Abscisic Acid Is an Endogenous Stimulator of Insulin Release from Human Pancreatic Islets with Cyclic ADP Ribose as Second Messenger

Abstract

Abscisic acid (ABA) is a plant stress hormone recently identified as an endogenous pro-inflammatory cytokine in human granulocytes. Because paracrine signaling between pancreatic β cells and inflammatory cells is increasingly recognized as a pathogenetic mechanism in the metabolic syndrome and type II diabetes, we investigated the effect of ABA on insulin secretion. Nanomolar ABA increases glucose-stimulated insulin secretion from RIN-m and INS-1 cells and from murine and human pancreatic islets. The signaling cascade triggered by ABA in insulin-releasing cells sequentially involves a pertussis toxin-sensitive G protein, cAMP overproduction, protein kinase A-mediated activation of the ADP-ribosyl cyclase CD38, and cyclic ADP-ribose overproduction. ABA is rapidly produced and released from human islets, RIN-m, and INS-1 cells stimulated with high glucose concentrations. In conclusion, ABA is an endogenous stimulator of insulin secretion in human and murine pancreatic β cells. Autocrine release of ABA by glucose-stimulated pancreatic β cells, and the paracrine production of the hormone by activated granulocytes and monocytes suggest that ABA may be involved in the physiology of insulin release as well as in its dysregulation under conditions of inflammation. Abscisic acid (ABA) is a plant stress hormone recently identified as an endogenous pro-inflammatory cytokine in human granulocytes. Because paracrine signaling between pancreatic β cells and inflammatory cells is increasingly recognized as a pathogenetic mechanism in the metabolic syndrome and type II diabetes, we investigated the effect of ABA on insulin secretion. Nanomolar ABA increases glucose-stimulated insulin secretion from RIN-m and INS-1 cells and from murine and human pancreatic islets. The signaling cascade triggered by ABA in insulin-releasing cells sequentially involves a pertussis toxin-sensitive G protein, cAMP overproduction, protein kinase A-mediated activation of the ADP-ribosyl cyclase CD38, and cyclic ADP-ribose overproduction. ABA is rapidly produced and released from human islets, RIN-m, and INS-1 cells stimulated with high glucose concentrations. In conclusion, ABA is an endogenous stimulator of insulin secretion in human and murine pancreatic β cells. Autocrine release of ABA by glucose-stimulated pancreatic β cells, and the paracrine production of the hormone by activated granulocytes and monocytes suggest that ABA may be involved in the physiology of insulin release as well as in its dysregulation under conditions of inflammation. Abscisic acid (ABA) 2The abbreviations used are: ABA, (±)-abscisic acid; cADPR, cyclic ADP-ribose; ADPRC, ADP-ribosyl cyclase; [Ca2+]i, intracellular calcium concentration; PKA, protein kinase A; I-PKA, protein kinase A inhibitor; PTX, pertussis toxin; PCA, perchloric acid; HBSS, Hanks' balanced salt solution; KRH, Krebs-Ringer-Hepes-buffer; LG, low glucose; HG, high glucose; MoAb, monoclonal antibody; HPLC, high pressure liquid chromatography; ANOVA, analysis of variance; ELISA, enzyme-linked immunosorbent assay; 8-Br-cAMP, 8-bromo-cAMP; SI, Stimulation Index. 2The abbreviations used are: ABA, (±)-abscisic acid; cADPR, cyclic ADP-ribose; ADPRC, ADP-ribosyl cyclase; [Ca2+]i, intracellular calcium concentration; PKA, protein kinase A; I-PKA, protein kinase A inhibitor; PTX, pertussis toxin; PCA, perchloric acid; HBSS, Hanks' balanced salt solution; KRH, Krebs-Ringer-Hepes-buffer; LG, low glucose; HG, high glucose; MoAb, monoclonal antibody; HPLC, high pressure liquid chromatography; ANOVA, analysis of variance; ELISA, enzyme-linked immunosorbent assay; 8-Br-cAMP, 8-bromo-cAMP; SI, Stimulation Index. is a plant hormone regulating several important physiological functions related to the response of higher Metaphyta to abiotic stress (temperature variations, water, and nutrient availability) (1Grill E. Himmelbach A. Curr. Opin. Plant Biol. 1998; 1: 412-418Crossref PubMed Scopus (116) Google Scholar). A similar physiological role for ABA has been recently unveiled also in lower Metazoa (marine sponges and Hydroids), where autocrine production of ABA in response to environmental stimuli, temperature rise in sponges or light exposure in Hydroids, has been shown to stimulate water filtration and tissue regeneration, respectively (2Zocchi E. Carpaneto A. Cerrano C. Bavestrello G. Giovine M. Bruzzone S. Guida L. Franco L. Usai C. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 14859-14864Crossref PubMed Scopus (98) Google Scholar, 3Zocchi E. Basile G. Cerrano C. Bavestrello G. Giovine M. Bruzzone S. Guida L. Carpaneto A. Magrassi R. Usai C. J. Cell Sci. 2003; 116: 629-636Crossref PubMed Scopus (43) Google Scholar, 4Puce S. Basile G. Bavestrello G. Bruzzone S. Cerrano C. Giovine M. Arillo A. Zocchi E. J. Biol. Chem. 2004; 279: 39783-39788Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The discovery of the synthesis and functional activity of a plant hormone in lower Metazoa suggested a possible role for ABA in animal cells. Indeed, most recent results indicate that ABA production occurs in human granulocytes stimulated with physical (temperature rise, latex beads) or chemical (phorbol myristate acetate) stimuli and that ABA activates several functional activities of granulocytes (including phagocytosis, migration, production of reactive oxygen species, and nitric oxide) involved in their defensive function (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). Thus, ABA behaves as an endogenous pro-inflammatory hormone in human granulocytes. The remarkable conservation of the role of ABA as a stress signal from plants to humans is paralleled by the strikingly similar signal transduction pathway of the hormone in plants and animals. This pathway sequentially involves phosphorylation and activation of ADP-ribosyl cyclase (ADPRC), overproduction of the universal calcium mobilizer cyclic ADP-ribose (cADPR) (6Lee H.C. Walseth T.F. Bratt G.T. Hayes R.N. Clapper D.L. J. Biol. Chem. 1989; 264: 1608-1615Abstract Full Text PDF PubMed Google Scholar, 7Lee H.C. Cyclic ADP-Ribose and NAADP: Structures, Metabolism and Functions. Kluwer Academic Publishers, Norwell, MA2002: 1-21Crossref Google Scholar, 8Guse A.H. FEBS J. 2005; 272: 4590-4597Crossref PubMed Scopus (119) Google Scholar), and increase of the intracellular Ca2+ concentration ([Ca2+]i) (2Zocchi E. Carpaneto A. Cerrano C. Bavestrello G. Giovine M. Bruzzone S. Guida L. Franco L. Usai C. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 14859-14864Crossref PubMed Scopus (98) Google Scholar, 4Puce S. Basile G. Bavestrello G. Bruzzone S. Cerrano C. Giovine M. Arillo A. Zocchi E. J. Biol. Chem. 2004; 279: 39783-39788Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 9Wu Y. Kuzma J. Maréchal E. Graeff R. Lee H.C. Foster R. Chua N.H. Science. 1997; 278: 2126-2130Crossref PubMed Scopus (326) Google Scholar). In human granulocytes, ABA binding to the plasma membrane occurs through a pertussis toxin (PTX)-sensitive receptor-G protein complex, leading to a rapid increase of the [cAMP]i, activation of protein kinase A (PKA), phosphorylation of the ADPRC CD38 with cADPR overproduction, eventually leading to an increase of the [Ca2+]i (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). The following considerations are suggested to explore whether ABA had an effect on insulin secretion from mammalian β cells: (i) acute physical stress (trauma, infections, and fever) is known to affect blood glucose levels, inducing hyperglycemia through complex mechanisms, partly involving the action of catecholamines and cortisol but also because of the effects of pro-inflammatory cytokines on pancreatic β cell function (10McCowen K.C. Malhotra A. Bistrian B.R. Crit. Care Clin. 2001; 17: 107-124Abstract Full Text Full Text PDF PubMed Scopus (914) Google Scholar, 11Marik P.E. Raghavan M. Intensive Care Med. 2004; 30: 748-756Crossref PubMed Scopus (298) Google Scholar, 12Gearhart M.M. Parbhoo S.K. AACN Clin. Issues. 2006; 17: 50-55Crossref PubMed Scopus (108) Google Scholar); (ii) the second messengers involved in ABA signaling, cAMP and cADPR, are known to play a role in the signaling pathway leading to glucose-induced insulin secretion (13Charles M.A. Fanska R. Schmid F.G. Forsham P.H. Grodsky G.M. Science. 1973; 179: 569-571Crossref PubMed Scopus (131) Google Scholar, 4Puce S. Basile G. Bavestrello G. Bruzzone S. Cerrano C. Giovine M. Arillo A. Zocchi E. J. Biol. Chem. 2004; 279: 39783-39788Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar, 6Lee H.C. Walseth T.F. Bratt G.T. Hayes R.N. Clapper D.L. J. Biol. Chem. 1989; 264: 1608-1615Abstract Full Text PDF PubMed Google Scholar, 17Islam M.S. Diabetes. 2002; 51: 1299-1309Crossref PubMed Scopus (85) Google Scholar). Results obtained indicate that ABA, at nanomolar concentrations, potentiates insulin release in response to glucose in rat insulinoma cells (RIN-m and INS-1) and in human and murine pancreatic islets. The signaling pathway of ABA in insulin-releasing cells involves a PTX-sensitive G protein, cAMP, PKA, and cADPR. High glucose stimulate ABA production and release from human and rat β cells, that ABA is an endogenous stimulator of insulin The that ABA is also produced by inflammatory cells, granulocytes (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google and monocytes De and A. as an Scholar), that hormone may to the complex of cytokine between inflammatory cells and pancreatic β cells, is increasingly recognized as a mechanism in the of the metabolic syndrome and A. A. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L. A. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, C. FEBS PubMed Scopus Google Scholar, Biol. PubMed Scopus Google Scholar). from The protein kinase A obtained from obtained from and from The monoclonal by of (ABA) and obtained from Cell rat insulinoma RIN-m cell obtained from and to the in with to with The rat insulinoma cell INS-1 by II of and in the as RIN-m cells, with in a at and pancreatic obtained from S. under the of the for for human of obtained from the of as M. M. L. M. C. L. R. G. R. G. Diabetes. 2001; PubMed Scopus Google Scholar). be used for because of low used by the used for the cells, with cells. cells in the by to their human at in a in with and and in the human pancreatic at for in an and used to insulin cADPR and ABA as pancreatic from as R. M. E. E. L. 2007; PubMed Scopus Google Scholar). and INS-1 cells in a the and cells for in glucose and with and The and cells as RIN-m cells for or for at with or High as with glucose to in the or of of INS-1 cells for in or as but in the or of of The and at for and insulin concentration by The human and murine human or murine and by with of in and for human and murine islets, for or at for and for of the insulin or with or ABA, to the for or at for and for of the insulin concentration with an that and human insulin insulin Results are as Stimulation stimulated of cAMP and INS-1 cells in the with and cells for at The and with Hanks' balanced salt ABA and by of and of of cells for at in the of the cAMP Cell and to the cAMP on the cell R. Lee H.C. J. 2002; PubMed Scopus Google by a The human and by with of in for at and the cAMP the The and with or ABA, to the for and by of the acid and the cAMP by of cADPR cells in the with LG, and cells for at The and with ABA by of and of of Cell and to the cADPR on the perchloric acid cell with a R. Lee H.C. J. 2002; PubMed Scopus Google Scholar). The human and by with of in for at the and or with or ABA to to the for The to the the acid and the cADPR with the R. Lee H.C. J. 2002; PubMed Scopus Google Scholar). of ADP-ribosyl cells or human pancreatic in of at with in the or in the of at and the by of of to The cADPR concentration by R. Lee H.C. J. 2002; PubMed Scopus Google Scholar). in to M. PubMed Scopus Google Scholar). of and RIN-m cells by at on in the of and and and the protein concentration in the M. PubMed Scopus Google Scholar). of the cell on a analysis and of CD38 with the to of the CD38 from human of in and with of protein for at on a The by and the in the of of on a for at of protein and for at on a and The with of of obtained by of a at for and the on a The and with the or with the to of the from RIN-m cells and from human the to the and of the synthesis The used as for in a The and human and by and from their as for rat CD38 and for human in in a of of and and of The an at for by of to and to at the of the of the a produced to analysis of the obtained the on the in of the to and to a of and by are as of in of pancreatic RIN-m cells, or INS-1 cells human blood cells, by or murine cells from the of pancreatic for at in or Cell for and of to Cell in of water and at for for of protein M. PubMed Scopus Google and of to the cell of as an to to of the and ABA as (2Zocchi E. Carpaneto A. Cerrano C. Bavestrello G. Giovine M. Bruzzone S. Guida L. Franco L. Usai C. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 14859-14864Crossref PubMed Scopus (98) Google Scholar). ABA in from cells and by a and to the ABA by and on of cell and of ABA (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). by or by or as of ABA on from RIN-m and INS-1 we the glucose of insulin release in RIN-m and INS-1 cells. In glucose or glucose insulin secretion by RIN-m or higher to that in In the of in inducing insulin release higher in by ANOVA, in LG, HG, and In INS-1 cells, insulin secretion in or in and to that in by ANOVA, in LG, HG, and In the of glucose in the insulin secretion from RIN-m cells by ABA to release in LG, with of the hormone as as by ANOVA, insulin secretion by ABA in between insulin release in and ABA in LG, by ABA stimulate insulin release from RIN-m cells in in secretion to by ABA in similar by to that in a high at ABA with at ABA also insulin secretion at high glucose concentrations, in a for ABA between and by ANOVA, between insulin release in and ABA in by at ABA concentration insulin release in higher in with the at the ABA concentration by in INS-1 cells, ABA insulin secretion in as well as in to release in ABA, or to release in ABA, to in RIN-m, of the hormone as as by ANOVA, insulin secretion by ABA in between insulin release at and ABA in LG, by ABA but stimulated insulin release from INS-1 cells in to ABA, as well as in ABA ABA at effect at glucose investigated whether ABA also insulin secretion in the of In RIN-m cells in KRH, ABA insulin secretion and also insulin secretion in ABA and in insulin release from RIN-m in with on the [Ca2+]i increase in human granulocytes (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). The that shown to the ABA signaling pathway in granulocytes (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google for their to insulin secretion from RIN-m cells in with insulin release The also insulin the cAMP 8-Br-cAMP, an of PKA, stimulated insulin secretion The ADP-ribosyl cyclase and the cADPR and insulin release and The role of an intracellular calcium increase in the insulin release by the of insulin release in the of the intracellular calcium results indicate of a PTX-sensitive complex, cAMP, PKA, and cADPR in the signaling pathway triggered by ABA and leading to insulin release in RIN-m cells. The signal transduction pathway shown to functional activation of human granulocytes (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). of ABA on from and obtained on the rat insulinoma cell to explore the effect of ABA on murine pancreatic islets. with ABA for stimulated insulin release from murine pancreatic in a as low as of the hormone insulin release in LG, and as as of the the in of insulin as by a increase of the we the of and glucose-stimulated insulin release in murine pancreatic glucose a response ABA at and at for and ABA, but at for and ABA by Stimulation by ABA of insulin release from the rat insulinoma cell and from murine pancreatic to explore the effect of the hormone on human pancreatic β cells. and from the of ABA, insulin secretion in The effect of ABA at as higher to increase insulin release The at similar in cells with ABA or with and by Stimulation of insulin secretion by HG, with that by and at of to in murine islets. The insulin secretion in or by of human with or with respectively as on RIN-m cells stimulated insulin as S. J. Biol. Chem. Full Text PDF PubMed Google Scholar), with an higher at at similar to with ABA results indicate that human and murine to nanomolar ABA with an insulin secretion similar to that triggered by and that a PTX-sensitive G protein and cADPR are involved in the human ABA signal transduction ABA in RIN-m and of insulin secretion from RIN-m cells by of the and and by the suggested of the second messengers cADPR and cAMP in ABA Thus, the intracellular of cAMP and of cADPR in RIN-m cells following exposure to The in the and in the of the The higher in RIN-m with the with cells, as also in M. C. 2006; PubMed Scopus Google and in INS-1 cells Diabetes. 2006; PubMed Scopus Google Scholar); the of increase of ABA similar in with a increase of the of RIN-m cells with PTX, in the of the the [cAMP]i, as in 2003; PubMed Scopus Google with the increase with ABA the also in INS-1 cells, from a of to cells in the of by ABA as as of the ABA the to a increase to The in RIN-m cells of ABA, with the increase in at also an increase of the at that activation of to overproduction of cADPR in RIN-m cells, as in cells S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus (51) Google Scholar, K.C. 2005; PubMed Scopus Google Scholar, S. Moreschi I. Guida L. Usai C. Zocchi E. De Flora A. J. 2006; PubMed Scopus Google Scholar, 5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). we the effect of ABA on the ADPRC activity for cADPR of ADPRC activity on cells, as ADPRC activity from of of protein RIN-m to protein of of RIN-m cells with ABA by to in RIN-m, ABA an increase of the and of the also in human islets. The in the of the the of ABA, with with the increase also in human of increase of with ABA and similar for ABA between and as well as for and of human with for the increase a role for a PTX-sensitive G protein in human insulin secretion The cADPR overproduction that activation to an increase of the in human islets. the in human for in with in with in rat S. M. A. S. I. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google and with the role for cADPR in glucose-stimulated insulin secretion S. Science. PubMed Scopus Google Scholar). to the effect on RIN-m cells, exposure to ABA stimulated ADPRC activity in human islets, from a of of protein to and of protein and of respectively by of CD38 in RIN-m cells and in human by analysis of cell with an MoAb, human and rat CD38 Flora A. Guida L. Franco L. Zocchi E. M. Usai C. C. E. G. M. J. PubMed Scopus Google Scholar). The of rat CD38 higher with the human protein as C. Bruzzone S. Zocchi E. E. U. De Flora A. M. J. 2001; PubMed Scopus (108) Google Scholar), and of CD38 higher in human with insulinoma cells The of CD38 in RIN-m and in β cells by activation by an increase of the in human the possible phosphorylation of CD38 following exposure of to ABA Indeed, of with ABA the phosphorylation of CD38 by and and respectively ABA from and Cell shown in and indicate that rat and human pancreatic β cells to ABA with a insulin secretion and with a of glucose-induced insulin whether ABA be produced by pancreatic β cells in response to human in the of or and the ABA in cell and by The intracellular ABA concentration in for in with and a increase of ABA in the results obtained on RIN-m the intracellular ABA concentration in cells to for and ABA in also ABA release from INS-1 cells, with a increase of the ABA in the with in of The that rat insulinoma cell release ABA with HG, to human islets, that ABA release be to pancreatic β cells. human cells murine pancreatic cell release ABA in the that glucose-induced ABA release from human is because of cell in the human The that glucose pancreatic cells to release ABA, in increases insulin secretion may a mechanism and insulin release in response to The results that ABA insulin secretion by pancreatic β cells. The that ABA potentiates glucose-induced insulin release and and insulin secretion in rat insulinoma cells and human pancreatic the that the effect of ABA is by cells cells, inflammatory cells, or cells the ABA on RIN-m cells and on human β cells through the signaling sequentially involving a PTX-sensitive G protein and cAMP overproduction A and CD38 phosphorylation and activation and increase of the and The signaling cascade is activated by ABA in human granulocytes (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). of RIN-m cells with the intracellular Ca2+ the insulin release Ca2+ the insulin as insulin release in the of intracellular Ca2+ J. 2005; PubMed Scopus Google Scholar). Thus, by of insulin release that the effect of ABA on insulin secretion is on the increase of the [Ca2+]i, similar to the of functional activities in granulocytes (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google Scholar). The intracellular Ca2+ mobilizer cADPR (6Lee H.C. Walseth T.F. Bratt G.T. Hayes R.N. Clapper D.L. J. Biol. Chem. 1989; 264: 1608-1615Abstract Full Text PDF PubMed Google Scholar, 7Lee H.C. Cyclic ADP-Ribose and NAADP: Structures, Metabolism and Functions. Kluwer Academic Publishers, Norwell, MA2002: 1-21Crossref Google is for the insulin as the cADPR and the insulin release in RIN-m cells also the insulin release from human of a role of cADPR in the insulin release the to an the between the and glucose-stimulated Ca2+ signaling suggested by the effect of ABA and glucose on insulin release The that and the insulin release in RIN-m cells may suggest of of intracellular Ca2+ increase related to cADPR and for of the insulin increase of the in RIN-m cells at the and and and investigated following of ABA the most intracellular Ca2+ mobilizer H.C. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), recently shown to be involved in glucose-stimulated [Ca2+]i rise in the pancreatic β cell cells R. A. Curr. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). in the following ABA of RIN-m and human a role for in the insulin release be In the by and on the insulin release in RIN-m cells a role for the pathway in the ABA signaling ABA is the of a hormone sequentially second cAMP and cADPR, to be involved in insulin release from pancreatic cells (13Charles M.A. Fanska R. Schmid F.G. Forsham P.H. Grodsky G.M. Science. 1973; 179: 569-571Crossref PubMed Scopus (131) Google Scholar, PubMed Scopus Google Scholar, Curr. Opin. 2006; Google Scholar, S. Science. PubMed Scopus Google Scholar, 17Islam M.S. Diabetes. 2002; 51: 1299-1309Crossref PubMed Scopus (85) Google Scholar). This may for the of glucose-induced insulin release by the physiological role of ABA in insulin ABA release from human and rat insulinoma cells in response to may a insulin secretion. The that of insulin secretion by ABA that with glucose and that autocrine ABA may glucose-induced insulin secretion in β cells. R. J. Clin. 2007; Full Text Full Text PDF PubMed Scopus Google that ABA glucose in high the a effect of ABA on insulin secretion. that ABA insulin secretion and potentiates glucose-induced insulin are with Because ABA has been shown to be released also by activated human granulocytes (5Bruzzone S. Moreschi I. Usai C. Guida L. Damonte G. Salis A. Scarfì S. Millo E. De Flora A. Zocchi E. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 5759-5764Crossref PubMed Scopus (160) Google and monocytes De and A. as an Scholar), paracrine of ABA may also play a role in of insulin secretion under conditions of or inflammation. the be whether ABA may as a or as an of insulin conditions of acute physical hyperglycemia may autocrine ABA release from pancreatic β cells, insulin secretion and glucose and effects A. Curr. Opin. Clin. 2007; PubMed Scopus Google Scholar). conditions of of β cells by ABA released from inflammatory cells may in an insulin eventually leading to insulin A. A. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L. A. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, C. FEBS PubMed Scopus Google Scholar, Biol. PubMed Scopus Google Scholar). The in plasma is De and A. as an and nanomolar of ABA insulin secretion and suggest a possible role for ABA in the physiology as well as in the dysregulation of human insulin secretion. by the S. through the for for are to for INS-1 cells.