{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T20:05:34Z","timestamp":1793736334942,"version":"4.6.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"7798","license":[{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2020,3,12]]},"DOI":"10.1038\/s41586-020-2074-6","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T12:02:21Z","timestamp":1583323341000},"page":"279-283","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":193,"title":["Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis"],"prefix":"10.1038","volume":"579","author":[{"given":"Rachel J.","family":"Perry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8187-2753","authenticated-orcid":false,"given":"Mateus T.","family":"Guerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5046-3578","authenticated-orcid":false,"given":"Allison L.","family":"Brill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh","family":"Goedeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali R.","family":"Nasiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviva","family":"Rabin-Court","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongliang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Dufour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-Man","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina M.","family":"Butrico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshia","family":"Toussaint","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Nozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Cline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kitt Falk","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Nathanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9657-9704","authenticated-orcid":false,"given":"Barbara E.","family":"Ehrlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1529-5668","authenticated-orcid":false,"given":"Gerald I.","family":"Shulman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,4]]},"reference":[{"key":"2074_CR1","doi-asserted-by":"publisher","first-page":"500","DOI":"10.2337\/diab.15.7.500","volume":"15","author":"RH Unger","year":"1966","unstructured":"Unger, R. H. Glucoregulatory hormones in health and disease. A teleologic model. Diabetes15, 500\u2013506 (1966).","journal-title":"Diabetes"},{"key":"2074_CR2","first-page":"265","volume":"17","author":"RH Unger","year":"1971","unstructured":"Unger, R. H. Pancreatic glucagon in health and disease. Adv. Intern. Med. 17, 265\u2013288 (1971).","journal-title":"Adv. Intern. Med."},{"key":"2074_CR3","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1152\/physrev.00025.2016","volume":"97","author":"TD M\u00fcller","year":"2017","unstructured":"M\u00fcller, T. D., Finan, B., Clemmensen, C., DiMarchi, R. D. & Tsch\u00f6p, M. H. The new biology and pharmacology of glucagon. Physiol. Rev. 97, 721\u2013766 (2017).","journal-title":"Physiol. Rev."},{"key":"2074_CR4","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1007\/BF00400461","volume":"37","author":"CL Brand","year":"1994","unstructured":"Brand, C. L. et al. Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia37, 985\u2013993 (1994).","journal-title":"Diabetologia"},{"key":"2074_CR5","doi-asserted-by":"publisher","first-page":"2843","DOI":"10.2337\/db06-0222","volume":"55","author":"H S\u00f8rensen","year":"2006","unstructured":"S\u00f8rensen, H. et al. Immunoneutralization of endogenous glucagon reduces hepatic glucose output and improves long-term glycemic control in diabetic ob\/ob mice. Diabetes55, 2843\u20132848 (2006).","journal-title":"Diabetes"},{"key":"2074_CR6","doi-asserted-by":"publisher","first-page":"2753","DOI":"10.1073\/pnas.1621069114","volume":"114","author":"H Okamoto","year":"2017","unstructured":"Okamoto, H. et al. Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice. Proc. Natl Acad. Sci. USA114, 2753\u20132758 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2074_CR7","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.2337\/dc15-1643","volume":"39","author":"CM Kazda","year":"2016","unstructured":"Kazda, C. M. et al. Evaluation of efficacy and safety of the glucagon receptor antagonist LY2409021 in patients with type 2 diabetes: 12- and 24-week phase 2 studies. Diabetes Care39, 1241\u20131249 (2016).","journal-title":"Diabetes Care"},{"key":"2074_CR8","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1111\/dom.12958","volume":"19","author":"CB Guzman","year":"2017","unstructured":"Guzman, C. B. et al. Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes Obes. Metab. 19, 1521\u20131528 (2017).","journal-title":"Diabetes Obes. Metab."},{"key":"2074_CR9","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1111\/dom.12904","volume":"19","author":"CM Kazda","year":"2017","unstructured":"Kazda, C. M. et al. Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes. Diabetes Obes. Metab. 19, 1071\u20131077 (2017).","journal-title":"Diabetes Obes. Metab."},{"key":"2074_CR10","doi-asserted-by":"publisher","first-page":"410","DOI":"10.2337\/diabetes.53.2.410","volume":"53","author":"Y Liang","year":"2004","unstructured":"Liang, Y. et al. Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db\/db mice. Diabetes 53, 410\u2013417 (2004).","journal-title":"Diabetes"},{"key":"2074_CR11","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1172\/JCI20911","volume":"113","author":"KW Sloop","year":"2004","unstructured":"Sloop, K. W. et al. Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J. Clin. Invest. 113, 1571\u20131581 (2004).","journal-title":"J. Clin. Invest."},{"key":"2074_CR12","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1111\/dom.12735","volume":"18","author":"SJ Henderson","year":"2016","unstructured":"Henderson, S. J. et al. Robust anti-obesity and metabolic effects of a dual GLP-1\/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes Obes. Metab. 18, 1176\u20131190 (2016).","journal-title":"Diabetes Obes. Metab."},{"key":"2074_CR13","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.cmet.2012.03.002","volume":"15","author":"L Ozcan","year":"2012","unstructured":"Ozcan, L. et al. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab. 15, 739\u2013751 (2012).","journal-title":"Cell Metab."},{"key":"2074_CR14","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/nature10988","volume":"485","author":"Y Wang","year":"2012","unstructured":"Wang, Y. et al. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature485, 128\u2013132 (2012).","journal-title":"Nature"},{"key":"2074_CR15","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/j.cmet.2013.10.011","volume":"18","author":"L Ozcan","year":"2013","unstructured":"Ozcan, L. et al. Activation of calcium\/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metab. 18, 803\u2013815 (2013).","journal-title":"Cell Metab."},{"key":"2074_CR16","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1002\/hep4.1012","volume":"1","author":"CN Feriod","year":"2017","unstructured":"Feriod, C. N. et al. Hepatic inositol 1,4,5 trisphosphate receptor type 1 mediates fatty liver. Hepatol. Commun. 1, 23\u201335 (2017).","journal-title":"Hepatol. Commun."},{"key":"2074_CR17","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.cell.2017.12.001","volume":"172","author":"RJ Perry","year":"2018","unstructured":"Perry, R. J. et al. Leptin mediates a glucose-fatty acid cycle to maintain glucose homeostasis in starvation. Cell172, 234\u2013248 (2018).","journal-title":"Cell"},{"key":"2074_CR18","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.cell.2015.01.012","volume":"160","author":"RJ Perry","year":"2015","unstructured":"Perry, R. J. et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell160, 745\u2013758 (2015).","journal-title":"Cell"},{"key":"2074_CR19","doi-asserted-by":"publisher","first-page":"4278","DOI":"10.1210\/en.2012-1127","volume":"153","author":"J Pagnon","year":"2012","unstructured":"Pagnon, J. et al. Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase. Endocrinology153, 4278\u20134289 (2012).","journal-title":"Endocrinology"},{"key":"2074_CR20","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1172\/JCI107537","volume":"53","author":"JE Liljenquist","year":"1974","unstructured":"Liljenquist, J. E. et al. Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men. J. Clin. Invest. 53, 190\u2013197 (1974).","journal-title":"J. Clin. Invest."},{"key":"2074_CR21","first-page":"2085","volume":"86","author":"CH Gravholt","year":"2001","unstructured":"Gravholt, C. H., M\u00f8ller, N., Jensen, M. D., Christiansen, J. S. & Schmitz, O. Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis. J. Clin. Endocrinol. Metab. 86, 2085\u20132089 (2001).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2074_CR22","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1210\/jcem-70-2-410","volume":"70","author":"MS Wu","year":"1990","unstructured":"Wu, M. S. et al. Does glucagon increase plasma free fatty acid concentration in humans with normal glucose tolerance? J. Clin. Endocrinol. Metab. 70, 410\u2013416 (1990).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2074_CR23","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1210\/jcem-72-2-308","volume":"72","author":"MD Jensen","year":"1991","unstructured":"Jensen, M. D., Heiling, V. J. & Miles, J. M. Effects of glucagon on free fatty acid metabolism in humans. J. Clin. Endocrinol. Metab. 72, 308\u2013315 (1991).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2074_CR24","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/BF01076578","volume":"149-150","author":"BJ Nichols","year":"1995","unstructured":"Nichols, B. J. & Denton, R. M. Towards the molecular basis for the regulation of mitochondrial dehydrogenases by calcium ions. Mol. Cell. Biochem. 149-150, 203\u2013212 (1995).","journal-title":"Mol. Cell. Biochem."},{"key":"2074_CR25","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1172\/JCI63967","volume":"122","author":"DW Foster","year":"2012","unstructured":"Foster, D. W. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J. Clin. Invest. 122, 1958\u20131959 (2012).","journal-title":"J. Clin. Invest."},{"key":"2074_CR26","doi-asserted-by":"publisher","first-page":"55","DOI":"10.4103\/0974-7788.59946","volume":"1","author":"P Kadam","year":"2010","unstructured":"Kadam, P. & Bhalerao, S. Sample size calculation. Int. J. Ayurveda Res. 1, 55\u201357 (2010).","journal-title":"Int. J. Ayurveda Res."},{"key":"2074_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01143-w","volume":"8","author":"RJ Perry","year":"2017","unstructured":"Perry, R. J. et al. Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA). Nat. Commun. 8, 798 (2017).","journal-title":"Nat. Commun."},{"key":"2074_CR28","doi-asserted-by":"publisher","first-page":"4671","DOI":"10.1172\/JCI129913","volume":"129","author":"KF Petersen","year":"2019","unstructured":"Petersen, K. F., Dufour, S., Cline, G. W. & Shulman, G. I. Regulation of hepatic mitochondrial oxidation by glucose\u2013alanine cycling during starvation in humans. J. Clin. Invest. 129, 4671\u20134675 (2019).","journal-title":"J. Clin. Invest."},{"key":"2074_CR29","doi-asserted-by":"publisher","first-page":"12161","DOI":"10.1074\/jbc.M116.720631","volume":"291","author":"RJ Perry","year":"2016","unstructured":"Perry, R. J. et al. Propionate increases hepatic pyruvate cycling and anaplerosis and alters mitochondrial metabolism. J. Biol. Chem. 291, 12161\u201312170 (2016).","journal-title":"J. Biol. Chem."},{"key":"2074_CR30","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1172\/JCI88477","volume":"127","author":"RJ Perry","year":"2017","unstructured":"Perry, R. J. et al. Mechanism for leptin\u2019s acute insulin-independent effect to reverse diabetic ketoacidosis. J. Clin. Invest. 127, 657\u2013669 (2017).","journal-title":"J. Clin. Invest."},{"key":"2074_CR31","doi-asserted-by":"publisher","first-page":"50230","DOI":"10.1074\/jbc.M200958200","volume":"277","author":"C Yu","year":"2002","unstructured":"Yu, C. et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277, 50230\u201350236 (2002).","journal-title":"J. Biol. Chem."},{"key":"2074_CR32","doi-asserted-by":"publisher","first-page":"890","DOI":"10.2337\/db10-1328","volume":"60","author":"MJ Jurczak","year":"2011","unstructured":"Jurczak, M. J. et al. SGLT2 deletion improves glucose homeostasis and preserves pancreatic \u03b2-cell function. Diabetes60, 890\u2013898 (2011).","journal-title":"Diabetes"},{"key":"2074_CR33","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1139\/o59-099","volume":"37","author":"EG Bligh","year":"1959","unstructured":"Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911\u2013917 (1959).","journal-title":"Can. J. Biochem. Physiol."},{"key":"2074_CR34","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1194\/jlr.M054080","volume":"56","author":"JP Camporez","year":"2015","unstructured":"Camporez, J. P. et al. ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content. J. Lipid Res. 56, 526\u2013536 (2015).","journal-title":"J. Lipid Res."},{"key":"2074_CR35","doi-asserted-by":"publisher","first-page":"3099","DOI":"10.1210\/en.2013-1191","volume":"154","author":"JP Camporez","year":"2013","unstructured":"Camporez, J. P. et al. Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. Endocrinology154, 3099\u20133109 (2013).","journal-title":"Endocrinology"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41586-020-2074-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41586-020-2074-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41586-020-2074-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T18:03:30Z","timestamp":1684605810000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-020-2074-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,4]]},"references-count":35,"journal-issue":{"issue":"7798","published-print":{"date-parts":[[2020,3,12]]}},"alternative-id":["2074"],"URL":"https:\/\/doi.org\/10.1038\/s41586-020-2074-6","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,4]]},"assertion":[{"value":"24 February 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 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"}}]}}