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

2013 ◽  
Vol 304 (12) ◽  
pp. E1263-E1272 ◽  
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.

scholarly journals Downregulation of lncRNA TUG1 Affects Apoptosis and Insulin Secretion in Mouse Pancreatic β Cells

2015 ◽  
Vol 35 (5) ◽  
pp. 1892-1904 ◽  
Author(s):  
Dan-dan Yin ◽  
Er-bao Zhang ◽  
Liang-hui You ◽  
Ning Wang ◽  
Lin-tao Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Annexin V ◽  
Pancreatic Tissue ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Lncrna Tug1

Background: Increasing evidence indicates that long noncoding RNAs (IncRNAs) perform specific biological functions in diverse processes. Recent studies have reported that IncRNAs may be involved in β cell function. The aim of this study was to characterize the role of IncRNA TUG1 in mouse pancreatic β cell functioning both in vitro and in vivo. Methods: qRT-PCR analyses were performed to detect the expression of lncRNA TUG1 in different tissues. RNAi, MTT, TUNEL and Annexin V-FITC assays and western blot, GSIS, ELISA and immunochemistry analyses were performed to detect the effect of lncRNA TUG1 on cell apoptosis and insulin secretion in vitro and in vivo. Results: lncRNA TUG1 was highly expressed in pancreatic tissue compared with other organ tissues, and expression was dynamically regulated by glucose in Nit-1 cells. Knockdown of lncRNA TUG1 expression resulted in an increased apoptosis ratio and decreased insulin secretion in β cells both in vitro and in vivo . Immunochemistry analyses suggested decreased relative islet area after treatment with lncRNA TUG1 siRNA. Conclusion: Downregulation of lncRNA TUG1 expression affected apoptosis and insulin secretion in pancreatic β cells in vitro and in vivo. lncRNA TUG1 may represent a factor that regulates the function of pancreatic β cells.

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

2007 ◽  
Vol 193 (1) ◽  
pp. 65-74 ◽  
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.

scholarly journals CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

2015 ◽  
Vol 112 (49) ◽  
pp. E6818-E6824 ◽  
Author(s):  
Mario Rossi ◽  
Inigo Ruiz de Azua ◽  
Luiz F. Barella ◽  
Wataru Sakamoto ◽  
Lu Zhu ◽  
...  
Keyword(s):  
Insulin Release ◽  
Cell Activity ◽  
Negative Regulator ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Release In Vitro

G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic β-cells. β-Cell M3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of β-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic β-cells, knockdown of CK2α expression, or genetic deletion of CK2α in β-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonist-induced phosphorylation of β-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R-stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R-dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on β-cell GPCRs may represent novel therapeutic targets.

scholarly journals Regulation of islet function and gene expression by prolactin during pregnancy

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.

scholarly journals Neratinib protects pancreatic beta cells in diabetes

2019 ◽  
Vol 10 (1) ◽  
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.

Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival

2017 ◽  
Vol 399 (1) ◽  
pp. 79-92 ◽  
Author(s):  
Dawood Khan ◽  
Srividya Vasu ◽  
R. Charlotte Moffett ◽  
Victor A. Gault ◽  
Peter R. Flatt ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Glucose Disposal ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Mouse Islets ◽  
Receptor Modulators

AbstractModulation of neuropeptide receptors is important for pancreatic β-cell function. Here, islet distribution and effects of the neurotensin (NT) receptor modulators, xenin and NT, was examined. Xenin, but not NT, significantly improved glucose disposal and insulin secretion, in mice. However, both peptides stimulated insulin secretion from rodent β-cells at 5.6 mmglucose, with xenin having similar insulinotropic actions at 16.7 mmglucose. In contrast, NT inhibited glucose-induced insulin secretion. Similar observations were made in human 1.1B4 β-cells and isolated mouse islets. Interestingly, similar xenin levels were recorded in pancreatic and small intestinal tissue. Arginine and glucose stimulated xenin release from islets. Streptozotocin treatment decreased and hydrocortisone treatment increased β-cell mass in mice. Xenin co-localisation with glucagon was increased by streptozotocin, but unaltered in hydrocortisone mice. This corresponded to elevated plasma xenin levels in streptozotocin mice. In addition, co-localisation of xenin with insulin was increased by hydrocortisone, and decreased by streptozotocin. Furtherin vitroinvestigations revealed that xenin and NT protected β-cells against streptozotocin-induced cytotoxicity. Xenin augmented rodent and human β-cell proliferation, whereas NT displayed proliferative actions only in human β-cells. These data highlight the involvement of NT signalling pathways for the possible modulation of β-cell function.

Glucose-dependent expansion of pancreatic β-cells by the protein p8 in vitro and in vivo

2006 ◽  
Vol 291 (6) ◽  
pp. E1168-E1176 ◽  
Author(s):  
Günter Päth ◽  
Anne Opel ◽  
Martin Gehlen ◽  
Veit Rothhammer ◽  
Xinjie Niu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Protein Expression ◽  
Cell Expansion ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
C Peptide

p8 protein expression is known to be upregulated in the exocrine pancreas during acute pancreatitis. Own previous work revealed glucose-dependent p8 expression also in endocrine pancreatic β-cells. Here we demonstrate that glucose-induced INS-1 β-cell expansion is preceded by p8 protein expression. Moreover, isopropylthiogalactoside (IPTG)-induced p8 overexpression in INS-1 β-cells (p8-INS-1) enhances cell proliferation and expansion in the presence of glucose only. Although β-cell-related gene expression (PDX-1, proinsulin I, GLUT2, glucokinase, amylin) and function (insulin content and secretion) are slightly reduced during p8 overexpression, removal of IPTG reverses β-cell function within 24 h to normal levels. In addition, insulin secretion of p8-INS-1 β-cells in response to 0–25 mM glucose is not altered by preceding p8-induced β-cell expansion. Adenovirally transduced p8 overexpression in primary human pancreatic islets increases proliferation, expansion, and cumulative insulin secretion in vitro. Transplantation of mock-transduced control islets under the kidney capsule of immunosuppressed streptozotocin-diabetic mice reduces blood glucose and increases human C-peptide serum concentrations to stable levels after 3 days. In contrast, transplantation of equal numbers of p8-transduced islets results in a continuous decrease of blood glucose and increase of human C-peptide beyond 3 days, indicating p8-induced expansion of transplanted human β-cells in vivo. This is underlined by a doubling of insulin content in kidneys containing p8-transduced islet grafts explanted on day 9. These results establish p8 as a novel molecular mediator of glucose-induced pancreatic β-cell expansion in vitro and in vivo and support the notion of existing β-cell replication in the adult organism.

scholarly journals Betacellulin-δ4, a Novel Differentiation Factor for Pancreatic β-Cells, Ameliorates Glucose Intolerance in Streptozotocin-Treated Rats

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4673-4681 ◽  
Author(s):  
Takeki Ogata ◽  
Andrew J. Dunbar ◽  
Yoritsuna Yamamoto ◽  
Yuji Tanaka ◽  
Masaharu Seno ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Cell Mass ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Independent Manner ◽  
Ductal Cells ◽  
Alternatively Spliced ◽  
Epidermal Growth

We previously described a novel alternatively spliced mRNA transcript of the betacellulin (BTC) gene. This splice isoform, termed BTC-δ4, lacks the C-loop of the epidermal growth factor motif and the transmembrane domain as a result of exon 4 ‘skipping’. In this study, we expressed BTC-δ4 recombinantly to explore its biological function. When BTC-δ4 was expressed in COS-7 cells, it was secreted largely into the culture medium, in contrast to BTC. Unlike BTC, highly purified recombinant BTC-δ4 produced in Escherichia coli failed to bind or induce tyrosine phosphorylation of either ErbB1 or ErbB4, nor did it antagonize the binding of BTC to these receptors. Consistent with this, BTC-δ4 failed to stimulate DNA synthesis in Balb/c 3T3 and INS-1 cells. However, BTC-δ4 induced differentiation of pancreatic β-cells; BTC-δ4 converted AR42J cells to insulin-producing cells. When recombinant BTC-δ4 was administered to streptozotocin-treated neonatal rats, it reduced the plasma glucose concentration and improved glucose tolerance. Importantly, BTC-δ4 significantly increased the insulin content, the β-cell mass, and the numbers of islet-like cell clusters and PDX-1-positive ductal cells. Thus, BTC-δ4 is a secreted protein that stimulates differentiation of β-cells in vitro and in vivo in an apparent ErbB1- and ErbB4-independent manner. The mechanism by which BTC-δ4 exerts this action on β-cells remains to be defined but presumably involves an, as yet, unidentified unique receptor.

scholarly journals Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic β-cells under glucolipotoxic stress

2019 ◽  
Author(s):  
Sarah A. White ◽  
Lisa Zhang ◽  
Yu Hsuan Carol Yang ◽  
Dan S. Luciani
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Unfolded Protein ◽  
Protein Response

ABSTRACTER stress and apoptosis contribute to the loss of pancreatic β-cells under the pro-diabetic conditions of glucolipotoxicity. Although activation of the canonical pathway of intrinsic apoptosis is known to require Bax and Bak, their individual and combined involvement in glucolipotoxic β-cell death have not been demonstrated. It has also remained an open question if Bax and Bak in β-cells have non-apoptotic roles in mitochondrial function and ER stress signaling, as suggested in other cell types. Using mice with individual or combined β-cell deletion of Bax and Bak, we demonstrated that glucolipotoxic β-cell death in vitro happens in sequential stages; first via non-apoptotic mechanisms and later by apoptosis, which Bax and Bak were redundant in triggering. In contrast, they had non-redundant roles in mediating staurosporine-induced β-cell apoptosis. We further established that Bax and Bak do not affect normal glucose-stimulated β-cell Ca2+ responses, insulin secretion, or in vivo glucose tolerance. Finally, our experiments revealed that Bax and Bak together dampen the unfolded protein response in β-cells during the early stages of chemical- or glucolipotoxicity-induced ER stress. These findings identify novel roles of the canonical apoptosis machinery in modulating stress signals that are important for the pathobiology of β-cells in diabetes.

The Effect of Oxidative Stress and Antioxidant Therapies on Pancreatic B-cell Dysfunction: Results from in Vitro and in Vivo Studies

2020 ◽  
Vol 27 ◽  
Author(s):  
Ioanna A. Anastasiou ◽  
Ioanna Eleftheriadou ◽  
Anastasios Tentolouris ◽  
Chrysi Koliaki ◽  
Ourania A. Kosta ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
In Vivo Studies ◽  
Limited Evidence ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Natural Extracts ◽  
Endogenous Antioxidant

Background: Oxidative stress is a hallmark of many diseases. A growing body of evidence suggests that hyperglycemiainduced oxidative stress plays an important role in pancreatic β-cells dysfunction and apoptosis as well as in the development and progression of diabetic complications. Considering the vulnerability of pancreatic β-cells to oxidative damage, induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed to protect pancreatic β-cells from damage. Objectives: The present review aims to provide evidence of the effect of oxidative stress and antioxidant therapies on pancreatic β-cell function, based on in vitro and in vivo studies. Methods: The medline and embase databases were searched to retrieve available data. Results: Due to poor endogenous antioxidant mechanisms pancreatic β-cells are extremely sensitive to reactive oxygen species (ROS). Many natural extracts have been tested in vitro in pancreatic β-cell lines in terms of their antioxidant and diabetes mellitus ameliorating effects, and the majority of them have shown a dose-dependent protective role. On the other hand, there is relatively limited evidence regarding the in vitro antioxidant effects of antidiabetic drugs on pancreatic β-cells. About in vivo studies several natural extracts have shown beneficial effects in the setting of diabetes by decreasing blood glucose and lipid levels, increasing insulin sensitivity, and by up-regulating intrinsic antioxidant enzyme activity. However, there is limited evidence obtained from in vivo studies regarding antidiabetic drugs. Conclusion: Antioxidants hold promise for developing strategies aimed at the prevention or treatment of diabetes mellitus associated with pancreatic β-cells dysfunction, as supported by in vitro and in vivo studies. However, more in vitro studies are required about drugs.

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