scholarly journals Hv1 channel supports insulin secretion in pancreatic β cells through calcium entry, depolarization and intracellular pH regulation

2017 ◽  
Author(s):  
Huimin Pang ◽  
Xudong Wang ◽  
Wang Xi ◽  
Qing Zhao ◽  
Shangrong Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Regulatory Mechanism ◽  
Ph Regulation ◽  
Membrane Depolarization ◽  
Calcium Entry ◽  
Proton Channel ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Cytosolic Ph ◽  
Deficient Mice

AbstractHere, we demonstrate that the voltage-gated proton channel Hv1 represents a regulatory mechanism for insulin secretion of pancreatic islet β cell. In vivo, Hv1-deficient mice display hyperglycemia and glucose intolerance due to reduced insulin secretion, but normal peripheral insulin sensitivity. In vitro, islets of Hv1-deficient and heterozygous mice, INS-1 (832/13) cells with siRNA-mediated knockdown of Hv1 exhibit a marked defect in glucose- and K+-induced insulin secretion. Hv1 deficiency decreases both insulin and proinsulin contents, and limits glucose-induced Ca2+ entry and membrane depolarization. Furthermore, loss of Hv1 increases insulin-containing granular pH and decreases cytosolic pH. In addition, histologic studies show a decrease in β cell mass in islets of Hv1-deficient mice. Collectively, our results indicate that Hv1 supports insulin secretion in the β cell by calcium entry, membrane depolarization and intracellular pH regulation.SIGNIFICANCE STATEMENTThe voltage-gated proton channel Hv1 is highly expressed in insulin-containing granules in pancreatic β cells. Hv1 supports insulin secretion in the β cell by calcium entry, membrane depolarization and regulation of intragranular and cytosolic pH, which represents a regulatory mechanism for insulin secretion of pancreatic islet β cell. Our research demonstrates that Hv1 expressed in β cell is required for insulin secretion and maintains glucose homeostasis, and reveals a significant role for the proton channel in the modulation of pancreatic β cell function.

scholarly journals Loss of the voltage-gated proton channel Hv1 decreases insulin secretion and leads to hyperglycemia and glucose intolerance in mice

2020 ◽  
Vol 295 (11) ◽  
pp. 3601-3613 ◽  
Author(s):  
Huimin Pang ◽  
Xudong Wang ◽  
Shiqun Zhao ◽  
Wang Xi ◽  
Jili Lv ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Glucose Homeostasis ◽  
Membrane Depolarization ◽  
Proton Channel ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Voltage Gated ◽  
Deficient Mice

Insulin secretion by pancreatic islet β-cells is regulated by glucose levels and is accompanied by proton generation. The voltage-gated proton channel Hv1 is present in pancreatic β-cells and extremely selective for protons. However, whether Hv1 is involved in insulin secretion is unclear. Here we demonstrate that Hv1 promotes insulin secretion of pancreatic β-cells and glucose homeostasis. Hv1-deficient mice displayed hyperglycemia and glucose intolerance because of reduced insulin secretion but retained normal peripheral insulin sensitivity. Moreover, Hv1 loss contributed much more to severe glucose intolerance as the mice got older. Islets of Hv1-deficient and heterozygous mice were markedly deficient in glucose- and K+-induced insulin secretion. In perifusion assays, Hv1 deletion dramatically reduced the first and second phase of glucose-stimulated insulin secretion. Islet insulin and proinsulin content was reduced, and histological analysis of pancreas slices revealed an accompanying modest reduction of β-cell mass in Hv1 knockout mice. EM observations also indicated a reduction in insulin granule size, but not granule number or granule docking, in Hv1-deficient mice. Mechanistically, Hv1 loss limited the capacity for glucose-induced membrane depolarization, accompanied by a reduced ability of glucose to raise Ca2+ levels in islets, as evidenced by decreased durations of individual calcium oscillations. Moreover, Hv1 expression was significantly reduced in pancreatic β-cells from streptozotocin-induced diabetic mice, indicating that Hv1 deficiency is associated with β-cell dysfunction and diabetes. We conclude that Hv1 regulates insulin secretion and glucose homeostasis through a mechanism that depends on intracellular Ca2+ levels and membrane depolarization.

Involvement of stretch-activated cation channels in hypotonically induced insulin secretion in rat pancreatic β-cells

2006 ◽  
Vol 291 (6) ◽  
pp. C1405-C1411 ◽  
Author(s):  
Miki Takii ◽  
Tomohisa Ishikawa ◽  
Hidetaka Tsuda ◽  
Kazumitsu Kanatani ◽  
Takaaki Sunouchi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Membrane Depolarization ◽  
Ruthenium Red ◽  
Cell Swelling ◽  
Cation Channels ◽  
Channel Blockers ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Voltage Dependent ◽  
Isolated Rat

In isolated rat pancreatic β-cells, hypotonic stimulation elicited an increase in cytosolic Ca2+ concentration ([Ca2+]c) at 2.8 mM glucose. The hypotonically induced [Ca2+]c elevation was significantly suppressed by nicardipine, a voltage-dependent Ca2+ channel blocker, and by Gd3+, amiloride, 2-aminoethoxydiphenylborate, and ruthenium red, all cation channel blockers. In contrast, the [Ca2+]c elevation was not inhibited by suramin, a P2 purinoceptor antagonist. Whole cell patch-clamp analyses showed that hypotonic stimulation induced membrane depolarization of β-cells and produced outwardly rectifying cation currents; Gd3+ inhibited both responses. Hypotonic stimulation also increased insulin secretion from isolated rat islets, and Gd3+ significantly suppressed this secretion. Together, these results suggest that osmotic cell swelling activates cation channels in rat pancreatic β-cells, thereby causing membrane depolarization and subsequent activation of voltage-dependent Ca2+ channels and thus elevating insulin secretion.

Chronic fetal hypoglycemia inhibits the later steps of stimulus-secretion coupling in pancreatic β-cells

2007 ◽  
Vol 292 (5) ◽  
pp. E1256-E1264 ◽  
Author(s):  
Paul J. Rozance ◽  
Sean W. Limesand ◽  
Gary O. Zerbe ◽  
William W. Hay
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Pancreatic Islet ◽  
Membrane Depolarization ◽  
Calcium Entry ◽  
Late Gestation ◽  
Β Cells ◽  
Β Cell ◽  
Stimulus Secretion Coupling ◽  
The Impact

We measured the impact of chronic late gestation hypoglycemia on pancreatic islet structure and function to determine the cause of decreased insulin secretion in this sheep model of fetal nutrient deprivation. Late gestation hypoglycemia did not decrease pancreas weight, insulin content, β-cell area, β-cell mass, or islet size. The pancreatic islet isolation procedure selected a group of islets that were larger and had an increased proportion of β-cells compared with islets measured in pancreatic sections, but there were no morphologic differences between islets isolated from control and hypoglycemic fetuses. The rates of glucose-stimulated pancreatic islet glucose utilization (126.2 ± 25.3 pmol glucose·islet−1·h−1, hypoglycemic, vs. 93.5 ± 5.5 pmol glucose·islet−1·h−1, control, P = 0.47) and oxidation (10.5 ± 1.7 pmol glucose·islet−1·h−1, hypoglycemic, vs. 10.6 ± 1.6 pmol glucose·islet−1·h−1, control) were not different in hypoglycemic fetuses compared with control fetuses. Chronic late gestation hypoglycemia decreased insulin secretion in isolated pancreatic islets by almost 70% in response to direct nonnutrient membrane depolarization and in response to increased extracellular calcium entry. β-Cell ultrastructure was abnormal with markedly distended rough endoplasmic reticulum in three of the seven hypoglycemic fetuses studied, but in vitro analysis of hypoglycemic control islets showed no evidence that these changes represented endoplasmic reticulum stress, as measured by transcription of glucose regulatory protein-78 and processing of X-box binding protein-1. In conclusion, these studies show that chronic hypoglycemia in late gestation decreases insulin secretion by inhibiting the later steps of stimulus-secretion coupling after glucose metabolism, membrane depolarization, and calcium entry.

Thapsigargin-sensitive cationic current leads to membrane depolarization, calcium entry, and insulin secretion in rat pancreatic β-cells

2005 ◽  
Vol 289 (3) ◽  
pp. E439-E445 ◽  
Author(s):  
R. Cruz-Cruz ◽  
A. Salgado ◽  
C. Sánchez-Soto ◽  
L. Vaca ◽  
M. Hiriart
Keyword(s):  
Insulin Secretion ◽  
Hormone Secretion ◽  
Plaque Assay ◽  
Membrane Depolarization ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Current Clamp ◽  
Cationic Current ◽  
Current Leads ◽  
Cationic Channel

Glucose-induced insulin secretion by pancreatic β-cells depends on membrane depolarization and [Ca2+]i increase. We correlated voltage- and current-clamp recordings, [Ca2+]i measurements, and insulin reverse hemolytic plaque assay to analyze the activity of a thapsigargin-sensitive cationic channel that can be important for membrane depolarization in single rat pancreatic β-cells. We demonstrate the presence of a thapsigargin-sensitive cationic current, which is mainly carried by Na+. Moreover, in basal glucose concentration (5.6 mM), thapsigargin depolarizes the plasma membrane, producing electrical activity and increasing [Ca2+]i. The latter is prevented by nifedipine, indicating that Ca2+ enters the cell through L-type Ca2+ channels, which are activated by membrane depolarization. Thapsigargin also increased insulin secretion by increasing the percentage of cells secreting insulin and amplifying hormone secretion by individual β-cells. Nifedipine blocked the increase completely in 5.6 mM glucose and partially in 15.6 mM glucose. We conclude that thapsigargin potentiates a cationic current that depolarizes the cell membrane. This, in turn, increases Ca2+ entry through L-type Ca2+ channels promoting insulin secretion.

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.

scholarly journals Author Correction: CD44 variant inhibits insulin secretion in pancreatic β cells by attenuating LAT1-mediated amino acid uptake

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nana Kobayashi ◽  
Shogo Okazaki ◽  
Oltea Sampetrean ◽  
Junichiro Irie ◽  
Hiroshi Itoh ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Amino Acid ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Cd44 Variant

scholarly journals D2-Like Receptors Mediate Dopamine-Inhibited Insulin Secretion via Ion Channels in Rat Pancreatic β-Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Mengmeng Liu ◽  
Lele Ren ◽  
Xiangqin Zhong ◽  
Yaqin Ding ◽  
Tao Liu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ion Channels ◽  
Β Cells ◽  
Pancreatic Β Cells

Jiawei Erzhiwan improves menopausal metabolic syndrome by enhancing insulin secretion in pancreatic β cells

2016 ◽  
Vol 14 (11) ◽  
pp. 823-834 ◽  
Author(s):  
Xiao-Meng WAN ◽  
Mu ZHANG ◽  
Pei ZHANG ◽  
Zhi-Shen XIE ◽  
Feng-Guo XU ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells
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