{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:29:22Z","timestamp":1787318962878,"version":"build-2736575974"},"reference-count":71,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"779","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for \u03b1 cell\u2013intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 (\n                    <jats:italic>G6PC2<\/jats:italic>\n                    ) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the\n                    <jats:italic>G6PC2<\/jats:italic>\n                    promoter are located in open chromatin not just in \u03b2 but also in \u03b1 cells and documented allele-specific\n                    <jats:italic>G6PC2<\/jats:italic>\n                    expression of linked variants in human \u03b1 cells. Using \u03b1 cell\u2013specific gene ablation of\n                    <jats:italic>G6pc2<\/jats:italic>\n                    in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid\u2013stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human \u03b1 cells. Collectively, our data demonstrate that\n                    <jats:italic>G6PC2<\/jats:italic>\n                    affects glycemic control via its action in \u03b1 cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adi6148","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T13:58:41Z","timestamp":1735739921000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic \u03b1 cells"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0789-8613","authenticated-orcid":true,"given":"Varun","family":"Bahl","sequence":"first","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Human Pancreas Analysis Program (RRID:SCR_016202); ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8611-2357","authenticated-orcid":true,"given":"Reut","family":"Rifkind","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel."},{"name":"Department of Developmental Biology and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Waite","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Human Pancreas Analysis Program (RRID:SCR_016202); ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zenab","family":"Hamdan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel."},{"name":"Department of Developmental Biology and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine Lee","family":"May","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Human Pancreas Analysis Program (RRID:SCR_016202); ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4110-3714","authenticated-orcid":true,"given":"Elisabetta","family":"Manduchi","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Human Pancreas Analysis Program (RRID:SCR_016202); ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6205-9994","authenticated-orcid":true,"given":"Benjamin F.","family":"Voight","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Human Pancreas Analysis Program (RRID:SCR_016202); ."},{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle Y. Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Human Pancreas Analysis Program (RRID:SCR_016202); ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Tigue","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0783-8782","authenticated-orcid":true,"given":"Nicholas","family":"Manuto","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4711-5000","authenticated-orcid":true,"given":"Benjamin","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2910-2452","authenticated-orcid":true,"given":"Dana","family":"Avrahami","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel."},{"name":"Department of Developmental Biology and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1228-021X","authenticated-orcid":true,"given":"Klaus H.","family":"Kaestner","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Human Pancreas Analysis Program (RRID:SCR_016202); ."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.38.030176.002033"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1677\/JOE-08-0290"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2010.01.026"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(75)92375-2"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2011.01449.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2006-0026"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.39.11.1381"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197007162830301"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03034-0"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-76863-z"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101193"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1530\/JME-20-0031"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1067"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0745"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-2875-3"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.2337\/db10-0389"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1156849"},{"key":"e_1_3_2_19_2","first-page":"2620","article-title":"Variations in the G6PC2\/ABCB11 genomic region are associated with fasting glucose levels","volume":"118","author":"Chen W. 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