{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:24:58Z","timestamp":1790796298444,"version":"4.1.0"},"reference-count":141,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"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":[[2025,12,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Until recently, the prevalence of endogenous Cushing syndrome has been considered to be low. However, improved diagnostic strategies and increased awareness have broadened our understanding of hypercortisolism and its role in the pathophysiology of type 2 diabetes, obesity, hypertension, and cardiovascular disease. Recent studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with difficult-to-control type 2 diabetes, despite treatment with multiple glucose-lowering agents, have hypercortisolism as a causative factor in their poorly managed diabetes. In this review, we examine the pathophysiologic mechanisms via which excess cortisol contributes to the impairment in glucose homeostasis and recommend that hypercortisolism be added to the Ominous Octet to form the Noxious Nine as the pathophysiologic foundation for the development of type 2 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in\u00a0vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0120","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T18:59:01Z","timestamp":1752605941000},"page":"2168-2178","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":24,"title":["Cushing Syndrome, Hypercortisolism, and Glucose Homeostasis: A Review"],"prefix":"10.2337","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-6273","authenticated-orcid":false,"given":"Ralph A.","family":"DeFronzo","sequence":"first","affiliation":[{"name":"Diabetes Division, UT Health and Texas Diabetes Institute 1 , San Antonio, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Auchus","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology, & Diabetes, University of Michigan School of Medicine and Ann Arbor VA Medical Center 2 , Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"2026061115170585700_B1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1001\/jama.2023.11305","article-title":"Cushing syndrome: a review","volume":"330","author":"Reincke","year":"2023","journal-title":"JAMA"},{"key":"2026061115170585700_B2","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1530\/eje.1.02045","article-title":"Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients","volume":"153","author":"Chiodini","year":"2005","journal-title":"Eur J Endocrinol"},{"key":"2026061115170585700_B3","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.jdiacomp.2016.05.006","article-title":"Prevalence of subclinical hypercortisolism in type 2 diabetic patients from the Rio de Janeiro Type 2 Diabetes Cohort Study","volume":"30","author":"Costa","year":"2016","journal-title":"J Diabetes Complications"},{"key":"2026061115170585700_B4","doi-asserted-by":"crossref","first-page":"5808","DOI":"10.1210\/jc.2003-030254","article-title":"Occult Cushing\u2019s syndrome in type-2 diabetes","volume":"88","author":"Catargi","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2026061115170585700_B5","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.2337\/dc24-2841","article-title":"Prevalence of hypercortisolism in difficult-to-control type 2 diabetes","volume":"48","author":"Buse","year":"2025","journal-title":"Diabetes Care"},{"key":"2026061115170585700_B6","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.2337\/dc25-1055","article-title":"Inadequately controlled type 2 diabetes and hypercortisolism: improved glycemia with mifepristone treatment","volume":"48","author":"DeFronzo","year":"2025","journal-title":"Diabetes Care"},{"key":"2026061115170585700_B7","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1056\/NEJMsa2032271","article-title":"Trends in diabetes treatment and control in U.S. adults, 1999\u20132018","volume":"384","author":"Fang","year":"2021","journal-title":"N Engl J Med"},{"key":"2026061115170585700_B8","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.clinthera.2022.07.009","article-title":"Use of concurrent anti-diabetes medications in patients with type 2 diabetes in clinical practice in the United States","volume":"44","author":"Luthra","year":"2022","journal-title":"Clin Ther"},{"key":"2026061115170585700_B9","doi-asserted-by":"crossref","first-page":"773","DOI":"10.2337\/db09-9028","article-title":"Banting Lecture. 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