{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T23:55:47Z","timestamp":1790553347127,"version":"4.1.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T00:00:00Z","timestamp":1581984000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T00:00:00Z","timestamp":1581984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000062","name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K01DK102492"],"award-info":[{"award-number":["K01DK102492"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK110324"],"award-info":[{"award-number":["R01DK110324"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK113103"],"award-info":[{"award-number":["R01DK113103"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases"},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX004715"],"award-info":[{"award-number":["BX004715"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX001880"],"award-info":[{"award-number":["BX001880"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases"},{"DOI":"10.13039\/100000049","name":"U.S. Department of Health & Human Services | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG062328"],"award-info":[{"award-number":["R01AG062328"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic \u03b2-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release\n                    <jats:italic>ex vivo<\/jats:italic>\n                    . GLP-1 is exclusively produced in approximately 50% of \u03b1-cells in lean mouse islets and 70% of \u03b1-cells in human islets, suggesting a paracrine \u03b1 to \u03b2-cell signaling through the \u03b2-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human \u03b2-cell function.\n                  <\/jats:p>","DOI":"10.1038\/s41598-020-59799-2","type":"journal-article","created":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T06:04:16Z","timestamp":1582005856000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Intra-islet GLP-1, but not CCK, is necessary for \u03b2-cell function in mouse and human islets"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7338-9262","authenticated-orcid":false,"given":"Arnaldo Henrique","family":"de Souza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanjot Kaur","family":"Yadev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel T.","family":"Saghafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carly R.","family":"Kibbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7356-4876","authenticated-orcid":false,"given":"Amelia K.","family":"Linnemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Merrins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn Belt","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,18]]},"reference":[{"key":"59799_CR1","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.cmet.2018.01.015","volume":"27","author":"R Rodriguez-Diaz","year":"2018","unstructured":"Rodriguez-Diaz, R. et al. Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point. Cell Metab. 27, 549\u2013558.e544, https:\/\/doi.org\/10.1016\/j.cmet.2018.01.015 (2018).","journal-title":"Cell Metab."},{"key":"59799_CR2","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1172\/JCI7456","volume":"105","author":"Y Nie","year":"2000","unstructured":"Nie, Y. et al. Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. J. Clin. Invest. 105, 955\u2013965, https:\/\/doi.org\/10.1172\/JCI7456 (2000).","journal-title":"J. Clin. Invest."},{"key":"59799_CR3","doi-asserted-by":"publisher","first-page":"3262","DOI":"10.1007\/s00125-012-2716-9","volume":"55","author":"P Marchetti","year":"2012","unstructured":"Marchetti, P. et al. A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia 55, 3262\u20133272, https:\/\/doi.org\/10.1007\/s00125-012-2716-9 (2012).","journal-title":"Diabetologia"},{"key":"59799_CR4","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1210\/me.2015-1030","volume":"29","author":"AK Linnemann","year":"2015","unstructured":"Linnemann, A. K. et al. Glucagon-Like Peptide-1 Regulates Cholecystokinin Production in \u03b2-Cells to Protect From Apoptosis. Mol. Endocrinol. 29, 978\u2013987, https:\/\/doi.org\/10.1210\/me.2015-1030 (2015).","journal-title":"Mol. Endocrinol."},{"key":"59799_CR5","doi-asserted-by":"publisher","first-page":"3577","DOI":"10.1210\/en.2010-0233","volume":"151","author":"JA Lavine","year":"2010","unstructured":"Lavine, J. A. et al. Cholecystokinin is up-regulated in obese mouse islets and expands beta-cell mass by increasing beta-cell survival. Endocrinol. 151, 3577\u20133588, https:\/\/doi.org\/10.1210\/en.2010-0233 (2010).","journal-title":"Endocrinol."},{"key":"59799_CR6","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1053\/j.gastro.2007.03.054","volume":"132","author":"LL Baggio","year":"2007","unstructured":"Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131\u20132157, https:\/\/doi.org\/10.1053\/j.gastro.2007.03.054 (2007).","journal-title":"Gastroenterology"},{"key":"59799_CR7","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1097\/MED.0b013e32834eb77d","volume":"19","author":"GJ Dockray","year":"2012","unstructured":"Dockray, G. J. Cholecystokinin. Curr. Opin. Endocrinol. Diabetes Obes. 19, 8\u201312, https:\/\/doi.org\/10.1097\/MED.0b013e32834eb77d (2012).","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"59799_CR8","doi-asserted-by":"publisher","first-page":"2927","DOI":"10.1113\/jphysiol.2014.270850","volume":"592","author":"GJ Dockray","year":"2014","unstructured":"Dockray, G. J. Gastrointestinal hormones and the dialogue between gut and brain. J. Physiol. 592, 2927\u20132941, https:\/\/doi.org\/10.1113\/jphysiol.2014.270850 (2014).","journal-title":"J. Physiol."},{"issue":"Suppl 1","key":"59799_CR9","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/jdi.12465","volume":"7","author":"AK Linnemann","year":"2016","unstructured":"Linnemann, A. K. & Davis, D. B. Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity. J. Diabetes Investig. 7(Suppl 1), 44\u201349, https:\/\/doi.org\/10.1111\/jdi.12465 (2016).","journal-title":"J. Diabetes Investig."},{"key":"59799_CR10","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1016\/j.cmet.2014.04.005","volume":"19","author":"EP Smith","year":"2014","unstructured":"Smith, E. P. et al. The role of \u03b2 cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs. Cell Metab. 19, 1050\u20131057, https:\/\/doi.org\/10.1016\/j.cmet.2014.04.005 (2014).","journal-title":"Cell Metab."},{"key":"59799_CR11","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.cmet.2009.07.005","volume":"10","author":"GW Cheung","year":"2009","unstructured":"Cheung, G. W., Kokorovic, A., Lam, C. K., Chari, M. & Lam, T. K. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 10, 99\u2013109, https:\/\/doi.org\/10.1016\/j.cmet.2009.07.005 (2009).","journal-title":"Cell Metab."},{"key":"59799_CR12","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1016\/j.jdiacomp.2016.05.016","volume":"30","author":"GE Fava","year":"2016","unstructured":"Fava, G. E., Dong, E. W. & Wu, H. Intra-islet glucagon-like peptide 1. J. Diabetes Complications 30, 1651\u20131658, https:\/\/doi.org\/10.1016\/j.jdiacomp.2016.05.016 (2016).","journal-title":"J. Diabetes Complications"},{"key":"59799_CR13","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1038\/nm.2513","volume":"17","author":"H Ellingsgaard","year":"2011","unstructured":"Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481\u20131489, https:\/\/doi.org\/10.1038\/nm.2513 (2011).","journal-title":"Nat. Med."},{"key":"59799_CR14","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1007\/s00125-011-2080-1","volume":"54","author":"AM Hansen","year":"2011","unstructured":"Hansen, A. M. et al. Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus\u2013an adaptive response to hyperglycaemia? Diabetologia 54, 1379\u20131387, https:\/\/doi.org\/10.1007\/s00125-011-2080-1 (2011).","journal-title":"Diabetologia"},{"key":"59799_CR15","doi-asserted-by":"publisher","first-page":"149","DOI":"10.4161\/isl.2.3.11396","volume":"2","author":"G Kilimnik","year":"2010","unstructured":"Kilimnik, G., Kim, A., Steiner, D. F., Friedman, T. C. & Hara, M. Intraislet production of GLP-1 by activation of prohormone convertase 1\/3 in pancreatic \u03b1-cells in mouse models of \u00df-cell regeneration. Islets 2, 149\u2013155 (2010).","journal-title":"Islets"},{"key":"59799_CR16","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1016\/j.cmet.2019.08.009","volume":"30","author":"Y Song","year":"2019","unstructured":"Song, Y. et al. Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice. Cell Metab. 30, 976\u2013986.e973, https:\/\/doi.org\/10.1016\/j.cmet.2019.08.009 (2019).","journal-title":"Cell Metab."},{"key":"59799_CR17","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1172\/JCI1349","volume":"101","author":"J Schirra","year":"1998","unstructured":"Schirra, J. et al. Exendin(9\u201339)amide is an antagonist of glucagon-like peptide-1(7\u201336)amide in humans. J. Clin. Invest. 101, 1421\u20131430, https:\/\/doi.org\/10.1172\/JCI1349 (1998).","journal-title":"J. Clin. Invest."},{"key":"59799_CR18","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1210\/endo.139.1.5691","volume":"139","author":"K Shimizu","year":"1998","unstructured":"Shimizu, K. et al. Evidence for the existence of CCK-producing cells in rat pancreatic islets. Endocrinol. 139, 389\u2013396, https:\/\/doi.org\/10.1210\/endo.139.1.5691 (1998).","journal-title":"Endocrinol."},{"key":"59799_CR19","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1677\/joe.0.1690233","volume":"169","author":"G Liu","year":"2001","unstructured":"Liu, G. et al. Cholecystokinin expression in the developing and regenerating pancreas and intestine. J. Endocrinol. 169, 233\u2013240 (2001).","journal-title":"J. Endocrinol."},{"key":"59799_CR20","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1152\/physrev.00014.2005","volume":"86","author":"M Dufresne","year":"2006","unstructured":"Dufresne, M., Seva, C. & Fourmy, D. Cholecystokinin and gastrin receptors. Physiol. Rev. 86, 805\u2013847, https:\/\/doi.org\/10.1152\/physrev.00014.2005 (2006).","journal-title":"Physiol. Rev."},{"key":"59799_CR21","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1006\/bbrc.1993.1538","volume":"192","author":"T Fridolf","year":"1993","unstructured":"Fridolf, T., Karlsson, S. & Ahr\u00e9n, B. Role of extracellular Na+ on CCK-8-induced insulin secretion. Biochem. Biophys. Res. Commun. 192, 1162\u20131168, https:\/\/doi.org\/10.1006\/bbrc.1993.1538 (1993).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"59799_CR22","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1093\/clinchem\/44.5.991","volume":"44","author":"JF Rehfeld","year":"1998","unstructured":"Rehfeld, J. F. Accurate measurement of cholecystokinin in plasma. Clin. Chem. 44, 991\u20131001 (1998).","journal-title":"Clin. Chem."},{"key":"59799_CR23","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1126\/science.6546809","volume":"224","author":"LR Watkins","year":"1984","unstructured":"Watkins, L. R., Kinscheck, I. B. & Mayer, D. J. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Sci. 224, 395\u2013396 (1984).","journal-title":"Sci."},{"key":"59799_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/00006676-199201000-00001","volume":"7","author":"C Niederau","year":"1992","unstructured":"Niederau, C. et al. Effects of cholecystokinin receptor blockade on circulating concentrations of glucose, insulin, C-peptide, and pancreatic polypeptide after various meals in healthy human volunteers. Pancreas 7, 1\u201310 (1992).","journal-title":"Pancreas"},{"key":"59799_CR25","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1210\/jcem.76.2.8432795","volume":"76","author":"RA Rushakoff","year":"1993","unstructured":"Rushakoff, R. A. et al. Reduced postprandial cholecystokinin (CCK) secretion in patients with noninsulin-dependent diabetes mellitus: evidence for a role for CCK in regulating postprandial hyperglycemia. J. Clin. Endocrinol. Metab. 76, 489\u2013493, https:\/\/doi.org\/10.1210\/jcem.76.2.8432795 (1993).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"59799_CR26","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1210\/jcem.85.3.6431","volume":"85","author":"B Ahr\u00e9n","year":"2000","unstructured":"Ahr\u00e9n, B., Holst, J. J. & Efendic, S. Antidiabetogenic action of cholecystokinin-8 in type 2 diabetes. J. Clin. Endocrinol. Metab. 85, 1043\u20131048, https:\/\/doi.org\/10.1210\/jcem.85.3.6431 (2000).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"59799_CR27","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1007\/s00125-012-2654-6","volume":"55","author":"N Irwin","year":"2012","unstructured":"Irwin, N. et al. Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity\/diabetes. Diabetologia 55, 2747\u20132758, https:\/\/doi.org\/10.1007\/s00125-012-2654-6 (2012).","journal-title":"Diabetologia"},{"key":"59799_CR28","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1097\/MPA.0000000000000983","volume":"47","author":"D Khan","year":"2018","unstructured":"Khan, D., Vasu, S., Moffett, R. C., Irwin, N. & Flatt, P. R. Expression of Gastrin Family Peptides in Pancreatic Islets and Their Role in \u03b2-Cell Function and Survival. Pancreas 47, 190\u2013199, https:\/\/doi.org\/10.1097\/MPA.0000000000000983 (2018).","journal-title":"Pancreas"},{"key":"59799_CR29","doi-asserted-by":"publisher","first-page":"R1303","DOI":"10.1152\/ajpregu.00050.2002","volume":"283","author":"SM Simasko","year":"2002","unstructured":"Simasko, S. M., Wiens, J., Karpiel, A., Covasa, M. & Ritter, R. C. Cholecystokinin increases cytosolic calcium in a subpopulation of cultured vagal afferent neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol 283, R1303\u20131313, https:\/\/doi.org\/10.1152\/ajpregu.00050.2002 (2002).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol"},{"key":"59799_CR30","doi-asserted-by":"publisher","first-page":"38251","DOI":"10.1074\/jbc.M110.125864","volume":"285","author":"F Cosker","year":"2010","unstructured":"Cosker, F. et al. The ecto-enzyme CD38 is a nicotinic acid adenine dinucleotide phosphate (NAADP) synthase that couples receptor activation to Ca2+ mobilization from lysosomes in pancreatic acinar cells. J. Biol. Chem. 285, 38251\u201338259, https:\/\/doi.org\/10.1074\/jbc.M110.125864 (2010).","journal-title":"J. Biol. Chem."},{"key":"59799_CR31","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.ceca.2014.09.001","volume":"56","author":"P Gilon","year":"2014","unstructured":"Gilon, P., Chae, H. Y., Rutter, G. A. & Ravier, M. A. Calcium signaling in pancreatic \u03b2-cells in health and in Type 2 diabetes. Cell Calcium 56, 340\u2013361, https:\/\/doi.org\/10.1016\/j.ceca.2014.09.001 (2014).","journal-title":"Cell Calcium"},{"key":"59799_CR32","doi-asserted-by":"publisher","first-page":"2346","DOI":"10.1210\/en.2005-0396","volume":"147","author":"S Thyssen","year":"2006","unstructured":"Thyssen, S., Arany, E. & Hill, D. J. Ontogeny of regeneration of beta-cells in the neonatal rat after treatment with streptozotocin. Endocrinol. 147, 2346\u20132356, https:\/\/doi.org\/10.1210\/en.2005-0396 (2006).","journal-title":"Endocrinol."},{"key":"59799_CR33","first-page":"94","volume":"22","author":"DF Steiner","year":"1996","unstructured":"Steiner, D. F. et al. The role of prohormone convertases in insulin biosynthesis: evidence for inherited defects in their action in man and experimental animals. Diabetes Metab. 22, 94\u2013104 (1996).","journal-title":"Diabetes Metab."},{"key":"59799_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-620","volume":"15","author":"C Benner","year":"2014","unstructured":"Benner, C. et al. The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15, 620, https:\/\/doi.org\/10.1186\/1471-2164-15-620 (2014).","journal-title":"BMC Genomics"},{"key":"59799_CR35","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1038\/nm.2371","volume":"17","author":"R Rodriguez-Diaz","year":"2011","unstructured":"Rodriguez-Diaz, R. et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat. Med. 17, 888\u2013892, https:\/\/doi.org\/10.1038\/nm.2371 (2011).","journal-title":"Nat. Med."},{"key":"59799_CR36","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.celrep.2018.10.018","volume":"25","author":"B Svendsen","year":"2018","unstructured":"Svendsen, B. et al. Insulin Secretion Depends on Intra-islet Glucagon Signaling. Cell Rep. 25, 1127\u20131134.e1122, https:\/\/doi.org\/10.1016\/j.celrep.2018.10.018 (2018).","journal-title":"Cell Rep."},{"key":"59799_CR37","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1124\/jpet.107.120006","volume":"322","author":"R Jorgensen","year":"2007","unstructured":"Jorgensen, R., Kubale, V., Vrecl, M., Schwartz, T. W. & Elling, C. E. Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s). J. Pharmacol. Exp. Ther. 322, 148\u2013154, https:\/\/doi.org\/10.1124\/jpet.107.120006 (2007).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"59799_CR38","doi-asserted-by":"publisher","unstructured":"Capozzi, M. E. et al. \u03b2 Cell tone is defined by proglucagon peptides through cAMP signaling. JCI Insight 4, https:\/\/doi.org\/10.1172\/jci.insight.126742 (2019).","DOI":"10.1172\/jci.insight.126742"},{"key":"59799_CR39","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1210\/endo-119-2-616","volume":"119","author":"WS Zawalich","year":"1986","unstructured":"Zawalich, W. S., Cote, S. B. & Diaz, V. A. Influence of cholecystokinin on insulin output from isolated perifused pancreatic islets. Endocrinol. 119, 616\u2013621, https:\/\/doi.org\/10.1210\/endo-119-2-616 (1986).","journal-title":"Endocrinol."},{"key":"59799_CR40","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/dom.12079","volume":"15","author":"N Irwin","year":"2013","unstructured":"Irwin, N., Hunter, K., Montgomery, I. A. & Flatt, P. R. Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat-fed mice. Diabetes Obes. Metab. 15, 650\u2013659, https:\/\/doi.org\/10.1111\/dom.12079 (2013).","journal-title":"Diabetes Obes. Metab."},{"key":"59799_CR41","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/bf00277407","volume":"31","author":"J Reimers","year":"1988","unstructured":"Reimers, J. et al. Lack of insulinotropic effect of endogenous and exogenous cholecystokinin in man. Diabetologia 31, 271\u2013280, https:\/\/doi.org\/10.1007\/bf00277407 (1988).","journal-title":"Diabetologia"},{"key":"59799_CR42","doi-asserted-by":"publisher","first-page":"E949","DOI":"10.1152\/ajpendo.1995.268.5.E949","volume":"268","author":"P Fieseler","year":"1995","unstructured":"Fieseler, P. et al. Physiological augmentation of amino acid-induced insulin secretion by GIP and GLP-I but not by CCK-8. Am. J. Physiol. 268, E949\u2013955, https:\/\/doi.org\/10.1152\/ajpendo.1995.268.5.E949 (1995).","journal-title":"Am. J. Physiol."},{"key":"59799_CR43","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/284033a0","volume":"284","author":"JF Rehfeld","year":"1980","unstructured":"Rehfeld, J. F. et al. Neural regulation of pancreatic hormone secretion by the C-terminal tetrapeptide of CCK. Nat. 284, 33\u201338, https:\/\/doi.org\/10.1038\/284033a0 (1980).","journal-title":"Nat."},{"key":"59799_CR44","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1210\/jcem-65-3-395","volume":"65","author":"RJ Rushakoff","year":"1987","unstructured":"Rushakoff, R. J., Goldfine, I. D., Carter, J. D. & Liddle, R. A. Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans. J. Clin. Endocrinol. Metab. 65, 395\u2013401, https:\/\/doi.org\/10.1210\/jcem-65-3-395 (1987).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"59799_CR45","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1097\/00006676-199005000-00019","volume":"5","author":"HC Fehmann","year":"1990","unstructured":"Fehmann, H. C. et al. Interaction of glucagon-like peptide-1 (7-36)amide and cholecystokinin-8 in the endocrine and exocrine rat pancreas. Pancreas 5, 361\u2013365, https:\/\/doi.org\/10.1097\/00006676-199005000-00019 (1990).","journal-title":"Pancreas"},{"key":"59799_CR46","doi-asserted-by":"publisher","first-page":"E819","DOI":"10.1152\/ajpendo.00159.2015","volume":"309","author":"JA Lavine","year":"2015","unstructured":"Lavine, J. A. et al. Cholecystokinin expression in the \u03b2-cell leads to increased \u03b2-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. Am. J. Physiol. Endocrinol. Metab. 309, E819\u2013828, https:\/\/doi.org\/10.1152\/ajpendo.00159.2015 (2015).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"59799_CR47","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.peptides.2017.09.007","volume":"100","author":"V Pathak","year":"2018","unstructured":"Pathak, V., Flatt, P. R. & Irwin, N. Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes. Peptides 100, 229\u2013235, https:\/\/doi.org\/10.1016\/j.peptides.2017.09.007 (2018).","journal-title":"Peptides"},{"key":"59799_CR48","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1053\/j.gastro.2010.01.049","volume":"138","author":"Y Fujita","year":"2010","unstructured":"Fujita, Y. et al. Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet alpha-cells and promotes insulin secretion. Gastroenterology 138, 1966\u20131975, https:\/\/doi.org\/10.1053\/j.gastro.2010.01.049 (2010).","journal-title":"Gastroenterology"},{"key":"59799_CR49","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.cmet.2017.03.020","volume":"25","author":"JF Habener","year":"2017","unstructured":"Habener, J. F. & Stanojevic, V. Pancreas and Not Gut Mediates the GLP-1-Induced Glucoincretin Effect. Cell Metab. 25, 757\u2013758, https:\/\/doi.org\/10.1016\/j.cmet.2017.03.020 (2017).","journal-title":"Cell Metab."},{"key":"59799_CR50","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.cmet.2017.02.008","volume":"25","author":"AP Chambers","year":"2017","unstructured":"Chambers, A. P. et al. The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice. Cell Metab. 25, 927\u2013934.e923, https:\/\/doi.org\/10.1016\/j.cmet.2017.02.008 (2017).","journal-title":"Cell Metab."},{"key":"59799_CR51","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.1007\/s00125-019-4963-5","volume":"62","author":"CR Hutch","year":"2019","unstructured":"Hutch, C. R. et al. The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice. Diabetologia 62, 1928\u20131937, https:\/\/doi.org\/10.1007\/s00125-019-4963-5 (2019).","journal-title":"Diabetologia"},{"key":"59799_CR52","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.mce.2016.09.022","volume":"439","author":"AH de Souza","year":"2017","unstructured":"de Souza, A. H. et al. NADPH oxidase-2 does not contribute to \u03b2-cell glucotoxicity in cultured pancreatic islets from C57BL\/6J mice. Mol. Cell Endocrinol. 439, 354\u2013362, https:\/\/doi.org\/10.1016\/j.mce.2016.09.022 (2017).","journal-title":"Mol. Cell Endocrinol."},{"key":"59799_CR53","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/s0026-0495(99)90008-2","volume":"48","author":"J van Delft","year":"1999","unstructured":"van Delft, J., Uttenthal, O., Koch, C. & Ghiglione, M. Immunoblockade of endogenous glucagon-like peptide-1 by monoclonal antibodies in conscious rats: effect on the insulin response to intragastric glucose. Metab. 48, 41\u201346, https:\/\/doi.org\/10.1016\/s0026-0495(99)90008-2 (1999).","journal-title":"Metab."},{"key":"59799_CR54","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.mce.2018.01.019","volume":"473","author":"M Bugliani","year":"2018","unstructured":"Bugliani, M. et al. DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes. Mol. Cell Endocrinol. 473, 186\u2013193, https:\/\/doi.org\/10.1016\/j.mce.2018.01.019 (2018).","journal-title":"Mol. Cell Endocrinol."},{"key":"59799_CR55","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1101\/gr.074914.107","volume":"18","author":"MP Keller","year":"2008","unstructured":"Keller, M. P. et al. A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res. 18, 706\u2013716, https:\/\/doi.org\/10.1101\/gr.074914.107 (2008).","journal-title":"Genome Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-59799-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-59799-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-59799-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T01:43:20Z","timestamp":1670291000000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-59799-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,18]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["59799"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-59799-2","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.737402844.793571750","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,18]]},"assertion":[{"value":"25 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2823"}}