{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:33:52Z","timestamp":1792017232388,"version":"4.4.0"},"reference-count":50,"publisher":"American Diabetes Association","issue":"1","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":3958,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,1,1]]},"abstract":"<jats:sec><jats:title>OBJECTIVE<\/jats:title><jats:p>The physiologic significance of the nitric oxide (NO)\/cGMP signaling pathway in islets is unclear. We hypothesized that cGMP-dependent protein kinase type I (cGKI) is directly involved in the secretion of islet hormones and glucose homeostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESEARCH DESIGN AND METHODS<\/jats:title><jats:p>Gene-targeted mice that lack cGKI in islets (conventional cGKI mutants and cGKI\u03b1 and I\u03b2 rescue mice [\u03b1\/\u03b2RM] that express cGKI only in smooth muscle) were studied in comparison to control (CTR) mice. cGKI expression was mapped in the endocrine pancreas by Western blot, immuno-histochemistry, and islet-specific recombination analysis. Insulin, glucagon secretion, and cytosolic Ca2+ ([Ca2+]i) were assayed by radioimmunoassay and FURA-2 measurements, respectively. Serum levels of islet hormones were analyzed at fasting and upon glucose challenge (2 g\/kg) in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Immunohistochemistry showed that cGKI is present in \u03b1- but not in \u03b2-cells in islets of Langerhans. Mice that lack \u03b1-cell cGKI had significantly elevated fasting glucose and glucagon levels, whereas serum insulin levels were unchanged. High glucose concentrations strongly suppressed the glucagon release in CTR mice, but had only a moderate effect on islets that lacked cGKI. 8-Br-cGMP reduced stimulated [Ca2+]i levels and glucagon release rates of CTR islets at 0.5 mmol\/l glucose, but was without effect on [Ca2+]i or hormone release in cGKI-deficient islets.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>We propose that cGKI modulates glucagon release by suppression of [Ca2+]i in \u03b1-cells.<\/jats:p><\/jats:sec>","DOI":"10.2337\/db10-0595","type":"journal-article","created":{"date-parts":[[2010,10,27]],"date-time":"2010-10-27T00:49:25Z","timestamp":1288140565000},"page":"148-156","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":23,"title":["Cyclic GMP Kinase I Modulates Glucagon Release From Pancreatic \u03b1-Cells"],"prefix":"10.2337","volume":"60","author":[{"given":"Veronika","family":"Leiss","sequence":"first","affiliation":[{"name":"FOR 923, Technische Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany, and Center for Integrated Protein Science, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany;"},{"name":"Institut f\u00fcr Pharmakologie und Toxikologie, Abteilung Pharmakologie und Experimentelle Therapie, Universit\u00e4tsklinikum T\u00fcbingen, T\u00fcbingen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Friebe","sequence":"additional","affiliation":[{"name":"Lehrstuhl f\u00fcr Physiologie I, Julius-Maximilians Universit\u00e4t W\u00fcrzburg, W\u00fcrzburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Welling","sequence":"additional","affiliation":[{"name":"FOR 923, Technische Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany, and Center for Integrated Protein Science, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany;"},{"name":"Institut f\u00fcr Pharmakologie und Toxikologie, Technische Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Hofmann","sequence":"additional","affiliation":[{"name":"FOR 923, Technische Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany, and Center for Integrated Protein Science, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Lukowski","sequence":"additional","affiliation":[{"name":"FOR 923, Technische Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany, and Center for Integrated Protein Science, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, M\u00fcnchen, Germany;"},{"name":"Institut f\u00fcr Pharmazie, Abteilung Pharmakologie, Toxikologie und Klinische Pharmazie, Universit\u00e4t T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2010,10,26]]},"reference":[{"key":"2022031210521912900_B1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1210\/er.2006-0007","article-title":"\u03b1-cells of the endocrine pancreas: 35 years of research but the enigma remains","volume":"28","author":"Gromada","year":"2007","journal-title":"Endocr Rev"},{"key":"2022031210521912900_B2","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1210\/en.2005-1249","article-title":"Insulin regulates islet \u03b1-cell function by reducing KATP channel sensitivity to adenosine 5\u2032-triphosphate inhibition","volume":"147","author":"Leung","year":"2006","journal-title":"Endocrinology"},{"key":"2022031210521912900_B3","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.2337\/diabetes.54.6.1789","article-title":"Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic \u03b1-cells","volume":"54","author":"Ravier","year":"2005","journal-title":"Diabetes"},{"key":"2022031210521912900_B4","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/341233a0","article-title":"Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels","volume":"341","author":"Rorsman","year":"1989","journal-title":"Nature"},{"key":"2022031210521912900_B5","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/j.1469-7793.2001.00519.x","article-title":"Somatostatin inhibits exocytosis in rat pancreatic \u03b1-cells by G(i2)-dependent activation of calcineurin and depriming of secretory granules","volume":"535","author":"Gromada","year":"2001","journal-title":"J Physiol"},{"key":"2022031210521912900_B6","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1007\/s00125-006-0511-1","article-title":"Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic \u03b1 cells","volume":"50","author":"Vieira","year":"2007","journal-title":"Diabetologia"},{"key":"2022031210521912900_B7","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s001250050906","article-title":"The early phase of glucose-stimulated insulin secretion requires nitric oxide","volume":"41","author":"Spinas","year":"1998","journal-title":"Diabetologia"},{"key":"2022031210521912900_B8","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0014-2999(92)90568-O","article-title":"Inhibition of islet nitric oxide synthase increases arginine-induced insulin release","volume":"229","author":"Panagiotidis","year":"1992","journal-title":"Eur J Pharmacol"},{"key":"2022031210521912900_B9","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1007\/s001250051256","article-title":"Morphological evidence for the existence of nitric oxide and carbon monoxide pathways in the rat islets of Langerhans: an immunocytochemical and confocal microscopical study","volume":"42","author":"Alm","year":"1999","journal-title":"Diabetologia"},{"key":"2022031210521912900_B10","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1126\/science.1371193","article-title":"Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides","volume":"255","author":"Schmidt","year":"1992","journal-title":"Science"},{"key":"2022031210521912900_B11","doi-asserted-by":"crossref","first-page":"C1634","DOI":"10.1152\/ajpcell.1996.270.6.C1634","article-title":"Islet constitutive nitric oxide synthase: biochemical determination and regulatory function","volume":"270","author":"Salehi","year":"1996","journal-title":"Am J Physiol"},{"key":"2022031210521912900_B12","doi-asserted-by":"crossref","first-page":"C296","DOI":"10.1152\/ajpcell.00537.2001","article-title":"Role of nitric oxide synthase isoforms in glucose-stimulated insulin release","volume":"283","author":"Henningsson","year":"2002","journal-title":"Am J Physiol Cell Physiol"},{"key":"2022031210521912900_B13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1677\/joe.0.1630039","article-title":"Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice","volume":"163","author":"Akesson","year":"1999","journal-title":"J Endocrinol"},{"key":"2022031210521912900_B14","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1007\/BF02221676","article-title":"Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans","volume":"35","author":"Jones","year":"1992","journal-title":"Diabetologia"},{"issue":"Pt 1","key":"2022031210521912900_B15","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1042\/bj2870229","article-title":"Nitric oxide and cyclic GMP formation induced by interleukin 1 \u03b2 in islets of Langerhans. Evidence for an effector role of nitric oxide in islet dysfunction","volume":"287","author":"Corbett","year":"1992","journal-title":"Biochem J"},{"key":"2022031210521912900_B16","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/978-3-642-57077-3_21","article-title":"Nitric oxide in the immunopathogenesis of type 1 diabetes","volume":"143","author":"Burkart","year":"2000","journal-title":"Handb Exp Pharmacol"},{"issue":"Pt 2","key":"2022031210521912900_B17","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/j.1469-7793.1999.463ac.x","article-title":"Influence of nitric oxide modulators on cholinergically stimulated hormone release from mouse islets","volume":"515","author":"Akesson","year":"1999","journal-title":"J Physiol"},{"key":"2022031210521912900_B18","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.2337\/diabetes.53.6.1488","article-title":"Regulation of \u03b1-cell function by the \u03b2-cell in isolated human and rat islets deprived of glucose: the \u201cswitch-off\u201d hypothesis","volume":"53","author":"Hope","year":"2004","journal-title":"Diabetes"},{"key":"2022031210521912900_B19","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1172\/JCI27657","article-title":"Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system","volume":"116","author":"Mergia","year":"2006","journal-title":"J Clin Invest"},{"key":"2022031210521912900_B20","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1210\/endo-129-6-3043","article-title":"L-arginine stimulates cyclic guanosine 3\u2032,5\u2032-monophosphate formation in rat islets of Langerhans and RINm5F insulinoma cells: evidence for L-arginine:nitric oxide synthase","volume":"129","author":"Laychock","year":"1991","journal-title":"Endocrinology"},{"key":"2022031210521912900_B21","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0167-4889(93)90220-J","article-title":"Sodium nitroprusside inhibits glucose-induced insulin release by activating ATP-sensitive K+ channels","volume":"1175","author":"Antoine","year":"1993","journal-title":"Biochim Biophys Acta"},{"key":"2022031210521912900_B22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00015.2005","article-title":"Function of cGMP-dependent protein kinases as revealed by gene deletion","volume":"86","author":"Hofmann","year":"2006","journal-title":"Physiol Rev"},{"key":"2022031210521912900_B23","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1093\/emboj\/17.11.3045","article-title":"Defective smooth muscle regulation in cGMP kinase I-deficient mice","volume":"17","author":"Pfeifer","year":"1998","journal-title":"Embo J"},{"key":"2022031210521912900_B24","doi-asserted-by":"crossref","first-page":"5646","DOI":"10.1073\/pnas.1001360107","article-title":"Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes","volume":"107","author":"Lukowski","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031210521912900_B25","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1161\/CIRCRESAHA.107.154351","article-title":"Rescue of cGMP kinase I knockout mice by smooth muscle specific expression of either isozyme","volume":"101","author":"Weber","year":"2007","journal-title":"Circ Res"},{"key":"2022031210521912900_B26","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1242\/dev.127.11.2317","article-title":"Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages","volume":"127","author":"Herrera","year":"2000","journal-title":"Development"},{"key":"2022031210521912900_B27","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1074\/jbc.274.1.305","article-title":"Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic \u03b2 cell-specific gene knock-outs using Cre recombinase","volume":"274","author":"Postic","year":"1999","journal-title":"J Biol Chem"},{"key":"2022031210521912900_B28","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1161\/hh0102.103222","article-title":"cGMP-dependent protein kinase I mediates the negative inotropic effect of cGMP in the murine myocardium","volume":"90","author":"Wegener","year":"2002","journal-title":"Circ Res"},{"key":"2022031210521912900_B29","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1113\/jphysiol.2005.102368","article-title":"Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells","volume":"572","author":"Vignali","year":"2006","journal-title":"J Physiol"},{"key":"2022031210521912900_B30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.febslet.2004.08.030","article-title":"Distribution of IRAG and cGKI-isoforms in murine tissues","volume":"575","author":"Geiselhoringer","year":"2004","journal-title":"FEBS Lett"},{"key":"2022031210521912900_B31","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.1210\/en.2010-0119","article-title":"The atrial natriuretic peptide and guanylyl cyclase-A system modulates pancreatic \u03b2-cell function","volume":"151","author":"Ropero","year":"2010","journal-title":"Endocrinology"},{"key":"2022031210521912900_B32","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0031-6997(24)01457-1","article-title":"Guanylyl cyclases and signaling by cyclic GMP","volume":"52","author":"Lucas","year":"2000","journal-title":"Pharmacol Rev"},{"key":"2022031210521912900_B33","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.2337\/db06-0080","article-title":"Paradoxical stimulation of glucagon secretion by high glucose concentrations","volume":"55","author":"Salehi","year":"2006","journal-title":"Diabetes"},{"key":"2022031210521912900_B34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1034\/j.1600-0773.2003.920102.x","article-title":"Mechanisms of exocytosis in insulin-secreting B-cells and glucagon-secreting A-cells","volume":"92","author":"Barg","year":"2003","journal-title":"Pharmacol Toxicol"},{"key":"2022031210521912900_B35","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1016\/j.febslet.2007.07.068","article-title":"The GluCre-ROSA26EYFP mouse: a new model for easy identification of living pancreatic \u03b1-cells","volume":"581","author":"Quoix","year":"2007","journal-title":"FEBS Lett"},{"key":"2022031210521912900_B36","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/0006-291X(90)90882-N","article-title":"Secretagogue-induced oscillations of cytoplasmic Ca2+ in single \u03b2 and \u03b1-cells obtained from pancreatic islets by fluorescence-activated cell sorting","volume":"166","author":"Wang","year":"1990","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031210521912900_B37","doi-asserted-by":"crossref","first-page":"4861","DOI":"10.1210\/en.2005-0800","article-title":"Glucose stimulates glucagon release in single rat \u03b1-cells by mechanisms that mirror the stimulus-secretion coupling in \u03b2-cells","volume":"146","author":"Olsen","year":"2005","journal-title":"Endocrinology"},{"key":"2022031210521912900_B38","doi-asserted-by":"crossref","first-page":"14389","DOI":"10.1074\/jbc.M109.069195","article-title":"Glucose suppression of glucagon secretion: metabolic and calcium responses from \u03b1-cells in intact mouse pancreatic islets","volume":"285","author":"Le Marchand","year":"2010","journal-title":"J Biol Chem"},{"key":"2022031210521912900_B39","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/0196-9781(96)00152-0","article-title":"Atrial natriuretic peptide (ANP)-induced inhibition of glucagon secretion: mechanism of action in isolated rat pancreatic islets","volume":"17","author":"Verspohl","year":"1996","journal-title":"Peptides"},{"key":"2022031210521912900_B40","first-page":"E579","article-title":"ANF inhibits glucose-stimulated insulin secretion in mouse and rat","volume":"255","author":"Ahren","year":"1988","journal-title":"Am J Physiol"},{"key":"2022031210521912900_B41","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/BF00399087","article-title":"Interleukin-1 beta effects on cyclic GMP and cyclic AMP in cultured rat islets of Langerhans-arginine-dependence and relationship to insulin secretion","volume":"36","author":"Green","year":"1993","journal-title":"Diabetologia"},{"key":"2022031210521912900_B42","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1476-5381.1995.tb13225.x","article-title":"Influence of nitric oxide synthase inhibition, nitric oxide and hydroperoxide on insulin release induced by various secretagogues","volume":"114","author":"Panagiotidis","year":"1995","journal-title":"Br J Pharmacol"},{"key":"2022031210521912900_B43","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0024-3205(02)01608-9","article-title":"Inhibition by nitric oxide of Ca(2+) responses in rat pancreatic \u03b1-cells","volume":"71","author":"Sugino","year":"2002","journal-title":"Life Sci"},{"key":"2022031210521912900_B44","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s00424-008-0447-z","article-title":"Dual regulation of the ATP-sensitive potassium channel by activation of cGMP-dependent protein kinase","volume":"456","author":"Chai","year":"2008","journal-title":"Pflugers Arch"},{"key":"2022031210521912900_B45","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/j.1469-7793.2000.00509.x","article-title":"Regulation of glucagon release in mouse cells by KATP channels and inactivation of TTX-sensitive Na+ channels","volume":"528","author":"Gopel","year":"2000","journal-title":"J Physiol"},{"key":"2022031210521912900_B46","doi-asserted-by":"crossref","first-page":"e143","DOI":"10.1371\/journal.pbio.0050143","article-title":"A K ATP channel-dependent pathway within \u03b1 cells regulates glucagon release from both rodent and human islets of Langerhans","volume":"5","author":"MacDonald","year":"2007","journal-title":"PLoS Biol"},{"key":"2022031210521912900_B47","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1210\/mend.16.3.0794","article-title":"A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas","volume":"16","author":"Ropero","year":"2002","journal-title":"Mol Endocrinol"},{"key":"2022031210521912900_B48","doi-asserted-by":"crossref","first-page":"3844","DOI":"10.1093\/emboj\/cdg389","article-title":"Impaired insulin secretion and glucose tolerance in \u03b2 cell-selective Ca(v)1.2 Ca2+ channel null mice","volume":"22","author":"Schulla","year":"2003","journal-title":"Embo J"},{"key":"2022031210521912900_B49","doi-asserted-by":"crossref","first-page":"14202","DOI":"10.1523\/JNEUROSCI.2216-08.2008","article-title":"Signaling through cGMP-dependent protein kinase I in the amygdala is critical for auditory-cued fear memory and long-term potentiation","volume":"28","author":"Paul","year":"2008","journal-title":"J Neurosci"},{"key":"2022031210521912900_B50","doi-asserted-by":"crossref","first-page":"ra78","DOI":"10.1126\/scisignal.2000511","article-title":"Protein kinase G controls brown fat cell differentiation and mitochondrial biogenesis","volume":"2","author":"Haas","year":"2009","journal-title":"Sci Signal"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/60\/1\/148\/400909\/zdb00111000148.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/60\/1\/148\/400909\/zdb00111000148.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T08:29:02Z","timestamp":1740644942000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/60\/1\/148\/15267\/Cyclic-GMP-Kinase-I-Modulates-Glucagon-Release"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,10,26]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2010,10,26]]},"published-print":{"date-parts":[[2011,1,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db10-0595","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,10,26]]}}}