{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T19:44:54Z","timestamp":1791575094866,"version":"4.3.4"},"reference-count":59,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T00:00:00Z","timestamp":1654214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,9,1]]},"abstract":"<jats:p>With the rising epidemics of obesity and nonalcoholic fatty liver disease (NAFLD) and its downstream consequences including steatohepatitis, cirrhosis, and type 2 diabetes in the U.S. and worldwide, new therapeutic approaches are urgently needed to treat these devastating conditions. Glucagon, known for a century to be a glucose-raising hormone and clearly demonstrated to contribute to fasting and postprandial hyperglycemia in both type 1 and type 2 diabetes, represents an unlikely target to improve health in those with metabolic syndrome. However, recent work from our group and others\u2019 identifies an unexpected role for glucagon as a potential means of treating NAFLD, improving insulin sensitivity, and improving the lipid profile. We propose a unifying, calcium-dependent mechanism for glucagon\u2019s effects both to stimulate hepatic gluconeogenesis and to enhance hepatic mitochondrial oxidation: signaling through the inositol 1,4,5-trisphosphate receptor type 1 (INSP3R1), glucagon activates phospholipase C (PKC)\/protein kinase A (PKA) signaling to enhance adipose triglyceride lipase (ATGL)-dependent intrahepatic lipolysis and, in turn, increase cytosolic gluconeogenesis by allosteric activation of pyruvate carboxylase. Simultaneously in the mitochondria, calcium transferred through mitochondria-associated membranes activates several dehydrogenases in the tricarboxylic acid cycle, correlated with an increase in mitochondrial energy expenditure and reduction in ectopic lipid. This model suggests that short-term, cyclic treatment with glucagon or other INSP3R1 antagonists could hold promise as a means to reset lipid homeostasis in patients with NAFLD.<\/jats:p>","DOI":"10.2337\/dbi22-0003","type":"journal-article","created":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T16:02:42Z","timestamp":1654272162000},"page":"1834-1841","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":18,"title":["Regulation of Hepatic Lipid and Glucose Metabolism by INSP3R1"],"prefix":"10.2337","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0748-8064","authenticated-orcid":false,"given":"Rachel J.","family":"Perry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,6,3]]},"reference":[{"key":"2022081918565852900_B1","first-page":"251","article-title":"The internal secretion of the pancreas","volume":"7","author":"Banting","year":"1922","journal-title":"J Lab Clin Med"},{"key":"2022081918565852900_B2","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0021-9258(18)85474-6","article-title":"Aqueous extracts of pancreas III. 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