scholarly journals SWELL1 is a glucose sensor required for β-cell excitability and insulin secretion

2017 ◽  
Author(s):  
Chen Kang ◽  
Susheel K. Gunasekar ◽  
Anil Mishra ◽  
Litao Xie ◽  
Yanhui Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Calcium Signaling ◽  
Glucose Sensor ◽  
Physiological Role ◽  
Ionic Currents ◽  
Cell Swelling ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion

AbstractInsulin secretion from the pancreatic β-cell initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane. The firing of VGCC depends on the β-cell membrane potential, which is in turn mediated by the balance of depolarizing (excitatory) and hyperpolarizing (inhibitory) ionic currents1-3. While much attention has focused on inhibitory potassium currents4-10 there is little knowledge about the excitatory currents required to depolarize the β-cell, including the molecular identity of these excitatory currents3. Here we show that SWELL1 (LRRC8a) mediates a swell-activated, depolarizing chloride current (ICl,SWELL) in β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated ICl,SWELL and this is required for both glucose-stimulated and hypotonic swell-mediated activation of VGCC-dependent intracellular calcium signaling in β-cells. SWELL1 KO MIN6 cells and β-cell targeted SWELL1 KO murine islets exhibit significantly impaired glucose-stimulated insulin secretion, with preserved insulin content in vitro. Tamoxifen-inducible β-cell targeted SWELL1 KO mice have normal fasting insulin levels but display markedly impaired glucose-stimulated insulin secretion. Our results reveal a physiological role for SWELL1 as a glucose sensor - linking glucose-mediated β-cell swelling to SWELL1-dependent activation of VGCC-triggered calcium signaling, and highlights SWELL1-mediated “swell-secretion” coupling as required for glucose-stimulated insulin secretion.

scholarly journals Fructose-1,6-Bisphosphatase Regulates Glucose-Stimulated Insulin Secretion of Mouse Pancreatic β-Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4688-4695 ◽  
Author(s):  
Ye Zhang ◽  
Zhifang Xie ◽  
Guangdi Zhou ◽  
Hai Zhang ◽  
Jian Lu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Specific Inhibitor ◽  
Physiological Role ◽  
Glucose Sensing ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Fructose 1,6 Bisphosphatase ◽  
Glucose Stimulated Insulin Secretion

Pancreatic β-cells can precisely sense glucose stimulation and accordingly adjust their insulin secretion. Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme, but its physiological significance in β-cells is not established. Here we determined its physiological role in regulating glucose sensing and insulin secretion of β-cells. Considerable FBPase mRNA was detected in normal mouse islets and β-cell lines, although their protein levels appeared to be quite low. Down-regulation of FBP1 in MIN6 cells by small interfering RNA could enhance the glucose-stimulated insulin secretion (GSIS), whereas FBP1-overexpressing MIN6 cells exhibited decreased GSIS. Inhibition of FBPase activity in islet β-cells by its specific inhibitor MB05032 led to significant increase of their glucose utilization and cellular ATP to ADP ratios and consequently enhanced GSIS in vitro. Pretreatment of mice with the MB05032 prodrug MB06322 could potentiate GSIS in vivo and improve their glucose tolerance. Therefore, FBPase plays an important role in regulating glucose sensing and insulin secretion of β-cells and serves a promising target for diabetes treatment.

scholarly journals Increased Pancreatic β-Cell Proliferation Mediated by CREB Binding Protein Gene Activation

2006 ◽  
Vol 26 (20) ◽  
pp. 7747-7759 ◽  
Author(s):  
Mehboob A. Hussain ◽  
Delia L. Porras ◽  
Matthew H. Rowe ◽  
Jason R. West ◽  
Woo-Jin Song ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Gene Activation ◽  
Phosphorylation Site ◽  
Creb Binding Protein ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion

ABSTRACT The cyclic AMP (cAMP) signaling pathway is central in β-cell gene expression and function. In the nucleus, protein kinase A (PKA) phosphorylates CREB, resulting in recruitment of the transcriptional coactivators p300 and CREB binding protein (CBP). CBP, but not p300, is phosphorylated at serine 436 in response to insulin action. CBP phosphorylation disrupts CREB-CBP interaction and thus reduces nuclear cAMP action. To elucidate the importance of the cAMP-PKA-CREB-CBP pathway in pancreatic β cells specifically at the nuclear level, we have examined mutant mice lacking the insulin-dependent phosphorylation site of CBP. In these mice, the CREB-CBP interaction is enhanced in both the absence and presence of cAMP stimulation. We found that islet and β-cell masses were increased twofold, while pancreas weights were not different from the weights of wild-type littermates. β-Cell proliferation was increased both in vivo and in vitro in isolated islet cultures. Surprisingly, glucose-stimulated insulin secretion from perfused, isolated mutant islets was reduced. However, β-cell depolarization with KCl induced similar levels of insulin release from mutant and wild-type islets, indicating normal insulin synthesis and storage. In addition, transcripts of pgc1a, which disrupts glucose-stimulated insulin secretion, were also markedly elevated. In conclusion, sustained activation of CBP-responsive genes results in increased β-cell proliferation. In these β cells, however, glucose-stimulated insulin secretion was diminished, resulting from concomitant CREB-CBP-mediated pgc1a gene activation.

scholarly journals The mitochondrial Ca2+ uniporter MCU is required for normal glucose-stimulated insulin secretion in vitro and in vivo

2019 ◽  
Author(s):  
Elizabeth Haythorne ◽  
Eleni Georgiadou ◽  
Matthew T. Dickerson ◽  
Livia Lopez-Noriega ◽  
Timothy J. Pullen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Β Cells ◽  
Β Cell ◽  
Compensatory Mechanisms ◽  
Glucose Stimulated Insulin Secretion

AbstractMitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ uptake into pancreatic β-cell mitochondria potentiates or antagonises this process is still a matter of debate. Although the mitochondrial importer (MCU) complex is thought to represent the main route for Ca2+ transport across the inner mitochondrial membrane, its role in β-cells has not previously been examined in vivo. Here, we inactivated the pore-forming subunit MCUa (MCU) selectively in the β-cell in mice using Ins1Cre-mediated recombination. Glucose-stimulated mitochondrial Ca2+ accumulation, ATP production and insulin secretion were strongly (p<0.05 and p<0.01) inhibited in MCU null animals (βMCU-KO) in vitro. Interestingly, cytosolic Ca2+ concentrations increased (p<0.001) whereas mitochondrial membrane depolarisation improved in βMCU-KO animals. Male βMCU-KO mice displayed impaired in vivo insulin secretion at 5 (p<0.001) but not 15 min. post intraperitoneal (IP) injection of glucose while the opposite phenomenon was observed following an oral gavage at 5 min. Unexpectedly, glucose tolerance was improved (p<0.05) in young βMCU-KO (<12 weeks), but not older animals. We conclude that MCU is crucial for mitochondrial Ca2+ uptake in pancreatic β-cells and is required for normal GSIS. The apparent compensatory mechanisms which maintain glucose tolerance in βMCU-KO mice remain to be established.

scholarly journals In vivo imaging of β-cell function reveals glucose-mediated heterogeneity of β-cell functional development

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jia Zhao ◽  
Weijian Zong ◽  
Yiwen Zhao ◽  
Dongzhou Gou ◽  
Shenghui Liang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
In Vivo Imaging ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Functional Development ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

How pancreatic β-cells acquire function in vivo is a long-standing mystery due to the lack of technology to visualize β-cell function in living animals. Here, we applied a high-resolution two-photon light-sheet microscope for the first in vivo imaging of Ca2+activity of every β-cell in Tg (ins:Rcamp1.07) zebrafish. We reveal that the heterogeneity of β-cell functional development in vivo occurred as two waves propagating from the islet mantle to the core, coordinated by islet vascularization. Increasing amounts of glucose induced functional acquisition and enhancement of β-cells via activating calcineurin/nuclear factor of activated T-cells (NFAT) signaling. Conserved in mammalians, calcineurin/NFAT prompted high-glucose-stimulated insulin secretion of neonatal mouse islets cultured in vitro. However, the reduction in low-glucose-stimulated insulin secretion was dependent on optimal glucose but independent of calcineurin/NFAT. Thus, combination of optimal glucose and calcineurin activation represents a previously unexplored strategy for promoting functional maturation of stem cell-derived β-like cells in vitro.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

scholarly journals Regulation of glucokinase in pancreatic islets by prolactin: a mechanism for increasing glucose-stimulated insulin secretion during pregnancy

2007 ◽  
Vol 193 (3) ◽  
pp. 367-381 ◽  
Author(s):  
Anthony J Weinhaus ◽  
Laurence E Stout ◽  
Nicholas V Bhagroo ◽  
T Clark Brelje ◽  
Robert L Sorenson
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Glucose Transporter ◽  
Β Cells ◽  
Glucose Transporter 2 ◽  
Underlying Mechanisms ◽  
Glucose Stimulated Insulin Secretion ◽  
Induced Changes

Glucokinase activity is increased in pancreatic islets during pregnancy and in vitro by prolactin (PRL). The underlying mechanisms that lead to increased glucokinase have not been resolved. Since glucose itself regulates glucokinase activity in β-cells, it was unclear whether the lactogen effects are direct or occur through changes in glucose metabolism. To clarify the roles of glucose metabolism in this process, we examined the interactions between glucose and PRL on glucose metabolism, insulin secretion, and glucokinase expression in insulin 1 (INS-1) cells and rat islets. Although the PRL-induced changes were more pronounced after culture at higher glucose concentrations, an increase in glucose metabolism, insulin secretion, and glucokinase expression occurred even in the absence of glucose. The presence of comparable levels of insulin secretion at similar rates of glucose metabolism from both control and PRL-treated INS-1 cells suggests the PRL-induced increase in glucose metabolism is responsible for the increase in insulin secretion. Similarly, increases in other known PRL responsive genes (e.g. the PRL receptor, glucose transporter-2, and insulin) were also detected after culture without glucose. We show that the upstream glucokinase promoter contains multiple STAT5 binding sequences with increased binding in response to PRL. Corresponding increases in glucokinase mRNA and protein synthesis were also detected. This suggests the PRL-induced increase in glucokinase mRNA and its translation are sufficient to account for the elevated glucokinase activity in β-cells with lactogens. Importantly, the increase in islet glucokinase observed with PRL is in line with that observed in islets during pregnancy.

scholarly journals L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jaeyong Cho ◽  
Yukio Horikawa ◽  
Mayumi Enya ◽  
Jun Takeda ◽  
Yoichi Imai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Direct Stimulation ◽  
Glucose Ratio ◽  
Glucose Stimulated Insulin Secretion

Abstract We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in β-cells by finding a protein with affinity to L-arginine using arginine-immobilized magnetic nanobeads technology. Glucokinase (GCK), the key regulator of GSIS and a disease-causing gene of maturity-onset diabetes of the young type 2 (MODY2), was found to bind L-arginine. L-Arginine stimulated production of glucose-6-phosphate (G6P) and induced insulin secretion. We analyzed glucokinase mutants and identified three glutamate residues that mediate binding to L-arginine. One MODY2 patient with GCKE442* demonstrated lower C-peptide-to-glucose ratio after arginine administration. In β-cell line, GCKE442* reduced L-arginine-induced insulin secretion compared with GCKWT. In addition, we elucidated that the binding of arginine protects glucokinase from degradation by E3 ubiquitin ligase cereblon mediated ubiquitination. We conclude that L-arginine induces insulin secretion by increasing G6P production by glucokinase through direct stimulation and by prevention of degradation.

scholarly journals The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells

2020 ◽  
Vol 117 (45) ◽  
pp. 28307-28315
Author(s):  
Baile Wang ◽  
Huige Lin ◽  
Xiaomu Li ◽  
Wenqi Lu ◽  
Jae Bum Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Adaptor Protein ◽  
Hek293 Cells ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Actin Remodeling ◽  
Actin Depolymerization ◽  
Glucose Stimulated Insulin Secretion

Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells.

scholarly journals Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

MedChemComm ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 280-293
Author(s):  
Anna Munder ◽  
Yoni Moskovitz ◽  
Aviv Meir ◽  
Shirin Kahremany ◽  
Laura Levy ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cellular Stress ◽  
Pamam Dendrimers ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Functions ◽  
Functional Maturation ◽  
Glucose Stimulated Insulin Secretion

The nanoscale composite improved β-cell functions in terms of rate of proliferation, glucose-stimulated insulin secretion, resistance to cellular stress and functional maturation.

Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in β-cells

2006 ◽  
Vol 290 (2) ◽  
pp. E334-E340 ◽  
Author(s):  
Robert C. Cooksey ◽  
Sumitha Pusuluri ◽  
Mark Hazel ◽  
Donald A. McClain
Keyword(s):  
Insulin Secretion ◽  
Glucose Oxidation ◽  
Nutrient Sensing ◽  
Wild Type ◽  
Β Cells ◽  
Enhanced Sensitivity ◽  
Peripheral Insulin Resistance ◽  
Glucose Stimulated Insulin Secretion ◽  
Rate Limiting

Hexosamines serve a nutrient-sensing function through enzymatic O-glycosylation of proteins. We previously characterized transgenic (Tg) mice with overexpression of the rate-limiting enzyme in hexosamine production, glutamine:fructose-6-phosphate amidotransferase, in β-cells. Animals were hyperinsulinemic, resulting in peripheral insulin resistance. Glucose tolerance deteriorated with age, and males developed diabetes. We therefore examined islet function in these mice by perifusion in vitro. Young (2-mo-old) Tg animals had enhanced sensitivity to glucose of insulin secretion. Insulin secretion was maximal at 20 mM and half maximal at 9.9 ± 0.5 mM glucose in Tg islets compared with maximal at 30 mM and half maximal at 13.5 ± 0.7 mM glucose in wild type (WT; P < 0.005). Young Tg animals secreted more insulin in response to 20 mM glucose (Tg, 1,254 ± 311; WT, 425 ± 231 pg·islet−1·35 min−1; P < 0.01). Islets from older (8-mo-old) Tg mice became desensitized to glucose, with half-maximal secretion at 16.1 ± 0.8 mM glucose, compared with 11.8 ± 0.7 mM in WT ( P < 0.05). Older Tg mice secreted less insulin in response to 20 mM glucose (Tg, 2,256 ± 342; WT, 3,493 ± 367 pg·islet−1·35 min−1; P < 0.05). Secretion in response to carbachol was similar in WT and Tg at both ages. Glucose oxidation was blunted in older Tg islets. At 5 mM glucose, islet CO2 production was comparable between Tg and WT. However, WT mice increased islet CO2 production 2.7 ± 0.4-fold in 20 mM glucose, compared with only 1.4 ± 0.1-fold in Tg ( P < 0.02). Results demonstrate that hexosamines are involved in nutrient sensing for insulin secretion, acting at least in part by modulating glucose oxidation pathways. Prolonged excess hexosamine flux results in glucose desensitization and mimics glucose toxicity.

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