PATAS, a first-in-class therapeutic peptide biologic, improves whole-body insulin resistance and associated comorbidities in vivo
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 ultra-rare 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 non-alcoholic liver disease and fibrosis. These phenotypes were reversed by specific adipocyte-ALMS1 reactivation in vivo. Subsequently, ALMS1 was found to bind to PKC alpha in the adipocyte and upon insulin signaling PKC alpha is released from ALMS1. Alpha helices in the kinase domain of PKC alpha were therefore screened to identify a peptide sequence that interfered with the ALMS1-PKC alpha 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, 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.