scholarly journals Steamed Ginger May Enhance Insulin Secretion through KATP Channel Closure in Pancreatic β-Cells Potentially by Increasing 1-Dehydro-6-Gingerdione Content

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 324 ◽  
Author(s):  
Youn Hee Nam ◽  
Bin Na Hong ◽  
Isabel Rodriguez ◽  
Min Seon Park ◽  
Seo Yule Jeong ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mouse Model ◽  
Pancreatic Islets ◽  
Therapeutic Index ◽  
Zingiber Officinale ◽  
Diabetic Mouse ◽  
Protective Effects ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Ginger Extract

Ginger (Zingiber officinale Roscoe) and its active compounds (gingerols, shogaols and paradols) have been reported as having beneficial functions for several diseases, including diabetes. In this study, we revealed that the steaming process could enhance the anti-diabetic potential of ginger. To confirm the anti-diabetic effect of steamed ginger extract (GG03), we assessed pancreatic islets impaired by alloxan in zebrafish and demonstrated anti-hyperglycemic efficacy in a mouse model. The EC50 values of ginger extract (GE) and GG03 showed that the efficacy of GG03 was greater than that of GE. In addition, LC50 values demonstrated that GG03 had lower toxicity than GE, and the comparison of the Therapeutic Index (TI) proved that GG03 is a safer functional food. Furthermore, our data showed that GG03 significantly lowered hyperglycemia in a diabetic mouse model. HPLC was performed to confirm the change in the composition of steamed ginger. Interestingly, GG03 showed a 375% increase in 1-dehydro-6-gingerdione (GD) compared with GE. GD has not yet been studied much pharmacologically. Thus, we identified the protective effects of GD in the damaged pancreatic islets of diabetic zebrafish. We further assessed whether the anti-diabetic mechanism of action of GG03 and GD involves insulin secretion. Our results suggest that GG03 and GD might stimulate insulin secretion by the closure of KATP channels in pancreatic β-cells.

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.

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 Effect of TNF-α on the expression of ABCA1 in pancreatic β-cells

2018 ◽  
Vol 61 (4) ◽  
pp. 185-193 ◽  
Author(s):  
Seisuke Sato ◽  
Hitomi Imachi ◽  
Jingya Lyu ◽  
Yumi Miyai ◽  
Kensaku Fukunaga ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Promoter Activity ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Tnf Α ◽  
Abca1 Expression ◽  
Glucose Stimulated Insulin Secretion ◽  
Rat Pancreatic Islet ◽  
Abca1 Mrna

ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic β-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation and apoptosis and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or LY-294002. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, β), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on either the decreased insulin content or the ABCA1 suppression caused by TNF-α in INS-1 cells. We checked the influence of TNF-α of insulin secretion and glucose-stimulated insulin secretion in rat pancreatic islet and INS-1 cell. TNF-α suppressed the insulin secretion and glucose-stimulated insulin secretion in both rat pancreatic islet and INS-1 cell. In summary, TNF-α suppressed the expression of endogenous ABCA1 and suppress the insulin secretion in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.

scholarly journals Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic β-Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 5136-5145 ◽  
Author(s):  
Fuzhen Xia ◽  
Li Xie ◽  
Anton Mihic ◽  
Xiaodong Gao ◽  
Yi Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cholesterol Biosynthesis ◽  
Squalene Epoxidase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Voltage Gated ◽  
Endogenous Cholesterol

Insulin secretion from pancreatic β-cells is mediated by the opening of voltage-gated Ca2+ channels (CaV) and exocytosis of insulin dense core vesicles facilitated by the secretory soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein machinery. We previously observed that β-cell exocytosis is sensitive to the acute removal of membrane cholesterol. However, less is known about the chronic changes in endogenous cholesterol and its biosynthesis in regulating β-cell stimulus-secretion coupling. We examined the effects of inhibiting endogenous β-cell cholesterol biosynthesis by using the squalene epoxidase inhibitor, NB598. The expression of squalene epoxidase in primary and clonal β-cells was confirmed by RT-PCR. Cholesterol reduction of 36–52% was observed in MIN6 cells, mouse and human pancreatic islets after a 48-h incubation with 10 μm NB598. A similar reduction in cholesterol was observed in the subcellular compartments of MIN6 cells. We found NB598 significantly inhibited both basal and glucose-stimulated insulin secretion from mouse pancreatic islets. CaV channels were markedly inhibited by NB598. Rapid photolytic release of intracellular caged Ca2+ and simultaneous measurements of the changes in membrane capacitance revealed that NB598 also inhibited exocytosis independently from CaV channels. These effects were reversed by cholesterol repletion. Our results indicate that endogenous cholesterol in pancreatic β-cells plays a critical role in regulating insulin secretion. Moreover, chronic inhibition of cholesterol biosynthesis regulates the functional activity of CaV channels and insulin secretory granule mobilization and membrane fusion. Dysregulation of cellular cholesterol may cause impairment of β-cell function, a possible pathogenesis leading to the development of type 2 diabetes.

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.

Ectonucleotidase NTPDase3 is abundant in pancreatic β-cells and regulates glucose-induced insulin secretion

2013 ◽  
Vol 305 (10) ◽  
pp. E1319-E1326 ◽  
Author(s):  
Samreen K. Syed ◽  
Audra L. Kauffman ◽  
Lisa S. Beavers ◽  
James T. Alston ◽  
Thomas B. Farb ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Purinergic Receptors ◽  
Atp Hydrolysis ◽  
Purinergic Receptor ◽  
Relative Proportion ◽  
Extracellular Atp ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Min6 Cells

Extracellular ATP released from pancreatic β-cells acts as a potent insulinotropic agent through activation of P2 purinergic receptors. Ectonucleotidases, a family of membrane-bound nucleotide-metabolizing enzymes, regulate extracellular ATP levels by degrading ATP and related nucleotides. Ectonucleotidase activity affects the relative proportion of ATP and its metabolites, which in turn will impact the level of purinergic receptor stimulation exerted by extracellular ATP. Therefore, we investigated the expression and role of ectonucleotidases in pancreatic β-cells. Of the ectonucleotidases studied, only ENTPD3 (gene encoding the NTPDase3 enzyme) mRNA was detected at fairly abundant levels in human and mouse pancreatic islets as well as in insulin-secreting MIN6 cells. ARL67156, a selective ectonucleotidase inhibitor, blocked degradation of extracellular ATP that was added to MIN6 cells. The compound also decreased degradation of endogenous ATP released from cells. Measurements of insulin secretion in MIN6 cells as well as in mouse and human pancreatic islets demonstrated that ARL67156 potentiated glucose-dependent insulin secretion. Downregulation of NTPDase3 expression in MIN6 cells with the specific siRNA replicated the effects of ARL67156 on extracellular ATP hydrolysis and insulin secretion. Our results demonstrate that NTPDase3 is the major ectonucleotidase in pancreatic β-cells in multiple species and that it modulates insulin secretion by controlling activation of purinergic receptors.

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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