Tectorigenin enhances PDX1 expression and protects pancreatic β-cells by activating ERK and reducing ER stress

Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet β-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to β-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve β-cell mass and function. Previously, we established a PDX1 promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for the PDX1 gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in β-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of β-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species and endoplasmic reticulum (ER) stress. These effects held true in vivo as well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet β-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring β-cell mass and islet size, respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD-impaired glucose metabolism in mice, as evidenced by ameliorating hyperglycemia and glucose intolerance. Taken together, TG, as an agent promoting PDX1 expression exhibits strong protective effects on islet β-cells both in vitro and in vivo.

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Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

Journal of Endocrinology ◽

10.1677/joe-06-0148 ◽

2007 ◽

Vol 193 (1) ◽

pp. 65-74 ◽

Cited By ~ 70

Author(s):

Shin Tsunekawa ◽

Naoki Yamamoto ◽

Katsura Tsukamoto ◽

Yuji Itoh ◽

Yukiko Kaneko ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Islet Cells ◽

Binding Protein ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic β-cells against their cell death. In in vivo experiments, we used β-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their β-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1α, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in β-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic β-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

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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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GLP-1(28–36) improves β-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/β-catenin signaling in β-cells in vitro

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00600.2012 ◽

2013 ◽

Vol 304 (12) ◽

pp. E1263-E1272 ◽

Cited By ~ 36

Author(s):

Weijuan Shao ◽

Zhaoxia Wang ◽

Wilfred Ip ◽

Yu-Ting Chiang ◽

Xiaoquan Xiong ◽

...

Keyword(s):

Cyclin D1 ◽

Cell Line ◽

Cell Mass ◽

Glucose Disposal ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

In Vitro Investigation

Recent studies have demonstrated that the COOH-terminal fragment of the incretin hormone glucagon-like peptide-1 (GLP-1), a nonapeptide GLP-1(28–36)amide, attenuates diabetes and hepatic steatosis in diet-induced obese mice. However, the effect of this nonapeptide in pancreatic β-cells remains largely unknown. Here, we show that in a streptozotocin-induced mouse diabetes model, GLP-1(28–36)amide improved glucose disposal and increased pancreatic β-cell mass and β-cell proliferation. An in vitro investigation revealed that GLP-1(28–36)amide stimulates β-catenin (β-cat) Ser675 phosphorylation in both the clonal INS-1 cell line and rat primary pancreatic islet cells. In INS-1 cells, the stimulation was accompanied by increased nuclear β-cat content. GLP-1(28–36)amide was also shown to increase cellular cAMP levels, PKA enzymatic activity, and cAMP response element-binding protein (CREB) and cyclic AMP-dependent transcription factor-1 (ATF-1) phosphorylation. Furthermore, GLP-1(28–36)amide treatment enhanced islet insulin secretion and increased the growth of INS-1 cells, which was associated with increased cyclin D1 expression. Finally, PKA inhibition attenuated the effect of GLP-1(28–36)amide on β-cat Ser675 phosphorylation and cyclin D1 expression in the INS-1 cell line. We have thus revealed the beneficial effect of GLP-1(28–36)amide in pancreatic β-cells in vitro and in vivo. Our observations suggest that GLP-1(28–36)amide may exert its effect through the PKA/β-catenin signaling pathway.

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Regulation of islet function and gene expression by prolactin during pregnancy

10.1101/830836 ◽

2019 ◽

Author(s):

Vipul Shrivastava ◽

Megan Lee ◽

Marle Pretorius ◽

Guneet Makkar ◽

Carol Huang

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

Serum Insulin ◽

Prolactin Receptor ◽

Cell Mass ◽

Insulin Level ◽

Β Cells ◽

Β Cell

AbstractPancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell proliferation and increase insulin secretion. Previously, we found that prolactin receptor (Prlr) signaling is important for this process, as heterozygous prolactin receptor-null (Prlr+/−) mice are glucose intolerant, had a lower number of β cells and lower serum insulin levels than wild type mice during pregnancy. However, since Prlr expression is ubiquitous, to determine its β-cell specific effects, we generated a transgenic mouse with a floxed Prlr allele under the control of an inducible promoter, allowing conditional deletion of Prlr from β cells in adult mice. In this study, we found that β-cell-specific Prlr reduction resulted in elevated blood glucose during pregnancy. Similar to our previous finding in mouse with global Prlr reduction, β-cell-specific Prlr loss led to a lower β-cell mass and a lower in vivo insulin level during pregnancy. However, these islets do not have an intrinsic insulin secretion defect when tested in vitro. Interestingly, when we compared the islet gene expression profile, using islets isolated from mice with global versus β-cell-specific Prlr reduction, we found some important differences in genes that regulate apoptosis and insulin secretion. This suggests that Prlr has both cell-autonomous and non-cell-autonomous effect on β cells, beyond its regulation of pro-proliferative genes.

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PFKFB3 DEPLETION ACTIVATES β–CELL REPLICATION BY CELL COMPETITIVE CULLING OF COMPROMISED β–CELLS UNDER STRESS

10.1101/2021.04.07.438857 ◽

2021 ◽

Author(s):

Jie Min ◽

Feyiang Ma ◽

Matteo Pellegrini ◽

Oppel Greeff ◽

Salvador Moncada ◽

...

Keyword(s):

Glucose Intolerance ◽

Critical Role ◽

Cell Mass ◽

Cell Replication ◽

Β Cells ◽

Β Cell ◽

Cell Competition ◽

Islet Amyloid ◽

And Function

Highly conserved hypoxia–inducible factor 1 alpha (HIF1α) and its target 6–phosphofructo–2–kinase/fructose–2,6–biphosphatase 3 (PFKFB3) play a critical role in the survival of damaged β–cells in type 2 diabetes (T2D) while rendering β–cells non–responsive to glucose stimulation by mitochondrial suppression. HIF1α –PFKFB3 is activated in 30–50% of all β–cells in diabetic islets, leaving an open question of whether targeting this pathway may adjust β–cell mass and function to the specific metabolic demands during diabetogenic stress. Our previous studies of β–cells under amyloidogenic stress by human islet amyloid polypeptide (hIAPP) revealed that PFKFB3 is a metabolic execution arm of the HIF1α pathway with potent implications on Ca2+ homeostasis, metabolome, and mitochondrial form and function. To discriminate the role of PFKFB3 from HIF1α in vivo, we generated mice with conditional β–cell specific disruption of the Pfkfb3 gene on a heterozygous hIAPP background and a high–fat diet (HFD) [PFKFB3βKO + diabetogenic stress (DS)]. PFKFB3 disruption in β–cells under diabetogenic stress led to selective purging of hIAPP–damaged β–cells and the disappearance of bihormonal insulin– and glucagon–positive cells, thus compromised β–cells. At the same time, PFKFB3 disruption led to a three–fold increase in β–cell replication resembling control levels as measured with minichromosome maintenance 2 protein (MCM2). PFKFB3 disruption depleted bihormonal cells while increased β–cell replication that was reflected in the increased β–/α–cell ratio and maintained β–cell mass. Analysis of metabolic performance indicated comparable glucose intolerance and reduced plasma insulin levels in PFKFB3βKO DS relative to PFKFB3WT DS mice. In the PFKFB3βKO DS group, plasma glucagon levels were reduced compared to PFKFB3WT DS mice and were in line with increased insulin sensitivity. Glucose intolerance in PFKFB3βKO DS mice could be explained by the compensatory expression of HIF1α after disruption of PFKFB3. Our data strongly suggest that the replication and functional recovery of β–cells under diabetogenic stress depend on selective purification of HIF1α and PFKFB3–positive β–cells. Thus, HIF1α–PFKFB3–dependent activation of cell competition and purging of compromised β–cells may yield functional competent β–cell mass in diabetes.

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Neratinib protects pancreatic beta cells in diabetes

Nature Communications ◽

10.1038/s41467-019-12880-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 11

Author(s):

Amin Ardestani ◽

Sijia Li ◽

Karthika Annamalai ◽

Blaz Lupse ◽

Shirin Geravandi ◽

...

Keyword(s):

Pancreatic Beta Cells ◽

Cell Function ◽

Cell Mass ◽

Human Islets ◽

Β Cells ◽

Β Cell

Abstract The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

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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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DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0039 ◽

2012 ◽

Vol 49 (2) ◽

pp. 125-135 ◽

Cited By ~ 23

Author(s):

Shinobu Shimizu ◽

Tetsuya Hosooka ◽

Tomokazu Matsuda ◽

Shun-ichiro Asahara ◽

Maki Koyanagi-Kimura ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endoplasmic Reticulum ◽

Serum Concentration ◽

Er Stress ◽

Cell Mass ◽

Protective Effects ◽

Β Cells ◽

Β Cell ◽

Dipeptidyl Peptidase 4

The development of type 2 diabetes is accompanied by a progressive decline in β-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on β cells was studied in diabetic mice. Diabetic pancreatic β cell-specific C/EBPB transgenic (TG) mice exhibit decreased β-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on β cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased β-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in β cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in β cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic β cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.

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RIPK3-mediated inflammation is a conserved β cell response to ER stress

Science Advances ◽

10.1126/sciadv.abd7272 ◽

2020 ◽

Vol 6 (51) ◽

pp. eabd7272

Author(s):

Bingyuan Yang ◽

Lisette A. Maddison ◽

Karolina E. Zaborska ◽

Chunhua Dai ◽

Linlin Yin ◽

...

Keyword(s):

Er Stress ◽

Cell Response ◽

Dependent Manner ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Proinflammatory Mediators ◽

Islet Inflammation

Islet inflammation is an important etiopathology of type 2 diabetes; however, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered RIPK3-dependent IL1B induction in β cells as an instigator of islet inflammation. In cultured β cells, ER stress activated RIPK3, leading to NF-kB–mediated proinflammatory gene expression. In a zebrafish muscle insulin resistance model, overnutrition caused islet inflammation, β cell dysfunction, and loss in an ER stress–, ripk3-, and il1b-dependent manner. In mouse islets, high-fat diet triggered the IL1B expression in β cells before macrophage recruitment in vivo, and RIPK3 inhibition suppressed palmitate-induced β cell dysfunction and Il1b expression in vitro. Furthermore, in human islets grafted in hyperglycemic mice, a marked increase in ER stress, RIPK3, and NF-kB activation in β cells were accompanied with murine macrophage infiltration. Thus, RIPK3-mediated induction of proinflammatory mediators is a conserved, previously unrecognized β cell response to metabolic stress and a mediator of the ensuing islet inflammation.

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Inhibition of inositol-requiring enzyme 1α RNase activity protects pancreatic beta cell and improves diabetic condition in insulin mutation-induced diabetes

10.1101/2020.08.30.274381 ◽

2020 ◽

Author(s):

Oana Herlea-Pana ◽

Venkateswararao Eeda ◽

Ram Babu Undi ◽

Iulia Rus ◽

Hui-Ying Lim ◽

...

Keyword(s):

Er Stress ◽

Serum Insulin ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Β Cell ◽

Cell Dysfunction ◽

Expression Of Genes ◽

And Function ◽

Akita Mice

ABSTRACTProinsulin misfolding in the endoplasmic reticulum (ER) plays an important role in β-cell dysfunction and death and the pathogenesis of mutant INS-gene-induced diabetes of youth (MIDY). There is no effective treatment for MIDY except the insulin administration. Here, we found that the ER stress sensor inositol-requiring enzyme 1α (IRE1α) was activated in the Akita mice, a mouse model of MIDY. Normalization of IRE1α RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional β-cell mass, as shown by the suppression of β-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with β-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1α RNase inhibitors. This study provides the first evidence of the in vivo efficacy of IRE1α RNase inhibition in Akita mice, pointing to the possibility of targeting IRE1α RNase as a therapeutic direction for the treatment of MIDY diabetes.

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