{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:13:07Z","timestamp":1768565587627,"version":"3.49.0"},"posted":{"date-parts":[[2023,6,28]]},"group-title":"Endocrinology (including Diabetes Mellitus and Metabolic Disease)","reference-count":59,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>\n                    The body has evolved homeostatic mechanisms to maintain free levels of Ca\n                    <jats:sup>+2<\/jats:sup>\n                    and 1,25-dihydroxyvitamin D [1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Crossover clinical trial studying participants before and after VitD3-supplementation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Setting<\/jats:title>\n                  <jats:p>Community.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] \u226420 ng\/mL).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interventions<\/jats:title>\n                  <jats:p>VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D\u226530 ng\/mL.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D\u226550 ng\/mL and achieved a minimum (\u223c90% suppression) with 25(OH)D&lt;10-20 ng\/mL. The 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\/24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D ratio better predicted modeled 24-hydroxylase activity (\n                    <jats:italic>h<\/jats:italic>\n                    ) (\u03c1=-0.85; p=0.001) compared to total plasma 25(OH)D (\u03c1=0.51; p=0.01) and the 24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\/25(OH)D ratio (\u03c1=0.37; p=0.3).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D. The 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\/24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D ratio provides a useful index of VitD status since it incorporates 24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity \u2013 thereby decreasing the level of 24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D and increasing the 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\/24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D ratio. Thus, an increased 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\/24,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.06.27.23291942","type":"posted-content","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T11:50:13Z","timestamp":1687953013000},"source":"Crossref","is-referenced-by-count":2,"title":["Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism"],"prefix":"10.64898","author":[{"given":"Zhinous Shahidzadeh","family":"Yazdi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth A.","family":"Streeten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary B.","family":"Whitlatch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"May E.","family":"Montasser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber L.","family":"Beitelshees","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7500-7854","authenticated-orcid":false,"given":"Simeon I.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024031105000674000_2023.06.27.23291942v4.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.05.038"},{"key":"2024031105000674000_2023.06.27.23291942v4.2","doi-asserted-by":"crossref","unstructured":"Fleet JC . 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