated whether tungstate could prevent the onset of diabetes in a scenario of dysregulated insulin/IGF signaling and massive β-cell death. To this end, we treated mice deficient in IRS2 ( Irs2−/−), which exhibit severe β-cell loss, with tungstate for 3 wk. Tungstate normalized glucose tolerance in Irs2−/− mice in correlation with increased β-cell mass, increased β-cell replication, and a striking threefold reduction in β-cell apoptosis. Islets from treated Irs2−/− exhibited increased phosphorylated Erk1/2. Interestingly, tungstate repressed apoptosis-related genes in Irs2−/− islets in vitro, and ERK1/2 blockade abolished some of these effects. Gene expression profiling showed evidence of a broad impact of tungstate on cell death pathways in islets from Irs2−/− mice, consistent with reduced apoptotic rates. Our results support the finding that β-cell death can be arrested in the absence of IRS2 and that therapies aimed at reversing β-cell mass decline are potential strategies to prevent the progression to T2D.

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Imeglimin Ameliorates β-cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

10.2337/figshare.16654780.v1 ◽

2021 ◽

Author(s):

Jinghe Li ◽

Ryota Inoue ◽

Yu Togashi ◽

Tomoko Okuyama ◽

Aoi Satoh ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Survival ◽

Cell Apoptosis ◽

Cell Function ◽

Cell Mass ◽

Β Cells ◽

Β Cell ◽

Akita Mice ◽

The Impact

The effects of imeglimin, a novel anti-diabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation, after treatment with thapsigargin, and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell (<a>hPSC)-derived β-like cells</a>. <a>Taken together, imeglimin modulates ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.</a>

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Mitogen-Inducible Gene 6 Triggers Apoptosis and Exacerbates ER Stress-Induced β-Cell Death

Molecular Endocrinology ◽

10.1210/me.2012-1174 ◽

2013 ◽

Vol 27 (1) ◽

pp. 162-171 ◽

Cited By ~ 15

Author(s):

Yi-Chun Chen ◽

E. Scott Colvin ◽

Bernhard F. Maier ◽

Raghavendra G. Mirmira ◽

Patrick T. Fueger

Keyword(s):

Cell Death ◽

Er Stress ◽

Caspase 3 ◽

Cell Mass ◽

Growth Factor Receptor ◽

Protein Translation ◽

Β Cells ◽

Β Cell ◽

Inducible Gene

The increased insulin secretory burden placed on pancreatic β-cells during obesity and insulin resistance can ultimately lead to β-cell dysfunction and death and the development of type 2 diabetes. Mitogen-inducible gene 6 (Mig6) is a cellular stress-responsive protein that can negatively regulate the duration and intensity of epidermal growth factor receptor signaling and has been classically viewed as a molecular brake for proliferation. In this study, we used Mig6 heterozygous knockout mice (Mig6+/−) to study the role of Mig6 in regulating β-cell proliferation and survival. Surprisingly, the proliferation rate of Mig6+/− pancreatic islets was lower than wild-type islets despite having comparable β-cell mass and glucose tolerance. We thus speculated that Mig6 regulates cellular death. Using adenoviral vectors to overexpress or knockdown Mig6, we found that caspase 3 activation during apoptosis was dependent on the level of Mig6. Interestingly, Mig6 expression was induced during endoplasmic reticulum (ER) stress, and its protein levels were maintained throughout ER stress. Using polyribosomal profiling, we identified that Mig6 protein translation was maintained, whereas the global protein translation was inhibited during ER stress. In addition, Mig6 overexpression exacerbated ER stress-induced caspase 3 activation in vitro. In conclusion, Mig6 is transcriptionally up-regulated and resistant to global translational inhibition during stressed conditions in β-cells and mediates apoptosis in the form of caspase 3 activation. The sustained production of Mig6 protein exacerbates ER stress-induced β-cell death. Thus, preventing the induction, translation, and/or function of Mig6 is warranted for increasing β-cell survival.

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The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

Nature Communications ◽

10.1038/s41467-021-25145-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ting Yuan ◽

Karthika Annamalai ◽

Shruti Naik ◽

Blaz Lupse ◽

Shirin Geravandi ◽

...

Keyword(s):

Cell Survival ◽

Cell Apoptosis ◽

Molecular Mechanisms ◽

Cell Mass ◽

Human Islets ◽

Hippo Signaling ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Large Tumor

AbstractDiabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.

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Imeglimin Ameliorates β-cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

10.2337/figshare.16654780 ◽

2021 ◽

Author(s):

Jinghe Li ◽

Ryota Inoue ◽

Yu Togashi ◽

Tomoko Okuyama ◽

Aoi Satoh ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Survival ◽

Cell Apoptosis ◽

Cell Function ◽

Cell Mass ◽

Β Cells ◽

Β Cell ◽

Akita Mice ◽

The Impact

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Downregulation of Fas activity rescues early onset of diabetes in c-KitWv/+ mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00453.2012 ◽

2013 ◽

Vol 304 (6) ◽

pp. E557-E565 ◽

Cited By ~ 14

Author(s):

Zhi-Chao Feng ◽

Matthew Riopel ◽

Jinming Li ◽

Lisa Donnelly ◽

Rennian Wang

Keyword(s):

Cell Survival ◽

Cell Apoptosis ◽

Fas Ligand ◽

Cell Function ◽

Cell Mass ◽

Β Cell ◽

Apoptotic Pathway ◽

Β Cell Function ◽

And Function

c-Kit and its ligand stem cell factor (SCF) are important for β-cell survival and maturation; meanwhile, interactions between the Fas receptor (Fas) and Fas ligand are capable of triggering β-cell apoptosis. Disruption of c-Kit signaling leads to severe loss of β-cell mass and function with upregulation of Fas expression in c-Kit Wv/+ mouse islets, suggesting that there is a critical balance between c-Kit and Fas activation in β-cells. In the present study, we investigated the interrelationship between c-Kit and Fas activation that mediates β-cell survival and function. We generated double mutant, c-Kit Wv/+ ;Fas lpr/lpr ( Wv −/−), mice to study the physiological and functional role of Fas with respect to β-cell function in c-Kit Wv/+ mice. Isolated islets from these mice and the INS-1 cell line were used. We observed that islets in c-Kit Wv/+ mice showed a significant increase in β-cell apoptosis along with upregulated p53 and Fas expression. These results were verified in vitro in INS-1 cells treated with SCF or c-Kit siRNA combined with a p53 inhibitor and Fas siRNA. In vivo, Wv −/− mice displayed improved β-cell function, with significantly enhanced insulin secretion and increased β-cell mass and proliferation compared with Wv +/+ mice. This improvement was associated with downregulation of the Fas-mediated caspase-dependent apoptotic pathway and upregulation of the cFlip/NF-κB pathway. These findings demonstrate that a balance between the c-Kit and Fas signaling pathways is critical in the regulation of β-cell survival and function.

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HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

The Journal of Lipid Research ◽

10.1194/jlr.ra119000509 ◽

2020 ◽

Vol 61 (4) ◽

pp. 492-504 ◽

Cited By ~ 3

Author(s):

Mustafa Yalcinkaya ◽

Anja Kerksiek ◽

Katrin Gebert ◽

Wijtske Annema ◽

Rahel Sibler ◽

...

Keyword(s):

Er Stress ◽

Cell Apoptosis ◽

Cell Mass ◽

Sterol Synthesis ◽

Atpase Inhibitor ◽

Β Cells ◽

Β Cell ◽

Beneficial Effects ◽

Hh Signaling

Loss of pancreatic β-cell mass and function as a result of sustained ER stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog (Hh) signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca2+-ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the Hh signaling receptor Smoothened (SMO) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced β-cell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and, in cells lacking ABCG1 or the 24-OHC synthesizing enzyme CYP46A1, restored the protective activity of HDL. Inhibition of SMO countered the beneficial effects of HDL and also LDL, and SMO agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the SMO-activated transcription factor glioma-associated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and β-cell death involves the transport, generation, and mobilization of oxysterols for activation of the Hh signaling receptor SMO

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Glucose promotes pancreatic islet β-cell survival through a PI 3-kinase/Akt-signaling pathway

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00177.2002 ◽

2002 ◽

Vol 283 (4) ◽

pp. E784-E793 ◽

Cited By ~ 65

Author(s):

Shanthi Srinivasan ◽

Ernesto Bernal-Mizrachi ◽

Mitsuru Ohsugi ◽

Marshall Alan Permutt

Keyword(s):

Cell Survival ◽

Signaling Pathway ◽

Calcium Influx ◽

Cell Mass ◽

Kinase Assay ◽

Β Cells ◽

Β Cell ◽

Akt Kinase ◽

Insulinoma Cells

The concentration of glucose in plasma is an important determinant of pancreatic β-cell mass, whereas the relative contributions of hypertrophy, proliferation, and cell survival to this process are unclear. Glucose results in depolarization and subsequent calcium influx into islet β-cells. Because depolarization and calcium (Ca2+) influx promote survival of neuronal cells, we hypothesized that glucose might alter survival of islet β-cells through a similar mechanism. In the present studies, cultured mouse islet β-cells showed a threefold decrease in apoptosis under conditions of 15 mM glucose compared with 2 mM glucose ( P < 0.05). MIN6 insulinoma cells incubated in 25 mM glucose for 24 h showed a threefold decrease in apoptosis compared with cells in 5 mM glucose (1.7 ± 0.2 vs. 6.3 ± 1%, respectively, P < 0.001). High glucose (25 mM) enhanced survival-required depolarization and Ca2+ influx and was blocked by phosphatidylinositol (PI) 3-kinase inhibitors. Glucose activation of the protein kinase Akt was demonstrated in both insulinoma cells and cultured mouse islets by means of an antibody specific for Ser473 phospho-Akt and by an in vitro Akt kinase assay. Akt phosphorylation was dependent on PI 3-kinase but not on MAPK. Transfection of insulinoma cells with an Akt kinase-dead plasmid (Akt-K179M) resulted in loss of glucose-mediated protection, whereas transfection with a constitutively active Akt enhanced survival in glucose-deprived insulinoma cells. The results of these studies defined a novel pathway for glucose-mediated activation of a PI 3-kinase/Akt survival-signaling pathway in islet β-cells. This pathway may provide important targets for therapeutic intervention.

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Deficiency of VCP-Interacting Membrane Selenoprotein (VIMP) Leads to G1 Cell Cycle Arrest and Cell Death in MIN6 Insulinoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000495865 ◽

2018 ◽

Vol 51 (5) ◽

pp. 2185-2197 ◽

Cited By ~ 1

Author(s):

Lili Men ◽

Juan Sun ◽

Decheng Ren

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Insulin Secretion ◽

Cell Apoptosis ◽

Β Cells ◽

Β Cell ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest ◽

Insulinoma Cells

Background/Aims: VCP-interacting membrane selenoprotein (VIMP), an ER resident selenoprotein, is highly expressed in β-cells, however, the role of VIMP in β-cells has not been characterized. In this study, we studied the relationship between VIMP deficiency and β-cell survival in MIN6 insulinoma cells. Methods: To determine the role of VIMP in β-cells, lentiviral VIMP shRNAs were used to knock down (KD) expression of VIMP in MIN6 cells. Cell death was quantified by propidium iodide (PI) staining followed by flow cytometric analyses using a FACS Caliber and FlowJo software. Cell apoptosis and proliferation were determined by TUNEL assay and Ki67 staining, respectively. Cell cycle was analyzed after PI staining. Results: The results show that 1) VIMP suppression induces β-cell apoptosis, which is associated with a decrease in Bcl-xL, and the β-cell apoptosis induced by VIMP suppression can be inhibited by overexpression of Bcl-xL; 2) VIMP knockdown (KD) decreases cell proliferation and G1 cell cycle arrest by accumulating p27 and decreasing E2F1; 3) VIMP KD suppresses unfolded protein response (UPR) activation by regulating the IRE1α and PERK pathways; 4) VIMP KD increases insulin secretion. Conclusion: These results suggest that VIMP may function as a novel regulator to modulate β-cell survival, proliferation, cell cycle, UPR and insulin secretion in MIN6 cells.

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A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽

10.1210/en.2017-00366 ◽

2017 ◽

Vol 158 (11) ◽

pp. 3900-3913 ◽

Cited By ~ 13

Author(s):

Xiao-Ting Huang ◽

Shao-Jie Yue ◽

Chen Li ◽

Yan-Hong Huang ◽

Qing-Mei Cheng ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Apoptosis ◽

Cell Function ◽

Cell Mass ◽

Nuclear Factor Κb ◽

Β Cells ◽

Β Cell ◽

Stimulation Of ◽

Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

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Harnessing immune cells to enhance β-cell mass in type 1 diabetes

Journal of Investigative Medicine ◽

10.1136/jim-d-15-00196 ◽

2016 ◽

Vol 64 (1) ◽

pp. 14-20 ◽

Cited By ~ 2

Author(s):

Ercument Dirice ◽

Rohit N Kulkarni

Keyword(s):

Type 1 Diabetes ◽

Mononuclear Cells ◽

Islet Cells ◽

Cell Mass ◽

Cell Loss ◽

Cell Types ◽

Β Cells ◽

Β Cell ◽

Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

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