Tolbutamide and diazoxide modulate phospholipase C-linked Ca2+ signaling and insulin secretion in β-cells

2000 ◽  
Vol 278 (4) ◽  
pp. E639-E647 ◽  
Author(s):  
Christof Schöfl ◽  
Julia Börger ◽  
Thilo Mader ◽  
Mark Waring ◽  
Alexander von zur Mühlen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Phospholipase C ◽  
Insulin Release ◽  
Arginine Vasopressin ◽  
Bay K 8644 ◽  
Free Medium ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Activating Receptors

Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca2+ and potentiate glucose-induced insulin release by activating receptors linked to phospholipase C (PLC). We examined whether tolbutamide and diazoxide, which close or open ATP-sensitive K+ channels (KATP channels), respectively, interact with PLC-linked Ca2+ signals in HIT-T15 and mouse β-cells and with PLC-linked insulin secretion from HIT-T15 cells. In the presence of glucose, the PLC-linked Ca2+ signals were enhanced by tolbutamide (3–300 μM) and inhibited by diazoxide (10–100 μM). The effects of tolbutamide and diazoxide on PLC-linked Ca2+ signaling were mimicked by BAY K 8644 and nifedipine, an activator and inhibitor of L-type voltage-sensitive Ca2+channels, respectively. Neither tolbutamide nor diazoxide affected PLC-linked mobilization of internal Ca2+ or store-operated Ca2+ influx through non-L-type Ca2+ channels. In the absence of glucose, PLC-linked Ca2+ signals were diminished or abolished; this effect could be partly antagonized by tolbutamide. In the presence of glucose, tolbutamide potentiated and diazoxide inhibited AVP- or bombesin-induced insulin secretion from HIT-T15 cells. Nifedipine (10 μM) blocked both the potentiating and inhibitory actions of tolbutamide and diazoxide on AVP-induced insulin release, respectively. In glucose-free medium, AVP-induced insulin release was reduced but was again potentiated by tolbutamide, whereas diazoxide caused no further inhibition. Thus tolbutamide and diazoxide regulate both PLC-linked Ca2+signaling and insulin secretion from pancreatic β-cells by modulating KATP channels, thereby determining voltage-sensitive Ca2+ influx.

Dihydropyridine-sensitive and -insensitive voltage-operated calcium channels participate in the control of glucose-induced insulin release from human pancreatic β cells

1996 ◽  
Vol 150 (2) ◽  
pp. 195-203 ◽  
Author(s):  
A M Davalli ◽  
E Biancardi ◽  
A Pollo ◽  
C Socci ◽  
A E Pontiroli ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Calcium Channels ◽  
Insulin Release ◽  
High Voltage ◽  
Human Islets ◽  
Bay K 8644 ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Patch Clamp Technique ◽  
Voltage Operated Calcium Channels

Abstract Calcium ion entry through voltage-operated calcium channels is a crucial step in the coupling of β cell depolarization with insulin secretion. Various calcium channel subtypes have been shown to be coexpressed in single neurons and endocrine cells. Using the patch-clamp technique, we investigated the biophysical and pharmacological properties of calcium channels in freshly dispersed human pancreatic β cells. Both low and high voltage activated currents were expressed, the two current types being easily distinguishable on the basis of biophysical criteria. The high voltage activated currents were not homogeneous: one component was affected by the dihydropyridine antagonist nitrendipine and the agonist Bay-K-8644; the other was insensitive to both dihydropyridines and ω-conotoxin GVIA. In line with this pharmacology, nitrendipine reduced and Bay-K-8644 increased glucose-induced insulin secretion from perifused human islets, whereas ω-conotoxin GVIA had no effect. However, about 20% of the glucose-induced insulin release was found to be resistant to high nitrendipine concentrations. These data show that human pancreatic β cells express heterogeneous voltage-operated calcium channels, only one of which is dihydropyridine-sensitive (L type). The L type channels are clearly involved in the control of insulin secretion, but our data suggest that dihydropyridine- and ω-conotoxin GVIA-insensitive channels may also play a role in the stimulus-secretion coupling of human β cells. Journal of Endocrinology (1996) 150, 195–203

Tetracaine stimulates insulin secretion through the mobilization of Ca2+ from thapsigargin- and IP3-insensitive Ca2+ reservoir in pancreatic β-cells

2000 ◽  
Vol 78 (6) ◽  
pp. 462-468 ◽  
Author(s):  
José Roberto Bosqueiro ◽  
Everardo Magalhães Carneiro ◽  
Silvana Bordin ◽  
Antonio Carlos Boschero
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Isolated Islets ◽  
Inositol Triphosphate ◽  
Free Medium ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Isolated Pancreatic Islets ◽  
High Concentrations

The effect of tetracaine on 45Ca efflux, cytoplasmic Ca2+ concentration [Ca2+]i, and insulin secretion in isolated pancreatic islets and β-cells was studied. In the absence of external Ca2+, tetracaine (0.1-2.0 mM) increased the 45Ca efflux from isolated islets in a dose-dependant manner. Tetracaine did not affect the increase in 45Ca efflux caused by 50 mM K+ or by the association of carbachol (0.2 mM) and 50 mM K+. Tetracaine permanently increased the [Ca2+]i in isolated β-cells in Ca2+-free medium enriched with 2.8 mM glucose and 25 µM D-600 (methoxiverapamil). This effect was also observed in the presence of 10 mM caffeine or 1 µM thapsigargin. In the presence of 16.7 mM glucose, tetracaine transiently increased the insulin secretion from islets perfused in the absence and presence of external Ca2+. These data indicate that tetracaine mobilises Ca2+ from a thapsigargin-insensitive store and stimulates insulin secretion in the absence of extracellular Ca2+. The increase in 45Ca efflux caused by high concentrations of K+ and by carbachol indicates that tetracaine did not interfere with a cation or inositol triphosphate sensitive Ca2+ pool in β-cells.

scholarly journals Somatostatin-induced paradoxical increase in intracellular Ca2+ concentration and insulin release in the presence of arginine vasopressin in clonal HIT-T15 β-cells

2002 ◽  
Vol 364 (1) ◽  
pp. 33-39 ◽  
Author(s):  
Henrique CHENG ◽  
Sirintorn YIBCHOK-ANUN ◽  
Seung-Chun PARK ◽  
Walter H. HSU
Keyword(s):  
Phospholipase C ◽  
Insulin Release ◽  
Arginine Vasopressin ◽  
Receptor Agonist ◽  
Calcium Concentration ◽  
Somatostatin Receptors ◽  
Rapid Decline ◽  
Atpase Inhibitor ◽  
Β Cells ◽  
Induced Changes

Somatostatin, a hormone that signals via Gi/Go, usually inhibits increases in intracellular calcium concentration ([Ca2+]i) and insulin release from β-cells. We have found that in the presence of arginine vasopressin (AVP), which signals via Gq, somatostatin increased [Ca2+]i, leading to insulin release in HIT-T15 cells. The increase in [Ca2+]i by somatostatin was observed even after 60min of AVP treatment. Somatostatin alone failed to increase [Ca2+]i and insulin release. Somatostatin induced changes in [Ca2+]i in a biphasic pattern, characterized by a sharp and transient increase followed by a rapid decline to sub-basal levels. Pretreatment with pertussis toxin, which inactivates Gi/Go, abolished the effects of somatostatin. U-73122, an inhibitor of phospholipase C, antagonized the somatostatin-induced increase in [Ca2+]i. In Ca2+-free medium, somatostatin still increased [Ca2+]i. Depletion of intracellular Ca2+ stores with thapsigargin, a microsomal Ca2+-ATPase inhibitor, abolished somatostatin's effect. In the presence of bradykinin, another Gq-coupled receptor agonist, somatostatin also increased [Ca2+]i, but not in the presence of isoproterenol (a Gs-coupled receptor agonist) or medetomidine (a Gi/Go-coupled receptor agonist). Our findings suggest that somatostatin signals through Gi/Go, and involves phospholipase C and Ca2+ release from the endoplasmic reticulum. The increase in [Ca2+]i by somatostatin leads to insulin release. This cross-talk is specific to Gq and Gi/Go, and is not limited to the AVP and somatostatin receptors.

scholarly journals Comparison of the effects of perchlorate and Bay K 8644 on the dynamics of cytoplasmic Ca2+ concentration and insulin secretion in mouse β-cells

1996 ◽  
Vol 314 (1) ◽  
pp. 167-173 ◽  
Author(s):  
Gerd LARSSON-NYRÉN ◽  
Janove SEHLIN
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Secretory Activity ◽  
Lag Time ◽  
Bay K 8644 ◽  
Β Cells ◽  
Β Cell ◽  
Isolated Pancreatic Islets ◽  
Dynamics Of Insulin Secretion ◽  
Peak Increase

Non-inbred ob/ob mice were used to study the dynamics of cytoplasmic Ca2+ concentration ([Ca2+]i) in isolated pancreatic β-cells using microfluorimetry with fura 2/AM as probe, and the dynamics of insulin secretion in isolated pancreatic islets. D-Glucose (20 mM) caused a transient peak increase in [Ca2+]i which changed to either an oscillating or a flat, elevated phase. The lag-time before the first peak increase in [Ca2+]i was markedly shortened by 12 mM ClO4- and the glucose-stimulated level of [Ca2+]i after the first peak was clearly elevated by the anion. ClO4- also amplified K+-stimulated (20 mM) [Ca2+]i. ClO4- did not change the basal [Ca2+]i at 3 mM glucose. Extracellular Ca2+ deficiency abolished the effect of high glucose and ClO4- on [Ca2+]i. This suggests that ClO4- acts as an amplifier of transmembrane Ca2+ inflow. The L-type Ca2+ channel agonist, Bay K 8644 (0.01–1.0 μM), strictly reproduced all the effects of perchlorate on the glucose-stimulated β-cell [Ca2+]i. Both phases of insulin release (20 mM glucose) were markedly enhanced by ClO4- (12 mM) or Bay K 8644 (1.0 μM). The lag-time for glucose-stimulated insulin release was shortened by both agents. Taken together, these data strengthen the idea that perchlorate amplifies the glucose-stimulation of [Ca2+]i and insulin release by directly modifying the function of the L-type Ca2+ channel. This effect can induce both a more prompt onset of and an amplified level of β-cell secretory activity.

Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet β-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release

2005 ◽  
Vol 289 (4) ◽  
pp. E670-E677 ◽  
Author(s):  
Ken Fujiwara ◽  
Fumihiko Maekawa ◽  
Toshihiko Yada
Keyword(s):  
Insulin Secretion ◽  
Oleic Acid ◽  
Insulin Release ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulinoma Cell ◽  
Transduction Mechanisms ◽  
Glucose Stimulated Insulin Secretion ◽  
Interfering Rna ◽  
G Protein Coupled

It has long been thought that long-chain free fatty acids (FFAs) stimulate insulin secretion via mechanisms involving their metabolism in pancreatic β-cells. Recently, it was reported that FFAs function as endogenous ligands for GPR40, a G protein-coupled receptor, to amplify glucose-stimulated insulin secretion in an insulinoma cell line and rat islets. However, signal transduction mechanisms for GPR40 in β-cells are little known. The present study was aimed at elucidating GPR40-linked Ca2+ signaling mechanisms in rat pancreatic β-cells. We employed oleic acid (OA), an FFA that has a high affinity for the rat GPR40, and examined its effect on cytosolic Ca2+ concentration ([Ca2+]i) in single β-cells by fura 2 fluorescence imaging. OA at 1–10 μM concentration-dependently increased [Ca2+]i in the presence of 5.6, 8.3, and 11.2 mM, but not 2.8 mM, glucose. OA-induced [Ca2+]i increases at 11.2 mM glucose were inhibited in β-cells transfected with small interfering RNA targeted to rat GPR40 mRNA. OA-induced [Ca2+]i increases were also inhibited by phospholipase C (PLC) inhibitors, U73122 and neomycin, Ca2+-free conditions, and an L-type Ca2+ channel blocker, nitrendipine. Furthermore, OA increased insulin release from isolated islets at 8.3 mM glucose, and it was markedly attenuated by PLC and L-type Ca2+ channel inhibitors. These results demonstrate that OA interacts with GPR40 to increase [Ca2+]i via PLC- and L-type Ca2+ channel-mediated pathway in rat islet β-cells, which may be link to insulin release.

Saturated and unsaturated (including arachidonic acid) non-esterified fatty acid modulation of insulin secretion from pancreatic β-cells

2008 ◽  
Vol 36 (5) ◽  
pp. 955-958 ◽  
Author(s):  
Deirdre Keane ◽  
Philip Newsholme
Keyword(s):  
Arachidonic Acid ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Insulin Release ◽  
Chronic Exposure ◽  
Cell Metabolism ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. In the present review, we focus on exogenous and endogenous effects of NEFAs, including the polyunsaturated fatty acid, arachidonic acid (or its metabolites generated from cyclo-oxygenase activity), on β-cell metabolism, and have explored the outcomes with respect to β-cell insulin secretion.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

2020 ◽  
Vol 33 (5) ◽  
pp. 671-674
Author(s):  
Tashunka Taylor-Miller ◽  
Jayne Houghton ◽  
Paul Munyard ◽  
Yadlapalli Kumar ◽  
Clinda Puvirajasinghe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Newborn Period ◽  
Case Presentation ◽  
Male Baby ◽  
Common Causes ◽  
Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

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