{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:31:19Z","timestamp":1788546679339,"version":"build-2803163510"},"reference-count":33,"publisher":"The Endocrine Society","issue":"7","license":[{"start":{"date-parts":[[2022,5,7]],"date-time":"2022-05-07T00:00:00Z","timestamp":1651881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["323706"],"award-info":[{"award-number":["323706"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017726","name":"Diabetes Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017726","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Vitamin D deficiency [ie, low plasma 25-hydroxyvitamin D (25-OH-D)] associates with the prevalence of metabolic diseases including type 1 diabetes; however, the molecular mechanisms are incompletely understood. Recent studies have indicated that both fasting and metabolic diseases suppress the cytochrome P450 (CYP) 2R1, the major hepatic vitamin D 25-hydroxylase. We specifically studied the effect of a mouse model of type 1 diabetes on the regulation of Cyp2r1 and vitamin D status. We show that streptozotocin-induced diabetes in mice suppresses the expression of the Cyp2r1 in the liver. While insulin therapy normalized the blood glucose levels in the diabetic mice, it did not rescue the diabetes-induced suppression of Cyp2r1. Similar regulation of Cyp2r1 was observed also in the kidney. Plasma 25-OH-D level was not decreased and was, in contrast, higher after 4 and 8 weeks of diabetes. Furthermore, the vitamin D 25-hydroxylase activity was increased in the livers of the diabetic mice, suggesting compensation of the Cyp2r1 repression by other vitamin D 25-hydroxylase enzymes. Cyp27b1, the vitamin D 1\u03b1-hydroxylase, expression in the kidney and the plasma 1\u03b1,25-dihydroxyvitamin D level were higher after 4 weeks of diabetes, while both were normalized after 13 weeks. In summary, these results indicate that in the mouse model of type 1 diabetes suppression of hepatic Cyp2r1 expression does not result in reduced hepatic vitamin D 25-hydroxylase activity and vitamin D deficiency. This may be due to induction of other vitamin D 25-hydroxylase enzymes in response to diabetes.<\/jats:p>","DOI":"10.1210\/endocr\/bqac060","type":"journal-article","created":{"date-parts":[[2022,5,7]],"date-time":"2022-05-07T12:55:31Z","timestamp":1651928131000},"source":"Crossref","is-referenced-by-count":6,"title":["Streptozotocin-induced Diabetes Represses Hepatic CYP2R1 Expression but Induces Vitamin D 25-Hydroxylation in Male Mice"],"prefix":"10.1210","volume":"163","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0805-1040","authenticated-orcid":false,"given":"Mahmoud-Sobhy","family":"Elkhwanky","sequence":"first","affiliation":[{"name":"Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu , Oulu , Finland"},{"name":"Medical Research Center Oulu, Oulu University Hospital and University of Oulu , Oulu , Finland"},{"name":"Biocenter Oulu, University of Oulu , Oulu , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0327-3496","authenticated-orcid":false,"given":"Outi","family":"Kummu","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu , Oulu , Finland"},{"name":"Medical Research Center Oulu, Oulu University Hospital and University of Oulu , Oulu , Finland"},{"name":"Biocenter Oulu, University of Oulu , Oulu , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5048-4363","authenticated-orcid":false,"given":"Jukka","family":"Hakkola","sequence":"additional","affiliation":[{"name":"Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu , Oulu , Finland"},{"name":"Medical Research Center Oulu, Oulu University Hospital and University of Oulu , Oulu , Finland"},{"name":"Biocenter Oulu, University of Oulu , Oulu , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2022,5,7]]},"reference":[{"issue":"1","key":"2022053122380908500_CIT0001","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1152\/physrev.00014.2015","article-title":"Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects","volume":"96","author":"Christakos","year":"2016","journal-title":"Physiol Rev."},{"issue":"39","key":"2022053122380908500_CIT0002","doi-asserted-by":"crossref","first-page":"15650","DOI":"10.1073\/pnas.1315006110","article-title":"CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo","volume":"110","author":"Zhu","year":"2013","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"7","key":"2022053122380908500_CIT0003","doi-asserted-by":"crossref","first-page":"E1005","DOI":"10.1210\/jc.2015-1746","article-title":"CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency","volume":"100","author":"Thacher","year":"2015","journal-title":"J Clin Endocrinol Metab."},{"issue":"9","key":"2022053122380908500_CIT0004","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1002\/jbmr.3181","article-title":"Vitamin D-dependent rickets type 1B (25-hydroxylase deficiency): a rare condition or a misdiagnosed condition?","volume":"32","author":"Molin","year":"2017","journal-title":"J Bone Miner Res."},{"issue":"9736","key":"2022053122380908500_CIT0005","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S0140-6736(10)60588-0","article-title":"Common genetic determinants of vitamin D insufficiency: a genome-wide association study","volume":"376","author":"Wang","year":"2010","journal-title":"Lancet."},{"issue":"2","key":"2022053122380908500_CIT0006","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.ajhg.2017.06.014","article-title":"Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis","volume":"101","author":"Manousaki","year":"2017","journal-title":"Am J Hum Genet."},{"issue":"2","key":"2022053122380908500_CIT0007","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s11154-017-9424-1","article-title":"The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention","volume":"18","author":"Holick","year":"2017","journal-title":"Rev Endocr Metab Disord."},{"issue":"9","key":"2022053122380908500_CIT0008","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1210\/jc.2014-1714","article-title":"25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype","volume":"99","author":"Jones","year":"2014","journal-title":"J Clin Endocrinol Metab."},{"issue":"11","key":"2022053122380908500_CIT0009","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1002\/jbmr.3884","article-title":"Vitamin D metabolism revised: fall of dogmas","volume":"34","author":"Bouillon","year":"2019","journal-title":"J Bone Miner Res."},{"issue":"5","key":"2022053122380908500_CIT0010","doi-asserted-by":"crossref","first-page":"918","DOI":"10.2337\/db18-1050","article-title":"Fasting-induced transcription factors repress vitamin D bioactivation, a mechanism for vitamin D deficiency in diabetes","volume":"68","author":"Aatsinki","year":"2019","journal-title":"Diabetes."},{"issue":"11","key":"2022053122380908500_CIT0011","doi-asserted-by":"crossref","DOI":"10.1002\/jbm4.10397","article-title":"Obesity represses CYP2R1, the vitamin D 25-hydroxylase, in the liver and extrahepatic tissues","volume":"4","author":"Elkhwanky","year":"2020","journal-title":"JBMR Plus."},{"issue":"6","key":"2022053122380908500_CIT0012","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/jbmr.3686","article-title":"Obesity decreases hepatic 25-hydroxylase activity causing low serum 25-hydroxyvitamin D","volume":"34","author":"Roizen","year":"2019","journal-title":"J Bone Miner Res."},{"issue":"11","key":"2022053122380908500_CIT0013","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1016\/0006-2952(90)90092-Y","article-title":"Immunochemical detection of human liver cytochrome P450 forms related to phenobarbital-inducible forms in the mouse","volume":"40","author":"Raunio","year":"1990","journal-title":"Biochem Pharmacol."},{"key":"2022053122380908500_CIT0014","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cbi.2015.11.032","article-title":"Challenges and issues with streptozotocin-induced diabetes\u2014a clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics","volume":"244","author":"Goyal","year":"2016","journal-title":"Chem Biol Interact."},{"issue":"8","key":"2022053122380908500_CIT0015","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1210\/en.2017-03028","article-title":"Decreased serum 25-hydroxyvitamin D in aging male mice is associated with reduced hepatic Cyp2r1 abundance","volume":"159","author":"Roizen","year":"2018","journal-title":"Endocrinology."},{"issue":"1","key":"2022053122380908500_CIT0016","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.abb.2012.01.013","article-title":"Vitamin D 25-hydroxylase\u2014four decades of searching, are we there yet?","volume":"523","author":"Zhu","year":"2012","journal-title":"Arch Biochem Biophys."},{"issue":"1","key":"2022053122380908500_CIT0017","first-page":"271","article-title":"The first genome-wide view of vitamin D receptor locations and their mechanistic implications","volume":"32","author":"Carlberg","year":"2012","journal-title":"Anticancer Res."},{"issue":"7","key":"2022053122380908500_CIT0018","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1016\/j.bbadis.2017.04.004","article-title":"Expression patterns of nuclear receptors in parenchymal and non-parenchymal mouse liver cells and their modulation in cholestasis","volume":"1863","author":"Gonzalez-Sanchez","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis."},{"issue":"9","key":"2022053122380908500_CIT0019","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/j.1463-1326.2010.01211.x","article-title":"Vitamin D and increasing incidence of type 1 diabetes-evidence for an association?","volume":"12","author":"Hypp\u00f6nen","year":"2010","journal-title":"Diabetes Obes Metab."},{"issue":"5","key":"2022053122380908500_CIT0020","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2337\/dbi19-0026","article-title":"The peripheral peril: injected insulin induces insulin insensitivity in type 1 diabetes","volume":"69","author":"Gregory","year":"2020","journal-title":"Diabetes."},{"key":"2022053122380908500_CIT0021","doi-asserted-by":"crossref","DOI":"10.1155\/2018\/2494016","article-title":"Effects of cholecalciferol on key components of vitamin D-endo\/para\/autocrine system in experimental type 1 diabetes","author":"Mazanova","year":"2018","journal-title":"Int J Endocrinol"},{"issue":"2","key":"2022053122380908500_CIT0022","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1210\/endo-113-2-790","article-title":"Vitamin D metabolism in the chronic streptozotocin-induced diabetic rat","volume":"113","author":"Hough","year":"1983","journal-title":"Endocrinology."},{"issue":"9","key":"2022053122380908500_CIT0023","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1097\/FPC.0b013e32810f2e58","article-title":"Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues","volume":"17","author":"Bi\u00e8che","year":"2007","journal-title":"Pharmacogenet Genomics."},{"issue":"2","key":"2022053122380908500_CIT0024","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1210\/jc.2004-0966","article-title":"CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis","volume":"90","author":"Gupta","year":"2005","journal-title":"J Clin Endocrinol Metab."},{"issue":"2","key":"2022053122380908500_CIT0025","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/hep.23025","article-title":"Constitutive androstane receptor mediates the induction of drug metabolism in mouse models of type 1 diabetes","volume":"50","author":"Dong","year":"2009","journal-title":"Hepatology."},{"key":"2022053122380908500_CIT0026","doi-asserted-by":"crossref","first-page":"9159","DOI":"10.12659\/MSM.917904","article-title":"Vitamin D3 is transformed into 1,25(OH)2D3 by triggering CYP3A11(CYP3A4) activity and hydrolyzing midazolam","volume":"25","author":"Zhu","year":"2019","journal-title":"Med Sci Monit."},{"issue":"12","key":"2022053122380908500_CIT0027","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1111\/bph.15433","article-title":"Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism","volume":"178","author":"Karpale","year":"2021","journal-title":"Br J Pharmacol."},{"key":"2022053122380908500_CIT0028","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.biochi.2015.10.024","article-title":"Adipocyte lipolysis and insulin resistance","volume":"125","author":"Morigny","year":"2016","journal-title":"Biochimie."},{"issue":"1","key":"2022053122380908500_CIT0029","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/jbmr.1735","article-title":"Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers","volume":"28","author":"Carpenter","year":"2013","journal-title":"J Bone Miner Res."},{"issue":"6","key":"2022053122380908500_CIT0030","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1210\/endo-116-6-2483","article-title":"1,25-Dihydroxyvitamin D and vitamin D-binding protein are both decreased in streptozotocin-diabetic rats","volume":"116","author":"Nyomba","year":"1985","journal-title":"Endocrinology"},{"issue":"8","key":"2022053122380908500_CIT0031","doi-asserted-by":"crossref","first-page":"911","DOI":"10.2337\/diab.35.8.911","article-title":"Vitamin D metabolites and their binding protein in adult diabetic patients","volume":"35","author":"Nyomba","year":"1986","journal-title":"Diabetes."},{"issue":"1","key":"2022053122380908500_CIT0032","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1210\/endo-107-1-300","article-title":"Experimental diabetes in the rat causes an insulin-reversible decrease in renal 25-hydroxyvitamin D3-1 alpha-hydroxylase activity","volume":"107","author":"Spencer","year":"1980","journal-title":"Endocrinology."},{"issue":"1","key":"2022053122380908500_CIT0033","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3164\/jcbn.19-79","article-title":"Association of increased renal Cyp24a1 gene expression with low plasma 1,25-dihydroxyvitamin D levels in rats with streptozotocin-induced diabetes","volume":"66","author":"Tajiri","year":"2020","journal-title":"J Clin Biochem Nutr."}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqac060\/43615218\/bqac060.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/163\/7\/bqac060\/43892852\/bqac060.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/163\/7\/bqac060\/43892852\/bqac060.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T22:39:13Z","timestamp":1654036753000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqac060\/6582260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,7]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,7,1]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqac060","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,7,1]]},"published":{"date-parts":[[2022,5,7]]},"article-number":"bqac060"}}