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Beyond its well-demonstrated roles in cardiovascular regulation and COVID-19 pathology, ACE2 is involved in a plethora of physiopathological processes. In this review, we summarize the latest discoveries on the role of ACE2 in glucose homeostasis and regulation of metabolism. In the endocrine pancreas, ACE2 is expressed at low levels in \u03b2-cells, but loss of its expression inhibits glucose-stimulated insulin secretion and impairs glucose tolerance. Conversely, overexpression of ACE2 improved glycemia, suggesting that recombinant ACE2 might be a future therapy for diabetes. In the skeletal muscle of ACE2-deficient mice a progressive triglyceride accumulation was observed, whereas in diabetic kidney the initial increase in ACE2 is followed by a chronic reduction of expression in kidney tubules and impairment of glucose metabolism. At the intestinal level dysregulation of the enzyme alters the amino acid absorption and intestinal microbiome, whereas at the hepatic level ACE2 protects against diabetic fatty liver disease. Not least, ACE2 is upregulated in adipocytes in response to nutritional stimuli, and administration of recombinant ACE2 decreased body weight and increased thermogenesis. In addition to tissue-specific regulation of ACE2 function, the enzyme undergoes complex cellular posttranslational modifications that are changed during diabetes evolution, with at least proteolytic cleavage and ubiquitination leading to modifications in ACE2 activity. Detailed characterization of ACE2 in a cellular and tissue-specific manner holds promise for improving therapeutic outcomes in diabetes and metabolic disorders. <\/jats:p>","DOI":"10.1152\/physrev.00027.2024","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T17:00:52Z","timestamp":1738947652000},"page":"935-973","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular dissection of the role of ACE2 in glucose homeostasis"],"prefix":"10.1152","volume":"105","author":[{"given":"Kavaljit H.","family":"Chhabra","sequence":"first","affiliation":[{"name":", University of Kentucky","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9972-7677","authenticated-orcid":false,"given":"Robin","family":"Shoemaker","sequence":"additional","affiliation":[{"name":"University of Kentucky","place":["United 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