{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:11:48Z","timestamp":1790784708754,"version":"4.1.0"},"reference-count":39,"publisher":"American Diabetes Association","issue":"2","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":113,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,2,1]]},"abstract":"<jats:p>Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alstr\u00f6m syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative AT failure in a monogenic obese cohort, a finding supported by observations in a novel conditional mouse model (Almsflin\/flin) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model (Almsflin\/flin; Adipo-Cre+\/\u2212) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative AT failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte-driven IR may assist development of AT-targeted therapeutic strategies for diabetes.<\/jats:p>","DOI":"10.2337\/db20-0647","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T01:06:04Z","timestamp":1601427964000},"page":"364-376","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":39,"title":["Relative Adipose Tissue Failure in Alstr\u00f6m Syndrome Drives Obesity-Induced Insulin Resistance"],"prefix":"10.2337","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3629-2338","authenticated-orcid":false,"given":"Tarekegn","family":"Geberhiwot","sequence":"first","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism, Queen Elizabeth Hospital Birmingham, Birmingham, U.K."},{"name":"Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, 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