scholarly journals External ATP triggers Ca2+ signals suited for synchronization of pancreatic β-cells

2005 ◽  
Vol 185 (1) ◽  
pp. 69-79 ◽  
Author(s):  
E Grapengiesser ◽  
H Dansk ◽  
B Hellman
Keyword(s):  
Cyclopiazonic Acid ◽  
Secretory Activity ◽  
Spontaneous Firing ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Kinase C ◽  
Initial Rise ◽  
Mouse Islets ◽  
Serca Pump ◽  
Insight Into

External ATP is supposed to trigger short-lived increases (transients) of cytoplasmic Ca2+ important for entraining insulin-secreting β-cells into a common rhythm. To get insight into this process, rises of the cytoplasmic Ca2+ concentration ([Ca2+]i) induced by external ATP were compared with those obtained with acetylcholine, another neurotransmitter with stimulatory effects on the inositol trisphosphate (IP3) production. A ratiometric fura-2 technique was used for measuring [Ca2+]i in individual β-cells and small aggregates isolated from ob/ob mouse islets and superfused with a medium containing methoxyverapamil. ATP and acetylcholine induced temporary rises of [Ca2+]I from a basal level manifested as solitary transients (<20 s) and bumps (≥20 s) superimposed or not with transients. Addition of ATP (1–100 μM) usually triggered transients whereas acetylcholine induced bumps lacking superimposed transients. After the initial rise there was a steady-state elevation of [Ca2+]i in β-cells exposed to acetylcholine but not to ATP. Similar differences were seen comparing the responses of rat β-cells to 100 μM ATP and acetylcholine. Inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump (with 50 μM cyclopiazonic acid) prevented both the ATP-induced rise of [Ca2+]i and the spontaneous firing of transients. Similar effects were seen after activation of protein kinase C (10 nM phorbol-12-myristate-13-acetate), whereas an inhibitor of this enzyme (2 μM bisindolylmaleimide) promoted the generation of transients. The results indicate that ATP fulfils the demands for a coordinator of the secretory activity of β-cells by generating distinct [Ca2+]i transients without sustained elevation of basal [Ca2+]i.

scholarly journals Pancreatic β-cells express hepcidin, an iron-uptake regulatory peptide

2008 ◽  
Vol 197 (2) ◽  
pp. 241-249 ◽  
Author(s):  
Hasan Kulaksiz ◽  
Evelyn Fein ◽  
Peter Redecker ◽  
Wolfgang Stremmel ◽  
Guido Adler ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Secretory Granules ◽  
Rinm5f Cells ◽  
Β Cells ◽  
Additional Source ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Vital Functions ◽  
Immunohistochemical Studies ◽  
Insight Into

Body iron is involved in various vital functions. Its uptake in the intestine is regulated by hepcidin, a bioactive peptide originally identified in plasma and urine and subsequently in the liver. In the present study, we provide evidence at the transcriptional and translational levels that hepcidin is also expressed in the pancreas of rat and man. Immunohistochemical studies localized the peptide exclusively to β-cells of the islets of Langerhans. Immunoelectron microscopical analyses revealed that hepcidin is confined to the insulin-storing β-cell secretory granules. As demonstrated in insulinoma-derived RINm5F cells, the expression of hepcidin in β-cells is regulated by iron. Based on the present findings we conclude that pancreatic islets are an additional source of the peptide hepcidin. The localization of this peptide to β-cells suggests that pancreatic β-cells may be involved in iron metabolism in addition to their genuine function in blood glucose regulation. In view of the various linked iron/glucose disorders in the pancreas, the present findings may provide an insight into the phenomenology of intriguing mutual relationships between iron and glucose metabolisms.

scholarly journals Bimodal role of conventional protein kinase C in insulin secretion from rat pancreatic β cells

2004 ◽  
Vol 561 (1) ◽  
pp. 133-147 ◽  
Author(s):  
Hui Zhang ◽  
Masahiro Nagasawa ◽  
Satoko Yamada ◽  
Hideo Mogami ◽  
Yuko Suzuki ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Kinase C

scholarly journals SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic β cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Li Hu ◽  
Fengli He ◽  
Meifeng Huang ◽  
Qian Zhao ◽  
Lamei Cheng ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Underlying Mechanism ◽  
Negative Regulator ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Promoting Effect ◽  
Down Regulation ◽  
Mouse Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
Phosphoinositide 3 Kinase

Abstract SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. Here, we showed that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. Overexpression of SPARC down-regulated RGS4, a negative regulator of β-cell M3 muscarinic receptors. Conversely, knockdown of SPARC up-regulated RGS4 in Min6 cells. RGS4 was up-regulated in islets from sparc −/− mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Furthermore, inhibition of RGS4 restored GSIS in the islets from sparc −/− mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M-stimulated insulin secretion. Phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 abolished SPARC-induced down-regulation of RGS4. Taken together, our data revealed that SPARC promoted GSIS by inhibiting RGS4 in pancreatic β cells.

scholarly journals The Orphan Nuclear Receptor NR4A1 Protects Pancreatic β-Cells from Endoplasmic Reticulum (ER) Stress-mediated Apoptosis

2015 ◽  
Vol 290 (34) ◽  
pp. 20687-20699 ◽  
Author(s):  
Cong Yu ◽  
Shang Cui ◽  
Chen Zong ◽  
Weina Gao ◽  
Tongfu Xu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Survivin Promoter ◽  
Min6 Cells ◽  
Chop Expression ◽  
Mouse Islets

The role of NR4A1 in apoptosis is controversial. Pancreatic β-cells often face endoplasmic reticulum (ER) stress under adverse conditions such as high free fatty acid (FFA) concentrations and sustained hyperglycemia. Severe ER stress results in β-cell apoptosis. The aim of this study was to analyze the role of NR4A1 in ER stress-mediated β-cell apoptosis and to characterize the related mechanisms. We confirmed that upon treatment with the ER stress inducers thapsigargin (TG) or palmitic acid (PA), the mRNA and protein levels of NR4A1 rapidly increased in both MIN6 cells and mouse islets. NR4A1 overexpression in MIN6 cells conferred resistance to cell loss induced by TG or PA, as assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and TUNEL assays indicated that NR4A1 overexpression also protected against ER stress-induced apoptosis. This conclusion was further confirmed by experiments exploiting siRNA to knockdown NR4A1 expression in MIN6 cells or exploiting NR4A1 knock-out mice. NR4A1 overexpression in MIN6 cells reduced C/EBP homologous protein (CHOP) expression and Caspase3 activation induced by TG or PA. NR4A1 overexpression in MIN6 cells or mouse islets resulted in Survivin up-regulation. A critical regulatory element was identified in Survivin promoter (−1872 bp to −1866 bp) with a putative NR4A1 binding site; ChIP assays demonstrated that NR4A1 physically associates with the Survivin promoter. In conclusion, NR4A1 protects pancreatic β-cells against ER stress-mediated apoptosis by up-regulating Survivin expression and down-regulating CHOP expression, which we termed as “positive and negative regulation.”

scholarly journals Store-operated influx of Ca2+ in pancreatic β-cells exhibits graded dependence on the filling of the endoplasmic reticulum

2001 ◽  
Vol 114 (11) ◽  
pp. 2179-2186 ◽  
Author(s):  
Oleg Dyachok ◽  
Erik Gylfe
Keyword(s):  
Endoplasmic Reticulum ◽  
Channel Blocker ◽  
Cyclopiazonic Acid ◽  
Atpase Inhibitor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Rate Of Increase ◽  
Voltage Dependent ◽  
Individual Mouse ◽  
Extracellular Ions

The store-operated pathway for Ca2+ entry was studied in individual mouse pancreatic β-cells by measuring the cytoplasmic concentrations of Ca2+ ([Ca2+]i) and Mn2+ ([Mn2+]i) with the fluorescent indicator fura-2. Influx through the store-operated pathway was initially shut off by pre-exposure to 20 mM glucose, which maximally stimulates intracellular Ca2+ sequestration. To avoid interference with voltage-dependent Ca2+ entry the cells were hyperpolarized with diazoxide and the channel blocker methoxyverapamil was present. Activation of the store-operated pathway in response to Ca2+ depletion of the endoplasmic reticulum was estimated from the sustained elevation of [Ca2+]i or from the rate of increase in [Mn2+]i due to influx of these extracellular ions. Increasing concentrations of the inositol 1,4,5-trisphosphate-generating agonist carbachol or the sarco(endo)plasmatic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid (CPA) cause gradual activation of the store-operated pathway. In addition, the carbachol- and CPA-induced influx of Mn2+ depended on store filling in a graded manner. The store-operated influx of Ca2+/Mn2+ was inhibited by Gd3+ and 2-aminoethoxydiphenyl borate but neither of these agents discriminated between store-operated and voltage-dependent entry. The finely tuned regulation of the store-operated mechanisms in the β-cell has direct implications for the control of membrane potential and insulin secretion.

Protein kinase C-dependent and -independent inhibition of Ca2+ influx by phorbol ester in rat pancreatic β-cells

2001 ◽  
Vol 13 (3) ◽  
pp. 199-205 ◽  
Author(s):  
Junko Nakamura ◽  
Toshihiro Suda ◽  
Yoshiji Ogawa ◽  
Teruko Takeo ◽  
Sechiko Suga ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Ester ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Kinase C

scholarly journals PERK Activation at Low Glucose Concentration Is Mediated by SERCA Pump Inhibition and Confers Preemptive Cytoprotection to Pancreatic β-Cells

2011 ◽  
Vol 32 (1) ◽  
pp. 153-153
Author(s):  
Claire E. Moore ◽  
Omotola Omikorede ◽  
Edith Gomez ◽  
Gary B. Willars ◽  
Terence P. Herbert
Keyword(s):  
Glucose Concentration ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Low Glucose ◽  
Serca Pump

scholarly journals Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion

2009 ◽  
Vol 296 (6) ◽  
pp. E1354-E1362 ◽  
Author(s):  
Emma Heart ◽  
Gary W. Cline ◽  
Leon P. Collis ◽  
Rebecca L. Pongratz ◽  
Joshua P. Gray ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Malic Enzyme ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Pyruvate Cycling ◽  
Mouse Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
Interfering Rna ◽  
Rat Insulinoma

Pyruvate cycling has been implicated in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. The operation of some pyruvate cycling pathways is proposed to necessitate malate export from the mitochondria and NADP+-dependent decarboxylation of malate to pyruvate by cytosolic malic enzyme (ME1). Evidence in favor of and against a role of ME1 in GSIS has been presented by others using small interfering RNA-mediated suppression of ME1. ME1 was also proposed to account for methyl succinate-stimulated insulin secretion (MSSIS), which has been hypothesized to occur via succinate entry into the mitochondria in exchange for malate and subsequent malate conversion to pyruvate. In contrast to rat, mouse β-cells lack ME1 activity, which was suggested to explain their lack of MSSIS. However, this hypothesis was not tested. In this report, we demonstrate that although adenoviral-mediated overexpression of ME1 greatly augments GSIS in rat insulinoma INS-1 832/13 cells, it does not restore MSSIS, nor does it significantly affect GSIS in mouse islets. The increase in GSIS following ME1 overexpression in INS-1 832/13 cells did not alter the ATP-to-ADP ratio but was accompanied by increases in malate and citrate levels. Increased malate and citrate levels were also observed after INS-1 832/13 cells were treated with the malate-permeable analog dimethyl malate. These data suggest that although ME1 overexpression augments anaplerosis and GSIS in INS-1 832/13 cells, it is not likely involved in MSSIS and GSIS in pancreatic islets.

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