PATAS, a First-in-Class Therapeutic Peptide Biologic, Improves Whole-Body Insulin Resistance and Associated Comorbidities In Vivo.
Diabetes
; 71(9): 2034-2047, 2022 09 01.
Article
en En
| MEDLINE
| ID: mdl-35822820
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Productos Biológicos
/
Resistencia a la Insulina
/
Diabetes Mellitus Tipo 2
/
Síndrome de Alstrom
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Diabetes
Año:
2022
Tipo del documento:
Article
País de afiliación:
Francia