PATAS, a First-in-Class Therapeutic Peptide Biologic, Improves Whole-Body Insulin Resistance and Associated Comorbidities In Vivo - Archive ouverte HAL Access content directly
Journal Articles Diabetes Year : 2022

PATAS, a First-in-Class Therapeutic Peptide Biologic, Improves Whole-Body Insulin Resistance and Associated Comorbidities In Vivo

Abstract

Adipose tissue is a key regulator of whole-body metabolic fitness because of its role in controlling insulin sensitivity. Obesity is associated with hypertrophic adipocytes with impaired glucose absorption, a phenomenon existing in the ultrarare monogenic disorder Alström syndrome consisting of severe insulin resistance. 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-α (PKCα) in the adipocyte, and upon insulin signaling, PKCα is released from ALMS1. α-Helices in the kinase domain of PKCα were therefore screened to identify a peptide sequence that interfered with the ALMS1-PKCα 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.

Dates and versions

hal-04225558 , version 1 (02-10-2023)

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Edwige Schreyer, Cathy Obringer, Nadia Messaddeq, Bruno Kieffer, Paul Zimmet, et al.. PATAS, a First-in-Class Therapeutic Peptide Biologic, Improves Whole-Body Insulin Resistance and Associated Comorbidities In Vivo. Diabetes, 2022, 71 (9), pp.2034-2047. ⟨10.2337/db22-0058⟩. ⟨hal-04225558⟩
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