Beta cell protective effect of Curcuma longa and Piper nigrum in cytokine cocktail induced apoptosis in Min6 pancreatic beta cells

Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.

Download Full-text

MicroRNA-24 promotes pancreatic beta cells toward dedifferentiation to avoid endoplasmic reticulum stress-induced apoptosis

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz004 ◽

2019 ◽

Vol 11 (9) ◽

pp. 747-760 ◽

Cited By ~ 11

Author(s):

Yunxia Zhu ◽

Yi Sun ◽

Yuncai Zhou ◽

Yan Zhang ◽

Tao Zhang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Beta Cell ◽

Er Stress ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Mass ◽

Beta Cell Mass ◽

Stress Conditions ◽

Beta Cell Apoptosis ◽

Induced Apoptosis

AbstractCurrent research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis; however, the mechanisms by which this occurs remain poorly understood. Our previous study demonstrated that elevation of microRNA-24 (miR-24) in a diabetic setting caused beta cell dysfunction and replicative deficiency. In this study, we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum (ER) stress conditions. We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucose-stimulated insulin secretion (GSIS) and enhancing the presence of dedifferentiation markers. Ingenuity® Pathway Analysis (IPA) revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4, which are downstream effectors of two key branches of ER stress, by inhibiting its direct target, Ire1α. Notably, elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells, thus guiding their dedifferentiation under ER stress conditions. Our results demonstrated that the elevated miR-24, to the utmost extent, preserves beta cell mass by inhibiting apoptosis and inducing dedifferentiation. This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.

Download Full-text

Protective effect ofcirsimaritinagainst streptozotocin-induced apoptosis in pancreatic beta cells

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.12719 ◽

2017 ◽

Vol 69 (7) ◽

pp. 875-883 ◽

Cited By ~ 18

Author(s):

Dahae Lee ◽

Ki Hyun Kim ◽

Jaemin Lee ◽

Gwi Seo Hwang ◽

Hye Lim Lee ◽

...

Keyword(s):

Protective Effect ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Induced Apoptosis

Download Full-text

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2021.705751 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fei Ding ◽

Xi Luo ◽

Yiting Tu ◽

Xianlan Duan ◽

Jia Liu ◽

...

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Pancreatic Beta Cell ◽

Min6 Cells ◽

Beta Cell Failure ◽

Tnf Α ◽

Induced Apoptosis ◽

Pro Inflammatory Cytokines

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

Download Full-text

PO270 GINSENOSIDE RG3 SUPPRESSES INTERMITTENT HIGH GLUCOSE-INDUCED APOPTOSIS AND IMPROVES INSULIN SECRETION IN INS-1 PANCREATIC BETA-CELLS

Diabetes Research and Clinical Practice ◽

10.1016/s0168-8227(14)70564-9 ◽

2014 ◽

Vol 106 ◽

pp. S187 ◽

Cited By ~ 1

Author(s):

Y.J. Kim ◽

S.M. Park ◽

E.J. Lee ◽

T.N. Kim ◽

M.J. Kwon ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cells ◽

High Glucose ◽

Pancreatic Beta Cells ◽

Ginsenoside Rg3 ◽

Intermittent High Glucose ◽

Induced Apoptosis

Download Full-text

Tetraethylammonium modifies gap junctions between pancreatic beta-cells

AJP Cell Physiology ◽

10.1152/ajpcell.1981.240.3.c116 ◽

1981 ◽

Vol 240 (3) ◽

pp. C116-C120 ◽

Cited By ~ 12

Author(s):

M. S. Sheppard ◽

P. Meda

Keyword(s):

Beta Cell ◽

Gap Junctions ◽

Beta Cells ◽

Insulin Release ◽

Pancreatic Beta Cells ◽

Freeze Fracture ◽

Potassium Conductance ◽

Median Number ◽

Rat Islets Of Langerhans ◽

Gap Junctional

Gap junctions between pancreatic beta-cells were quantitatively assessed in freeze-fracture replicas of isolated rat islets of Langerhans incubated for 90 min with or without the potassium conductance blocker tetraethylammonium (TEA). The results show that TEA increases the median number of particles per beta-cell gap junction but not the frequency of gap junctions at both nonstimulating and threshold-stimulating concentrations of glucose. TEA increased the relative gap junctional area at both concentrations of glucose. TEA had no effect on insulin release at a basal concentration of glucose but potentiated that release at the threshold glucose level. Thus TEA modifies beta-cell gap junctions independently of its effect on insulin release. However, the junctional changes observed were greater when insulin release was also elevated.

Download Full-text

Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

Biomolecules ◽

10.3390/biom12010104 ◽

2022 ◽

Vol 12 (1) ◽

pp. 104

Author(s):

Elisa Fernández-Millán ◽

Carlos Guillén

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Cell Biology ◽

Pancreatic Beta Cells ◽

Metabolic Diseases ◽

Cell Function ◽

Cell Mass ◽

Beta Cell Mass ◽

Short Chain Fatty Acids

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions.

Download Full-text

Glucose controls co-translation of structurally related mRNAs via the mTOR and eIF2 pathways in human pancreatic beta cells

10.1101/2021.09.13.460006 ◽

2021 ◽

Author(s):

Manuel Bulfoni ◽

Costas Bouyioukos ◽

Albatoul Zakaria ◽

Fabienne Nigon ◽

Roberta Rapone ◽

...

Keyword(s):

Gene Expression ◽

Protein Synthesis ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Gene Expression Regulation ◽

Human Cells ◽

Rodent Models ◽

Polysome Profiling ◽

Acute Increase

ABSTRACTPancreatic beta cell response to glucose is critical for the maintenance of normoglycemia. A strong transcriptional response was classically described in rodent models but, interestingly, not in human cells. In this study, we exposed human pancreatic beta cells to an increased concentration of glucose and analysed at a global level the mRNAs steady state levels and their translationalability. Polysome profiling analysis showed an early acute increase in protein synthesis and a specific translation regulation of more than 400 mRNAs, independently of their transcriptional regulation. We clustered the co-regulated mRNAs according to their behaviour in translation in response to glucose and discovered common structural and sequence mRNA features. Among them mTOR- and eIF2-sensitive elements have a predominant role to increase mostly the translation of mRNAs encoding for proteins of the translational machinery. Furthermore, we show that mTOR and eIF2α pathways are independently regulated in response to glucose, participating to a translational reshaping to adapt beta cell metabolism. The early acute increase in the translation machinery components prepare the beta cell for further protein demand due to glucose-mediated metabolism changes.AUTHOR SUMMARYAdaptation and response to glucose of pancreatic beta cells is critical for the maintenance of normoglycemia. Its deregulation is associated to Diabetic Mellitus (DM), a significant public health concern worldwide with an increased incidence of morbidity and mortality. Despite extensive research in rodent models, gene expression regulation in response to glucose remains largely unexplored in human cells. In our work, we have tackled this question by exposing human EndoC-BH1 cells to high glucose concentration. Using polysome profiling, the gold standard technique to analyse cellular translation activity, we observed a global protein synthesis increase, independent from transcription activity. Among the specific differentially translated mRNAs, we found transcripts coding for ribosomal proteins, allowing the cell machinery to be engaged in a metabolic response to glucose. Therefore, the regulation in response to glucose occurs mainly at the translational level in human cells, and not at the transcriptional level as described in the classically used rodent models.Furthermore, by comparing the features of the differentially translated mRNAs, and classifying them according to their translational response, we show that the early response to glucose occurs through the coupling of mRNA structure and sequence features impacting translation and regulation of specific signalling pathways. Collectively, our results support a new paradigm of gene expression regulation on the translation level in human beta cells.

Download Full-text

Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

Mediators of Inflammation ◽

10.1155/2013/750540 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 14

Author(s):

Alessandra Puddu ◽

Roberta Sanguineti ◽

François Mach ◽

Franco Dallegri ◽

Giorgio Luciano Viviani ◽

...

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Beta Cell Dysfunction ◽

Molecular Pathways ◽

Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

Download Full-text

High dose of histone deacetylase inhibitors affects insulin secretory mechanism of pancreatic beta cell line

Endocrine Regulations ◽

10.2478/enr-2018-0004 ◽

2018 ◽

Vol 52 (1) ◽

pp. 21-26 ◽

Cited By ~ 5

Author(s):

Eiji Yamato

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Cell Line ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Pancreatic Beta Cell ◽

High Dose ◽

Min6 Cells ◽

Beta Cell Line ◽

High Doses

Abstract Objective. Histone deacytylase inhibitors (HDACis) inhibit the deacetylation of the lysine residue of proteins, including histones, and regulate the transcription of a variety of genes. Recently, HDACis have been used clinically as anti-cancer drugs and possible anti-diabetic drugs. Even though HDACis have been proven to protect the cytokine-induced damage of pancreatic beta cells, evidence also shows that high doses of HDACis are cytotoxic. In the present study, we, therefore, investigated the eff ect of HDACis on insulin secretion in a pancreatic beta cell line. Methods. Pancreatic beta cells MIN6 were treated with selected HDACis (trichostatin A, TSA; valproic acid, VPA; and sodium butyrate, NaB) in medium supplemented with 25 mM glucose and 13% heat-inactivated fetal bovine serum (FBS) for indicated time intervals. Protein expression of Pdx1 and Mafa in MIN6 cells was demonstrated by immunohistochemistry and immunocytochemistry, expression of Pdx1 and Mafa genes was measured by quantitative RT-PCR method. Insulin release from MIN6 cells and insulin cell content were estimated by ELISA kit. Superoxide production in MIN6 cells was measured using a Total ROS/Superoxide Detection System. Results. TSA, VPA, and NaB inhibited the expression of Pdx1 and Mafa genes and their products. TSA treatment led to beta cell malfunction, characterized by enhanced insulin secretion at 3 and 9 mM glucose, but impaired insulin secretion at 15 and 25 mM glucose. Th us, TSA induced dysregulation of the insulin secretion mechanism. TSA also enhanced reactive oxygen species production in pancreatic beta cells. Conclusions. Our results showed that HDACis caused failure to suppress insulin secretion at low glucose concentrations and enhance insulin secretion at high glucose concentrations. In other words, when these HDACis are used clinically, high doses of HDACis may cause hypoglycemia in the fasting state and hyperglycemia in the fed state. When using HDACis, physicians should, therefore, be aware of the capacity of these drugs to modulate the insulin secretory capacity of pancreatic beta cells.

Download Full-text