scholarly journals Distinguishing Features of Leucine and α-Ketoisocaproate Sensing in Pancreatic β-Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 1949-1957 ◽  
Author(s):  
Zhiyong Gao ◽  
Robert A. Young ◽  
Guizhu Li ◽  
Habiba Najafi ◽  
Carol Buettger ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Aminooxyacetic Acid ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Rat Islets ◽  
Cell Extracts ◽  
Glutamate Dehydrogenase Activity ◽  
Low Glucose ◽  
Mouse Islets ◽  
Stimulation Of

Culturing rat islets in high glucose (HG) increased 1-14C-α-ketoisocaproate (KIC) oxidation compared with culturing them in low glucose. Leucine caused insulin secretion (IS) in low glucose but not in HG rat islets, whereas KIC did so in both. Pretreatment with HG for 40 min abolished leucine stimulation of IS by mouse islets and prevented the cytosolic Ca2+ rise without inhibiting IS and Ca2+ increments caused by KIC. When islets were pretreated without glucose and glutamine, aminooxyacetic acid (AOA) markedly decreased KIC effects. When islets were pretreated without glucose and with glutamine, AOA potentiated leucine effects but attenuated KIC effects. AOA stimulated glutamine oxidation in the presence but not the absence of ±2-amino-2-norbornane-carboxylic acid, a nonmetabolized leucine analog. Pretreatment with HG and glutamine partially reversed AOA inhibition of KIC effects. Glucose increased intracellular ATP and GTP, whereas it decreased ADP and GDP in βHC9 cells. Glutamate dehydrogenase activity of βHC9 cell extracts was increased by leucine and attenuated by GTP, but it was potentiated by ADP. In conclusion, leucine and KIC stimulated β-cells via distinct mechanisms. Glutamate dehydrogenase is the sensor of leucine, whereas transamination plays an important role in KIC stimulation of pancreatic β-cells.

scholarly journals Mitochondrial–Endoplasmic Reticulum Interplay: A Lifelong On–Off Relationship?

Contact ◽  
2019 ◽  
Vol 2 ◽  
pp. 251525641986122 ◽  
Author(s):  
Corina T. Madreiter-Sokolowski ◽  
Roland M. Malli ◽  
Wolfgang F. Graier
Keyword(s):  
Endoplasmic Reticulum ◽  
Adenosine Triphosphate ◽  
Therapeutic Strategies ◽  
Mitochondrial Activity ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Potential Target ◽  
Pathological Conditions ◽  
Elevated Glucose ◽  
Stimulation Of

This article comments recent publications that highlight an intriguing importance of specific settings in the interaction between the mitochondria and the endoplasmic reticulum to ensure cell-specific functions like the responsiveness to elevated glucose in pancreatic β-cells. Hence, alterations of the mitochondria–endoplasmic reticulum communications under various pathological conditions like aging or cancer often come with enhanced Ca2+ transfer that, in turn, yields stimulation of basal mitochondrial activity to meet the increasing adenosine triphosphate demand of the very cell. Such observations identify mitochondria-associated membranes as potential target for new therapeutic strategies against aging or cancer.

Secretin and its C-terminal hexapeptide potentiates insulin release in mouse islets

1986 ◽  
Vol 250 (2) ◽  
pp. E107-E113 ◽  
Author(s):  
H. Kofod ◽  
B. Hansen ◽  
A. Lernmark ◽  
C. J. Hedeskov
Keyword(s):  
Glutamate Dehydrogenase ◽  
Dehydrogenase Activity ◽  
Insulin Release ◽  
Maximal Effect ◽  
Terminal Sequence ◽  
Terminal Part ◽  
Mouse Pancreatic Islets ◽  
Glutamate Dehydrogenase Activity ◽  
Mouse Islets

Peptides representing the C-terminal end of secretin were synthetized and their effects tested along with secretin on column-perifused isolated mouse pancreatic islets. Insulin release induced by 10 mmol/l D-glucose was potentiated by secretin tested in a concentration range of 0.01-10 micrograms/ml; the maximal effect was obtained with 1 microgram/ml secretin. This effect was mimicked by 50-500 micrograms/ml NH2-Leu-Leu-Gln-Gly-Leu-Val-NH2, [S-(22-27)], which represents an amidated C-terminal sequence of the secretin molecule. The consecutive smaller secretin C-terminal peptides had either no effects [Val-NH2, S-(24-27)] or only marginally [S-(26-27), S-(23-27)] potentiating effects on insulin release in the presence of 10 mmol/l D-glucose. The effects of secretin and S-(22-27) were not influenced by 2 mmol/l glutamine. The intact hormone and the five synthetic peptides as well as Val-NH2 had no stimulatory effect on islet glutamate dehydrogenase activity. In fact, S-(23-27), S-(24-27), and S-(25-27) inhibited the islet glutamate dehydrogenase activity, the activation by which amino acids and amino acid derivatives are known to elicit a potentiation of insulin release. Our results suggest that the C-terminal part is important to the marked potentiation of glucose-induced insulin release in vitro by secretin.

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 A Minimum of Fuel Is Necessary for Tolbutamide to Mimic the Effects of Glucose on Electrical Activity in Pancreatic β-Cells*

Endocrinology ◽  
1998 ◽  
Vol 139 (3) ◽  
pp. 993-998 ◽  
Author(s):  
Jean-Claude Henquin
Keyword(s):  
Membrane Potential ◽  
Electrical Activity ◽  
Slow Waves ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Low Concentrations ◽  
Low Glucose ◽  
Intracellular Microelectrodes

Glucose stimulation of pancreatic β-cells triggers electrical activity (slow waves of membrane potential with superimposed spikes) that is best monitored with intracellular microelectrodes. Closure of ATP-sensitive K+ channels underlies the depolarization to the threshold potential and participates in the increase in electrical activity produced by suprathreshold (>7 mm) concentrations of glucose, but it is still unclear whether this is the sole mechanism of control. This was investigated by testing whether blockade of ATP-sensitive K+ channels by low concentrations of tolbutamide is able to mimic the effects of glucose on mouse β-cell electrical activity even in the absence of the sugar. The response to tolbutamide was influenced by the duration of the perifusion with the low glucose medium. Tolbutamide (25 μm) caused a rapid and sustained depolarization with continuous activity after 6 min of perifusion of the islet with 3 mm glucose, and a progressive depolarization with slow waves of the membrane potential after 20 min. In the absence of glucose, the β-cell response to tolbutamide was a transient phase of depolarization with rare slow waves (6 min) or a silent, small, but sustained, depolarization (20 min). Readministration of 3 mm glucose was sufficient to restore slow waves, whereas an increase in the glucose concentration to 5 and 7 mm was followed by a lengthening of the slow waves and a shortening of the intervals. In contrast, induction of slow waves by tolbutamide proved very difficult in the absence of glucose, because the β-cell membrane tended to depolarize from a silent level to the plateau level, at which electrical activity is continuous. Azide, a mitochondrial poison, abrogated the electrical activity induced by tolbutamide in the absence of glucose, which demonstrates the influence of the metabolism of endogenous fuels on the response to the sulfonylurea. The partial repolarization that azide also produced was reversed by increasing the concentration of tolbutamide, but reappearance of the spikes required the addition of glucose. It is concluded that inhibition of ATP-sensitive K+ channels is not the only mechanism by which glucose controls electrical activity inβ -cells.

Studies of the mechanism of amino acid-induced stimulation of insulin secretion from clonal pancreatic β-cells

2000 ◽  
Vol 28 (5) ◽  
pp. A196-A196
Author(s):  
A. Shine ◽  
N. H. Mc Clenaghan ◽  
P. Flatt ◽  
JPG Malthouse ◽  
C. Hewage ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Amino Acid ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Stimulation Of

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.”

Carbamoylcholine regulation of polyphosphoinositide synthesis and hydrolysis in cultured, dispersed, digitonin-permeabilized mouse pancreatic islet cells

1997 ◽  
Vol 136 (5) ◽  
pp. 539-545 ◽  
Author(s):  
Andrew M Kardasz ◽  
Peter Thams ◽  
Kirsten Capito ◽  
Carl J Hedeskov
Keyword(s):  
Pancreatic Islet ◽  
Kinase Activity ◽  
Inositol Phosphates ◽  
Islet Cells ◽  
Pancreatic Islet Cells ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Mouse Pancreatic Islet ◽  
Phosphatidylinositol 4 ◽  
Stimulation Of

Abstract Continuing formation of inositol phosphates during stimulation of pancreatic β-cells by hormones and neurotransmitters requires the continued synthesis of the polyphosphoinositides phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5 bisphosphate (PIP2) from phosphatidylinositol (PI). In the present study we have investigated how this pathway and the activity of phosphoinositide-specific phospholipase C (PI-PLC) are regulated by carbamoylcholine (CCh), Ca2+, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), GTPγS and NaF in 44-h [3H]inositol-labelled, dispersed and digitonin-permeabilized mouse pancreatic islet cells. CCh stimulated not only PI-PLC (G-protein-mediated) but also, by an as yet unknown mechanism, significantly enhanced PI 4-kinase activity, estimated as the PIP:PI ratio, by 100%, and further increased the flux from PI to PIP and PIP2. GTPγS and NaF mimicked the effects of CCh on PI-PLC but had no effect on the levels of PIP and PIP2. TPA raised the PIP:PI ratio by 75%. In addition TPA counteracted the CCh stimulation of PI-PLC. There was no effect of 10−6 mol/l Ca2+ on the levels of PIP and PIP2. Experiments with quinacrine and adenosine confirmed that PI-PLC and PI 4-kinase could be regulated independently of each other. In conclusion, these data point to differential regulation of polyphosphoinositide synthesis and breakdown. European Journal of Endocrinology 136 539–545

scholarly journals Propofol inhibits stromatoxin-1-sensitive voltage-dependent K+ channels in pancreatic β-cells and enhances insulin secretion

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8157 ◽  
Author(s):  
Munenori Kusunoki ◽  
Mikio Hayashi ◽  
Tomohiro Shoji ◽  
Takeo Uba ◽  
Hiromasa Tanaka ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Energy Metabolism ◽  
Glycemic Control ◽  
Potassium Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Kv Channels ◽  
Voltage Dependent ◽  
Cellular Oxygen ◽  
Low Glucose

Background Proper glycemic control is an important goal of critical care medicine, including perioperative patient care that can influence patients’ prognosis. Insulin secretion from pancreatic β-cells is generally assumed to play a critical role in glycemic control in response to an elevated blood glucose concentration. Many animal and human studies have demonstrated that perioperative drugs, including volatile anesthetics, have an impact on glucose-stimulated insulin secretion (GSIS). However, the effects of the intravenous anesthetic propofol on glucose metabolism and insulin sensitivity are largely unknown at present. Methods The effect of propofol on insulin secretion under low glucose or high glucose was examined in mouse MIN6 cells, rat INS-1 cells, and mouse pancreatic β-cells/islets. Cellular oxygen or energy metabolism was measured by Extracellular Flux Analyzer. Expression of glucose transporter 2 (GLUT2), potassium channels, and insulin mRNA was assessed by qRT-PCR. Protein expression of voltage-dependent potassium channels (Kv2) was also assessed by immunoblot. Propofol’s effects on potassium channels including stromatoxin-1-sensitive Kv channels and cellular oxygen and energy metabolisms were also examined. Results We showed that propofol, at clinically relevant doses, facilitates insulin secretion under low glucose conditions and GSIS in MIN6, INS-1 cells, and pancreatic β-cells/islets. Propofol did not affect intracellular ATP or ADP concentrations and cellular oxygen or energy metabolism. The mRNA expression of GLUT2 and channels including the voltage-dependent calcium channels Cav1.2, Kir6.2, and SUR1 subunit of KATP, and Kv2 were not affected by glucose or propofol. Finally, we demonstrated that propofol specifically blocks Kv currents in β-cells, resulting in insulin secretion in the presence of glucose. Conclusions Our data support the hypothesis that glucose induces membrane depolarization at the distal site, leading to KATP channel closure, and that the closure of Kv channels by propofol depolarization in β-cells enhances Ca2+ entry, leading to insulin secretion. Because its activity is dependent on GSIS, propofol and its derivatives are potential compounds that enhance and initiate β-cell electrical activity.

scholarly journals Direct Stimulation of Basal Insulin Secretion by Physiological Concentrations of Leptin in Pancreatic β Cells

Endocrinology ◽  
1997 ◽  
Vol 138 (10) ◽  
pp. 4513-4516 ◽  
Author(s):  
Yukio Tanizawa ◽  
Shigeru Okuya ◽  
Hisamitsu Ishihara ◽  
Tomoichiro Asano ◽  
Toshihiko Yada ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Basal Insulin ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Direct Stimulation ◽  
Basal Insulin Secretion ◽  
Stimulation Of

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.

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