{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T13:46:59Z","timestamp":1762004819336},"reference-count":27,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2017,1,2]],"date-time":"2017-01-02T00:00:00Z","timestamp":1483315200000},"content-version":"vor","delay-in-days":160,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,1]]},"abstract":"<jats:sec>\n                  <jats:title>Context:<\/jats:title>\n                  <jats:p>The mechanism of action of metformin remains unclear. Given the regulation of the cortisol-regenerating enzyme 11\u03b2hydroxysteroid dehydrogenase 1 (11\u03b2HSD1) by insulin and the limited efficacy of selective 11\u03b2HSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11\u03b2HSD1 activity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>To determine whether metformin regulates 11\u03b2HSD1 activity in vivo in obese men with and without type 2 diabetes mellitus.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design:<\/jats:title>\n                  <jats:p>Double-blind, randomized, placebo-controlled, crossover study.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Setting:<\/jats:title>\n                  <jats:p>A hospital clinical research facility.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Participants:<\/jats:title>\n                  <jats:p>Eight obese nondiabetic (OND) men and eight obese men with type 2 diabetes (ODM).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Intervention:<\/jats:title>\n                  <jats:p>Participants received 28 days of metformin (1 g twice daily), placebo, or (in the ODM group) gliclazide (80 mg twice daily) in random order. A deuterated cortisol infusion at the end of each phase measured cortisol regeneration by 11\u03b2HSD1. Oral cortisone was given to measure hepatic 11\u03b2HSD1 activity in the ODM group. The effect of metformin on 11\u03b2HSD1 was also assessed in human hepatocytes and Simpson-Golabi-Behmel syndrome adipocytes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Main Outcome Measures:<\/jats:title>\n                  <jats:p>The effect of metformin on whole-body and hepatic 11\u03b2HSD1 activity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>Whole-body 11\u03b2HSD1 activity was approximately 25% higher in the ODM group than the OND group. Metformin increased whole-body cortisol regeneration by 11\u03b2HSD1 in both groups compared with placebo and gliclazide and tended to increase hepatic 11\u03b2HSD1 activity. In vitro, metformin did not increase 11\u03b2HSD1 activity in hepatocytes or adipocytes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>Metformin increases whole-body cortisol generation by 11\u03b2HSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11\u03b2HSD1 inhibitors.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2016-2069","type":"journal-article","created":{"date-parts":[[2016,7,26]],"date-time":"2016-07-26T17:05:38Z","timestamp":1469552738000},"page":"3787-3793","source":"Crossref","is-referenced-by-count":13,"title":["Metformin Increases Cortisol Regeneration by 11\u03b2HSD1 in Obese Men With and Without Type 2 Diabetes Mellitus"],"prefix":"10.1210","volume":"101","author":[{"given":"Anna J.","family":"Anderson","sequence":"first","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Andrew","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie Z.","family":"Homer","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory C.","family":"Jones","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"},{"name":"Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth","family":"Smith","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"},{"name":"Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn E.","family":"Livingstone","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian R.","family":"Walker","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland H.","family":"Stimson","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2016,7,26]]},"reference":[{"key":"2020071614212338500_B1","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.2337\/diabetes.49.12.2063","article-title":"Mechanism by which metformin reduces glucose production in type 2 diabetes","volume":"49","author":"Hundal","year":"2000","journal-title":"Diabetes"},{"key":"2020071614212338500_B2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrendo.2013.256","article-title":"Metformin\u2013mode of action and clinical implications for diabetes and cancer","volume":"10","author":"Pernicova","year":"2014","journal-title":"Nat Rev Endocrinol"},{"key":"2020071614212338500_B3","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1007\/s00125-013-2991-0","article-title":"Molecular mechanism of action of metformin: old or new insights?","volume":"56","author":"Rena","year":"2013","journal-title":"Diabetologia"},{"key":"2020071614212338500_B4","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1210\/jcem.86.3.7453","article-title":"Tissue-specific dysregulation of cortisol metabolism in human obesity","volume":"86","author":"Rask","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614212338500_B5","first-page":"3330","article-title":"Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11\u03b2-hydroxysteroid dehydrogenase type 1 activity","volume":"87","author":"Rask","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614212338500_B6","doi-asserted-by":"crossref","first-page":"720","DOI":"10.2337\/db10-0726","article-title":"Increased whole-body and sustained liver cortisol regeneration by 11\u03b2-hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes provides a target for enzyme inhibition","volume":"60","author":"Stimson","year":"2011","journal-title":"Diabetes"},{"key":"2020071614212338500_B7","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S0140-6736(87)91014-2","article-title":"Mineralocorticoid activity of liquorice: 11\u03b2-hydroxysteroid dehydrogenase deficiency comes of age","volume":"2","author":"Stewart","year":"1987","journal-title":"Lancet"},{"key":"2020071614212338500_B8","doi-asserted-by":"crossref","first-page":"46","DOI":"10.2337\/db08-0969","article-title":"Cortisol release from adipose tissue by 11\u03b2-hydroxysteroid dehydrogenase type 1 in humans","volume":"58","author":"Stimson","year":"2009","journal-title":"Diabetes"},{"key":"2020071614212338500_B9","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1126\/science.1066285","article-title":"A transgenic model of visceral obesity and the metabolic syndrome","volume":"294","author":"Masuzaki","year":"2001","journal-title":"Science"},{"key":"2020071614212338500_B10","doi-asserted-by":"crossref","first-page":"7088","DOI":"10.1073\/pnas.0305524101","article-title":"Metabolic syndrome without obesity: hepatic overexpression of 11\u03b2-hydroxysteroid dehydrogenase type 1 in transgenic mice","volume":"101","author":"Paterson","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614212338500_B11","doi-asserted-by":"crossref","first-page":"872","DOI":"10.2337\/diabetes.54.3.872","article-title":"Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11\u03b2-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone","volume":"54","author":"Sandeep","year":"2005","journal-title":"Diabetes"},{"key":"2020071614212338500_B12","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1007\/s00125-014-3240-x","article-title":"Hepatic 11\u03b2-hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol technique","volume":"57","author":"Dube","year":"2014","journal-title":"Diabetologia"},{"key":"2020071614212338500_B13","doi-asserted-by":"crossref","first-page":"4754","DOI":"10.1210\/endo.136.11.7588203","article-title":"11 \u03b2-Hydroxysteroid dehydrogenase is an exclusive 11 \u03b2- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations","volume":"136","author":"Jamieson","year":"1995","journal-title":"Endocrinology"},{"key":"2020071614212338500_B14","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s40265-013-0112-5","article-title":"11\u03b2-HSD1 inhibitors for the treatment of type 2 diabetes and cardiovascular disease","volume":"73","author":"Anderson","year":"2013","journal-title":"Drugs"},{"key":"2020071614212338500_B15","first-page":"277","article-title":"Distinguishing the activities of 11beta-hydroxysteroid dehydrogenases in vivo using isotopically labeled cortisol","volume":"87","author":"Andrew","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614212338500_B16","doi-asserted-by":"crossref","first-page":"4480","DOI":"10.1210\/jc.2007-0692","article-title":"Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men","volume":"92","author":"Stimson","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614212338500_B17","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1097\/gme.0b013e318258aad7","article-title":"Association of 11\u03b2-hydroxysteroid dehydrogenase type I expression and activity with estrogen receptor \u03b2 in adipose tissue from postmenopausal women","volume":"19","author":"McInnes","year":"2012","journal-title":"Menopause"},{"key":"2020071614212338500_B18","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.2337\/diabetes.54.5.1364","article-title":"The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans","volume":"54","author":"Andrew","year":"2005","journal-title":"Diabetes"},{"key":"2020071614212338500_B19","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2337\/db08-1079","article-title":"Liver is the site of splanchnic cortisol production in obese nondiabetic humans","volume":"58","author":"Basu","year":"2009","journal-title":"Diabetes"},{"key":"2020071614212338500_B20","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.2337\/db11-1345","article-title":"Recycling between cortisol and cortisone in human splanchnic, subcutaneous adipose, and skeletal muscle tissues in vivo","volume":"61","author":"Hughes","year":"2012","journal-title":"Diabetes"},{"key":"2020071614212338500_B21","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1210\/jc.2004-2390","article-title":"Obesity and type 2 diabetes do not alter splanchnic cortisol production in humans","volume":"90","author":"Basu","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614212338500_B22","doi-asserted-by":"crossref","first-page":"4755","DOI":"10.1210\/jc.2003-032240","article-title":"11\u03b2-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus","volume":"89","author":"Valsamakis","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614212338500_B23","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1464-5491.1992.tb01716.x","article-title":"The effect of intravenous metformin on glucose metabolism during hyperglycaemia in type 2 diabetes","volume":"9","author":"Sum","year":"1992","journal-title":"Diabet Med"},{"key":"2020071614212338500_B24","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3109\/00498259409043220","article-title":"Accumulation of metformin by tissues of the normal and diabetic mouse","volume":"24","author":"Wilcock","year":"1994","journal-title":"Xenobiotica"},{"key":"2020071614212338500_B25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.taap.2008.08.013","article-title":"Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro","volume":"233","author":"Dykens","year":"2008","journal-title":"Toxicol Appl Pharmacol"},{"key":"2020071614212338500_B26","doi-asserted-by":"crossref","first-page":"8145","DOI":"10.1038\/srep08145","article-title":"Antihyperglycemic mechanism of metformin occurs via the AMPK\/LXR\u03b1\/POMC pathway","volume":"5","author":"Cho","year":"2015","journal-title":"Sci Rep"},{"key":"2020071614212338500_B27","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1210\/jcem.87.4.8398","article-title":"Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia\/insulin resistance","volume":"87","author":"Arslanian","year":"2002","journal-title":"J Clin Endocrinol Metab"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/101\/10\/3787\/20287766\/jcem3787.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/101\/10\/3787\/20287766\/jcem3787.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T02:03:26Z","timestamp":1594951406000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/101\/10\/3787\/2764942"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,26]]},"references-count":27,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2016,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2016-2069","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,26]]}}}