scholarly journals Protective Effects of Astragaloside IV on Uric Acid-Induced Pancreatic β-Cell Injury through PI3K/AKT Pathway Activation

2022 ◽  
Vol 2022 ◽  
pp. 1-8
Author(s):  
Zhenhuan Jiang ◽  
Gang Wang ◽  
Lingling Meng ◽  
Yunzhao Tang ◽  
Min Yang ◽  
...  
Keyword(s):  
Uric Acid ◽  
Insulin Secretion ◽  
Akt Pathway ◽  
Dependent Manner ◽  
Protective Effects ◽  
Pancreatic Β Cell ◽  
Astragaloside Iv ◽  
Β Cell ◽  
Min6 Cells ◽  
Dose Dependent

Background. Elevated uric acid (UA) has been found to damage pancreatic β-cell, promote oxidative stress, and cause insulin resistance in type 2 diabetes (T2D). Astragaloside IV (AS-IV), a major active monomer extracted from Astragalus membranaceus (Fisch.) Bunge. which belongs to TRIB. Galegeae (Br.) Torrey et Gray, Papilionaceae, exhibits various activities in a pathophysiological environment and has been widely employed to treat diseases. However, the effects of AS-IV on UA-induced pancreatic β-cell damage need to be investigated and the associating mechanism needs to be elucidated. This study was designed to determine the protective effects and underlying mechanism of AS-IV on UA-induced pancreatic β-cell dysfunction in T2D. Methods. UA-treated Min6 cells were exposed to AS-IV or wortmannin. Thereafter, the 3-(45)-dimethylthiahiazo(-z-y1)-35-di-phenytetrazoliumromide (MTT) assay and flow cytometry were employed to determine the effect of AS-IV on cell proliferation and apoptosis, respectively. Insulin secretion was evaluated using the glucose-stimulated insulin secretion (GSIS) assay. Finally, western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to determine the effect of AS-IV on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway in UA-treated cells. Results. AS-IV had no cytotoxic effects on Min6 cells. UA significantly suppressed Min6 cell growth, promoted cell apoptosis, and enhanced caspase-3 activity; however, AS-IV abolished these effects in a dose-dependent manner. Further, decreased insulin secretion was found in UA-treated Min6 cells compared to control cells, and the production of insulin was enhanced by AS-IV in a dose-dependent manner. AS-IV significantly increased phosphorylated (p)-AKT expression and the ratio of p-AKT/AKT in Min6 cells exposed to UA. No evident change in AKT mRNA level was found in the different groups. However, the effects of AS-IV on UA-stimulated Min6 cells were reversed by 100 nM wortmannin. Conclusion. Collectively, our data suggest that AS-IV protected pancreatic β-cells from UA-treated dysfunction by activating the PI3K/AKT pathway. Such findings suggest that AS-IV may be an efficient natural agent against T2D.

scholarly journals Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity

2014 ◽  
Vol 223 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Michael Rouse ◽  
Antoine Younès ◽  
Josephine M Egan
Keyword(s):  
Insulin Secretion ◽  
Cell Lines ◽  
Cell Function ◽  
Human Islets ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pde Inhibitors ◽  
Β Cell Function

Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against β-cell dysfunction, we studied their mechanism(s) of action in β-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic β-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic β-cells. In our current study, we found that both RES (0.1–10 μmol/l) and CUR (1–100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating β-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in β-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic β-cell function.

scholarly journals SUN-658 CHL1 Increases Insulin Secretion&Negatively Regulates the Poliferation of Pancreatic β Cell

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Tao Yang ◽  
Qi Fu ◽  
Hemin Jiang
Keyword(s):  
Cell Cycle ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Nod Mice ◽  
Pancreatic Β Cell ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Min6 Cells

Abstract CHL1 Increases Insulin Secretion & Negatively Regulates The Poliferation Of Pancreatic β Cell Objective: CHL1 belongs to neural recognition molecules of the immunoglobulin superfamily, is mainly expressed in the nervous system. CHL1 is involved in neuronal migration, axonal growth, and dendritic projection. RNA sequencing of single human islet cells confirmed that CHL1 had an expression difference in β cells of type 2 diabetes and healthy controls. However, whether CHL1 gene regulates islet function remained to be explored. Methods: PCR and Western Blot were applied to investigate the tissue distribution of CHL1 in wild-type C57BL/6J mice. The islet expression of CHL1 gene was observed in pancreatic islets of NOD mice and high-fat-diet C57BL/6J mice of different ages. MIN6 cells with siRNA to silence CHL1 or with lentivirus to overexpress CHL1 were constructed. Effects of the gene on proliferation, apoptosis, cell cycle and insulin secretion were determined by using CCK8, EdU, TUNEL, AV/PI, GSIS, electron microscopy and flow cytometry. Results: CHL1 was localized on the cell membrane and expressed in the nervous system, islet of pancreas and gastrointestinal tract. CHL1 was hypoexpressed in the pancreatic islets of obese mice, hyperexpressed in the pancreatic islets of NOD mice and in vitro after treated with cytokines. After silencing CHL1 in MIN6 cells, insulin secretion decreased in 20 mM glucose with down-regulation of INS1, SLC2A2 gene, and transmission electron microscope showed the number of insulin secretary granules <50nm from the cell membrane was significantly reduced. Silencing of CHL1 in MIN6 cells induced cell proliferation, reduced apoptosis rate, prolonged the S phase of cell cycle and shortened the G1 phase with downregulated expression of p21, p53 and up-regulated expression of cyclin D1, opposite results were found in CHL1 over-expressing MIN6 cells. Proliferation induced by silencing of CHL1 was inhibited by ERK inhibitor (PD98059), which indicates that ERK pathway is essential for signaling by these molecules in pancreatic β cell. Conclusion: The expression of CHL1 gene was significantly decreased in the pancreatic islets of obese mice induced by high-fat diet. The low expression of CHL1 gene promotes the proliferation of MIN6 cells through the ERK pathway and affect cell cycle through the p53 pathway. This may be one of the mechanisms that pancreatic β cells compensatory hyperplasia in the stage of obesity-induced pre-diabetes.

scholarly journals Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

2014 ◽  
Vol 224 (3) ◽  
pp. 261-271 ◽  
Author(s):  
Vinicius Fernandes Cruzat ◽  
Kevin Noel Keane ◽  
Anita Lavarda Scheinpflug ◽  
Robson Cordeiro ◽  
Mario J Soares ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Ex Vivo ◽  
Sirtuin 1 ◽  
Protective Effects ◽  
Pancreatic Β Cell ◽  
Cell Integrity ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell

Obesity-associated diabetes and concomitant inflammation may compromise pancreatic β-cell integrity and function. l-glutamine and l-alanine are potent insulin secretagogues, with antioxidant and cytoprotective properties. Herein, we studied whether the dipeptide l-alanyl-l-glutamine (Ala-Gln) could exert protective effects via sirtuin 1/HUR (SIRT1/HUR) signalling in β-cells, against detrimental responses following ex vivo stimulation with inflammatory mediators derived from macrophages (IMMs). The macrophages were derived from blood obtained from obese subjects. Macrophages were exposed (or not) to lipopolysaccharide (LPS) to generate a pro-inflammatory cytokine cocktail. The cytokine profile was determined following analysis by flow cytometry. Insulin-secreting BRIN–BD11 β-cells were exposed to IMMs and then cultured with or without Ala-Gln for 24 h. Chronic insulin secretion, the l-glutamine–glutathione (GSH) axis, and the level of insulin receptor β (IR-β), heat shock protein 70 (HSP70), SIRT1/HUR, CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome c oxidase IV (COX IV) were evaluated. Concentrations of cytokines, including interleukin 1β (IL1β), IL6, IL10 and tumour necrosis factor alpha (TNFα) in the IMMs, were higher following exposure to LPS. Subsequently, when β-cells were exposed to IMMs, chronic insulin secretion, and IR-β and COX IV levels were decreased, but these effects were partially or fully attenuated by the addition of Ala-Gln. The glutamine–GSH axis and HSP70 levels, which were compromised by IMMs, were also restored by Ala-Gln, possibly due to protection of SIRT1/HUR levels, and a reduction of CHOP expression. Using an ex vivo inflammatory approach, we have demonstrated Ala-Gln-dependent β-cell protection mediated by coordinated effects on the glutamine–GSH axis, and the HSP pathway, maintenance of mitochondrial metabolism and stimulus–secretion coupling essential for insulin release.

scholarly journals The Investigation of Antidiabetic Effects of Leontice leontopetalum Extract on Human Pancreatic β Cell Lines (1.1B4) Treated with Streptozotocin

2018 ◽  
Vol 6 (6) ◽  
pp. 792
Author(s):  
Celal Güven ◽  
Eylem Taşkın ◽  
Önder Yumrutaş ◽  
Leyla Türker Şener ◽  
Fulya Dal ◽  
...  
Keyword(s):  
Beta Cell ◽  
Cell Survival ◽  
Pancreatic Beta Cell ◽  
Insulin Content ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucose Levels ◽  
Dose Dependent ◽  
Antidiabetic Effects

One of the alternative therapeutic methods is herbal medicine. Leontice leontopetalum belongs to Berberidaceae family. The aim of study was investigated the extract of LL on human pancreatic beta cell-treated with STZ. Materials and methods: The human pancreatic beta cell (1.1B4) line was used the current study. LL’s extracts (1, 10, 100, and 1000 ug/ml) were supplemented in media for twenty-four hours and/or after STZ treatment (10 and 20 mM). Cells survivals (MTT), cells proliferation were shown by using xCelligence. Insulin content and releasing were measured at 1.1, 8.4 and 16.7 mM glucose concentrations. Results: The result of MTT was shown that cell survival was decreased, based on dose-dependent. When looked at xCelligence results, cell proliferation in STZ groups and the lowest and highest concentrations of LL were attenuated in a dose-dependent manner. Also, cotreatments of LL and STZ were decreased as well. The result of insulin-releasing on glucose induction was shown that STZ concentration gave rise to reduce insulin content at low and high glucose levels. Also, co-treatment of LL and STZ attenuated insulin content based on dose. Conclusion: It was considered that LL treatment led to increased insulin realizing, resulting from decreasing insulin content in diabetic beta cells, but decrease cell survival.

scholarly journals Amino acid taste receptor regulates insulin secretion in pancreatic β-cell line MIN6 cells

2011 ◽  
Vol 16 (5) ◽  
pp. 608-616 ◽  
Author(s):  
Manami Oya ◽  
Hideyuki Suzuki ◽  
Yuichiro Watanabe ◽  
Moritoshi Sato ◽  
Takashi Tsuboi
Keyword(s):  
Insulin Secretion ◽  
Amino Acid ◽  
Cell Line ◽  
Taste Receptor ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Min6 Cells

scholarly journals Hypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia

2020 ◽  
Vol 319 (5) ◽  
pp. C922-C932
Author(s):  
Ning Wang ◽  
Xue-Feng Shi ◽  
Shakil A. Khan ◽  
Benjamin Wang ◽  
Gregg L. Semenza ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Basal Insulin ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Min6 Cells ◽  
Cell Dysfunction ◽  
Obstructive Sleep ◽  
Basal Insulin Secretion

The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific HIF-1−/− mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in β-HIF-1−/− mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic β-cell dysfunction.

Extracellular calcium influx activates adenylate cyclase 1 and potentiates insulin secretion in MIN6 cells

2013 ◽  
Vol 450 (2) ◽  
pp. 365-373 ◽  
Author(s):  
Tetsuya Kitaguchi ◽  
Manami Oya ◽  
Yoshiko Wada ◽  
Takashi Tsuboi ◽  
Atsushi Miyawaki
Keyword(s):  
Insulin Secretion ◽  
Adenylate Cyclase ◽  
Calcium Influx ◽  
Second Messengers ◽  
Pcr Analysis ◽  
Intracellular Camp ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Small Interference Rna ◽  
Min6 Cells

Intracellular cAMP and Ca2+ are important second messengers that regulate insulin secretion in pancreatic β-cells; however, the molecular mechanism underlying their mutual interaction for exocytosis is not fully understood. In the present study, we investigated the interplay between intracellular cAMP and Ca2+ concentrations ([cAMP]i and [Ca2+]i respectively) in the pancreatic β-cell line MIN6 using total internal reflection fluorescence microscopy. For measuring [cAMP]i, we developed a genetically encoded yellow fluorescent biosensor for cAMP [Flamindo (fluorescent cAMP indicator)], which changes fluorescence intensity with cAMP binding. Application of high-KCl or glucose to MIN6 cells induced the elevation of [cAMP]i and exocytosis. Furthermore, application of an L-type Ca2+ channel agonist or ionomycin to induce extracellular Ca2+ influx evoked the elevation of [cAMP]i, whereas application of carbachol or thapsigargin, which mobilize Ca2+ from internal stores, did not evoke the elevation of [cAMP]i. We performed RT (reverse transcription)–PCR analysis and found that Ca2+-sensitive Adcy1 (adenylate cyclase 1) was expressed in MIN6 cells. Knockdown of endogenous ADCY1 by small interference RNA significantly suppressed glucose-induced exocytosis and the elevation of both [cAMP]i and [Ca2+]i. Taken together, the findings of the present study demonstrate that ADCY1 plays an important role in the control of pancreatic β-cell cAMP homoeostasis and insulin secretion.

scholarly journals Vitamin B6 deficiency disrupts serotonin signaling in pancreatic islets and induces gestational diabetes in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ashley M. Fields ◽  
Kevin Welle ◽  
Elaine S. Ho ◽  
Clementina Mesaros ◽  
Martha Susiarjo
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucose Intolerance ◽  
Vitamin B6 ◽  
Serotonin Receptor ◽  
Dependent Manner ◽  
Β Cell ◽  
Vitamin B6 Deficiency ◽  
Maternal Glucose

AbstractIn pancreatic islets, catabolism of tryptophan into serotonin and serotonin receptor 2B (HTR2B) activation is crucial for β-cell proliferation and maternal glucose regulation during pregnancy. Factors that reduce serotonin synthesis and perturb HTR2B signaling are associated with decreased β-cell number, impaired insulin secretion, and gestational glucose intolerance in mice. Albeit the tryptophan-serotonin pathway is dependent on vitamin B6 bioavailability, how vitamin B6 deficiency impacts β-cell proliferation during pregnancy has not been investigated. In this study, we created a vitamin B6 deficient mouse model and investigated how gestational deficiency influences maternal glucose tolerance. Our studies show that gestational vitamin B6 deficiency decreases serotonin levels in maternal pancreatic islets and reduces β-cell proliferation in an HTR2B-dependent manner. These changes were associated with glucose intolerance and insulin resistance, however insulin secretion remained intact. Our findings suggest that vitamin B6 deficiency-induced gestational glucose intolerance involves additional mechanisms that are complex and insulin independent.

scholarly journals Necroptosis protects against exacerbation of acute pancreatitis

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Michittra Boonchan ◽  
Hideki Arimochi ◽  
Kunihiro Otsuka ◽  
Tomoko Kobayashi ◽  
Hisanori Uehara ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Necrotizing Pancreatitis ◽  
Neutrophil Infiltration ◽  
Dependent Manner ◽  
Protective Effects ◽  
Interacting Protein ◽  
Inflammatory Conditions ◽  
Edematous Pancreatitis ◽  
Genetic Deletion ◽  
Dose Dependent

AbstractThe sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3−/− or Mlkl−/− mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3−/− mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl−/− mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl−/− mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.

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