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Inactivation of ALMS1 directly inhibits insulin-mediated glucose absorption in the white adipose tissue and induces severe insulin resistance, which leads to type 2 diabetes, accelerated nonalcoholic liver disease, and fibrosis. These phenotypes were reversed by specific adipocyte-ALMS1 reactivation in vivo. Subsequently, ALMS1 was found to bind to protein kinase C-\u03b1 (PKC\u03b1) in the adipocyte, and upon insulin signaling, PKC\u03b1 is released from ALMS1. \u03b1-Helices in the kinase domain of PKC\u03b1 were therefore screened to identify a peptide sequence that interfered with the ALMS1-PKC\u03b1 protein interaction. When incubated with cultured human adipocytes, the stapled peptide termed PATAS, for Peptide derived of PKC Alpha Targeting AlmS, triggered insulin-independent glucose absorption, de novo lipogenesis, and cellular glucose utilization. In vivo, PATAS reduced whole-body insulin resistance, and improved glucose intolerance, fasting glucose, liver steatosis, and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.<\/jats:p>","DOI":"10.2337\/db22-0058","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T12:08:45Z","timestamp":1657714125000},"page":"2034-2047","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":11,"title":["PATAS, a First-in-Class Therapeutic Peptide Biologic, Improves Whole-Body Insulin Resistance and Associated Comorbidities In Vivo"],"prefix":"10.2337","volume":"71","author":[{"given":"Edwige","family":"Schreyer","sequence":"first","affiliation":[{"name":"1AdipoPharma SAS, Parc d\u2019Innovation, Illkirch-Graffenstaden, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Obringer","sequence":"additional","affiliation":[{"name":"2INSERM, UMR_U1112, Ciliopathies Modeling and Associated Therapies Group, 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