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 Alströom syndrome con-sisting of severe insulin resistance. Inactivation of ALMS1 directly inhibits insulin-mediated glucose absorption in the white adipose tissue and induces severe insulin resis-tance, 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 sig-naling, 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 insu-lin-independent glucose absorption, de novo lipogenesis, and cellular glucose utilization. In vivo, PATAS reduced whole-body insulin resistance, and improved glucose in-tolerance, 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.