{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T16:46:30Z","timestamp":1776703590509,"version":"3.51.2"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23247045"],"award-info":[{"award-number":["23247045"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19500684"],"award-info":[{"award-number":["19500684"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Glucagon dysregulation is a hallmark of type 2 diabetes mellitus (T2DM), yet its early hepatic effects remain unclear. Here, we demonstrate that glucagon-induced gluconeogenesis is markedly enhanced in primary hepatocytes from prediabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a well-established model of human T2DM. Compared to control LETO rats, OLETF hepatocytes showed significantly higher glucagon-stimulated expression of gluconeogenic genes (Pepck, G6pase, and Fbp1) at both mRNA and protein levels, along with elevated glucose production. Notably, mRNA decay analysis revealed prolonged half-lives of gluconeogenic transcripts in OLETF hepatocytes, indicating enhanced mRNA stability as a novel mechanism contributing to increased hepatic glucose output. These findings highlight aberrant glucagon responsiveness and posttranscriptional regulation as potential predisposing factors in genetically susceptible models prior to the onset of overt metabolic abnormality, which may be of interest for preventive or therapeutic strategies for controlling fasting hyperglycemia.<\/jats:p>","DOI":"10.1093\/bbb\/zbaf133","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T11:31:42Z","timestamp":1757417502000},"page":"1680-1686","source":"Crossref","is-referenced-by-count":1,"title":["Augmented glucagon-induced gluconeogenesis in primary hepatocytes from Otsuka Long-Evans Tokushima Fatty rats"],"prefix":"10.1093","volume":"89","author":[{"given":"Miwako","family":"Deguchi","sequence":"first","affiliation":[{"name":"Osaka Metropolitan University Department of Nutrition, Graduate School of Human Life and Ecology, , Osaka ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akemi","family":"Hosoda","sequence":"additional","affiliation":[{"name":"Faculty of Healthcare, Tokyo Healthcare University , Tokyo ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoe","family":"Fukumura","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University Department of Nutrition, Graduate School of Human Life and Ecology, , Osaka ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeru","family":"Saeki","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University Department of Nutrition, Graduate School of Human Life and Ecology, , Osaka ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"DongHo","family":"Kim","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University Department of Nutrition, Graduate School of Human Life and Ecology, , Osaka ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"2025112507222934200_bib1","doi-asserted-by":"publisher","first-page":"e1840","DOI":"10.1002\/wrna.1840","article-title":"Emerging roles of RNA-binding proteins in fatty liver disease","volume":"15","author":"Adesanya","year":"2024","journal-title":"Wiley Interdiscip Rev RNA"},{"key":"2025112507222934200_bib2","doi-asserted-by":"publisher","first-page":"E718","DOI":"10.1152\/ajpendo.00156.2003","article-title":"Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice","volume":"285","author":"Altomonte","year":"2003","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2025112507222934200_bib3","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1007\/BF01212238","article-title":"Abnormalities in hepatic enzyme activities during development of diabetes in db mice","volume":"6","author":"Chang","year":"1970","journal-title":"Diabetologia"},{"key":"2025112507222934200_bib4","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.diabres.2018.02.023","article-title":"IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045","volume":"138","author":"Cho","year":"2018","journal-title":"Diabetes Res Clin Pract"},{"key":"2025112507222934200_bib5","doi-asserted-by":"publisher","first-page":"6648","DOI":"10.3390\/ijms21186648","article-title":"mRNA post-transcriptional regulation by AU-rich element-binding proteins in liver inflammation and cancer","volume":"21","author":"Dolicka","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2025112507222934200_bib6","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1056\/NEJM199205143262003","article-title":"Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus","volume":"326","author":"Gutniak","year":"1992","journal-title":"N Engl J Med"},{"key":"2025112507222934200_bib7","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/ncb1111","article-title":"SREBPs suppress IRS-2-mediated insulin signalling in the liver","volume":"6","author":"Ide","year":"2004","journal-title":"Nat Cell Biol"},{"key":"2025112507222934200_bib8","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1530\/acta.0.1290585","article-title":"Plasma glucagon responses to insulin-induced hypoglycemia and arginine in spontaneous non-insulin-dependent diabetes mellitus (NIDDM) rats, Otsuka Long Evans Tokushima Fatty (OLETF) strain","volume":"129","author":"Ishida","year":"1993","journal-title":"Acta Endocrinol (Copenh)"},{"key":"2025112507222934200_bib9","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/S0021-9258(19)35415-8","article-title":"Stimulation by insulin of glucokinase gene transcription in liver of diabetic rats","volume":"263","author":"Iynedjian","year":"1988","journal-title":"J Biol Chem"},{"key":"2025112507222934200_bib10","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S0168-8227(97)00102-2","article-title":"Alterations of insulin and glucagon secretion from the perfused pancreas before, at the onset and after the development of diabetes in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats","volume":"38","author":"Kanazawa","year":"1997","journal-title":"Diabetes Res Clin Pract"},{"key":"2025112507222934200_bib11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1161\/CIRCRESAHA.107.151621","article-title":"Adiposity and cardiovascular disorders: disturbance of the regulatory system consisting of humoral and neuronal signals","volume":"101","author":"Katagiri","year":"2007","journal-title":"Circ Res"},{"key":"2025112507222934200_bib12","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.2337\/diab.41.11.1422","article-title":"Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima fatty (OLETF) strain","volume":"41","author":"Kawano","year":"1992","journal-title":"Diabetes"},{"key":"2025112507222934200_bib13","doi-asserted-by":"publisher","first-page":"3141","DOI":"10.2337\/db13-1015","article-title":"MicroRNA-29 fine-tunes the expression of key FOXA2-activated lipid metabolism genes and is dysregulated in animal models of insulin resistance and diabetes","volume":"63","author":"Kurtz","year":"2014","journal-title":"Diabetes"},{"key":"2025112507222934200_bib14","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1172\/JCI115997","article-title":"Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study","volume":"90","author":"Magnusson","year":"1992","journal-title":"J Clin Invest"},{"key":"2025112507222934200_bib15","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1056\/NEJM197007162830301","article-title":"Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion","volume":"283","author":"M\u00fcller","year":"1970","journal-title":"N Engl J Med"},{"key":"2025112507222934200_bib16","doi-asserted-by":"publisher","first-page":"12587","DOI":"10.1073\/pnas.0705408104","article-title":"The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome","volume":"104","author":"Petersen","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025112507222934200_bib17","doi-asserted-by":"publisher","first-page":"30028","DOI":"10.1074\/jbc.274.42.30028","article-title":"Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus","volume":"274","author":"Shimomura","year":"1999","journal-title":"J Biol Chem"},{"key":"2025112507222934200_bib18","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/S1097-2765(05)00010-9","article-title":"Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob\/ob mice","volume":"6","author":"Shimomura","year":"2000","journal-title":"Mol Cell"},{"key":"2025112507222934200_bib19","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1507\/endocrj1954.36.65","article-title":"Pathogenesis of hyperglycemia in genetically obese-hyperglycemic rats, wistar fatty: presence of hepatic insulin resistance","volume":"36","author":"Sugiyama","year":"1989","journal-title":"Endocrinol Jpn"},{"key":"2025112507222934200_bib20","doi-asserted-by":"publisher","first-page":"23301","DOI":"10.1074\/jbc.M200964200","article-title":"Phosphoenolpyruvate carboxykinase overexpression selectively attenuates insulin signaling and hepatic insulin sensitivity in transgenic mice","volume":"277","author":"Sun","year":"2002","journal-title":"J Biol Chem"},{"key":"2025112507222934200_bib21","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1177\/193229681000400607","article-title":"The physiology of glucagon","volume":"4","author":"Taborsky","year":"2010","journal-title":"J Diabetes Sci Technol"},{"key":"2025112507222934200_bib22","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1007\/s00125-004-1366-y","article-title":"Genes for systemic vascular complications are differentially expressed in the livers of type 2 diabetic patients","volume":"47","author":"Takamura","year":"2004","journal-title":"Diabetologia"},{"key":"2025112507222934200_bib23","doi-asserted-by":"publisher","first-page":"e1002977","DOI":"10.1371\/journal.pgen.1002977","article-title":"The p38\/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation","volume":"8","author":"Tiedje","year":"2012","journal-title":"PLoS Genet"},{"key":"2025112507222934200_bib24","doi-asserted-by":"publisher","first-page":"31615","DOI":"10.1074\/jbc.273.47.31615","article-title":"Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats","volume":"273","author":"Trinh","year":"1998","journal-title":"J Biol Chem"},{"key":"2025112507222934200_bib25","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1172\/JCI60016","article-title":"Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover","volume":"122","author":"Unger","year":"2012","journal-title":"J Clin Invest"},{"key":"2025112507222934200_bib26","doi-asserted-by":"publisher","first-page":"9151","DOI":"10.1073\/pnas.91.19.9151","article-title":"Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus","volume":"91","author":"Valera","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025112507222934200_bib27","doi-asserted-by":"publisher","first-page":"E1132","DOI":"10.1152\/ajpendo.90552.2008","article-title":"Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver","volume":"295","author":"Visinoni","year":"2008","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2025112507222934200_bib28","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.1074\/jbc.270.6.2729","article-title":"Upstream mechanisms of glycogen synthase activation by insulin and insulin-like growth factor-I. Glycogen synthase activation is antagonized by wortmannin or LY294002 but not by rapamycin or by inhibiting p21ras","volume":"270","author":"Yamamoto-Honda","year":"1995","journal-title":"J Biol Chem"},{"key":"2025112507222934200_bib29","doi-asserted-by":"publisher","first-page":"273","DOI":"10.3390\/biom13020273","article-title":"The epigenetic regulation of RNA N6-methyladenosine methylation in glycolipid metabolism","volume":"13","author":"Yang","year":"2023","journal-title":"Biomolecules"}],"container-title":["Bioscience, Biotechnology, and Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bbb\/advance-article-pdf\/doi\/10.1093\/bbb\/zbaf133\/64236494\/zbaf133.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bbb\/article-pdf\/89\/12\/1680\/64236494\/zbaf133.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bbb\/article-pdf\/89\/12\/1680\/64236494\/zbaf133.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T12:22:52Z","timestamp":1764073372000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bbb\/article\/89\/12\/1680\/8250642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":29,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,9,10]]},"published-print":{"date-parts":[[2025,11,25]]}},"URL":"https:\/\/doi.org\/10.1093\/bbb\/zbaf133","relation":{},"ISSN":["1347-6947"],"issn-type":[{"value":"1347-6947","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,9,10]]}}}