AGDMP1 alleviates insulin resistance by modulating heat shock protein 60-mediated IRS-1/AKT/GLUT4 pathway and adipose inflammation: A potential therapeutic peptide for gestational diabetes mellitus

Abstract

Gestational Diabetes Mellitus (GDM) is the most frequent complication during pregnancy. Pharmacological interventions, such as peptide drugs that focused on improving the insulin sensitivity might be promising in the prevention and treatment of GDM. In this study, we aimed to investigate the role and mechanism of a novel peptide, named AGDMP1 (Anti-GDM peptide 1), which we previously identified lower in the serum of GDM patients using mass spectrometry, on the adipose insulin resistance in GDM. We found that AGDMP1 had a high affinity for adipose tissues in vivo. AGDMP1 markedly improved glucose homeostasis and insulin resistance in GDM mice. This was associated with reduced inflammation and upregulated AKT/GLUT4 signaling pathway in white adipose tissue. In vitro, AGDMP1 could increase glucose uptake and insulin sensitivity of adipocytes by activating the IRS-1/AKT/GLUT4 signaling pathway under basal, insulin-stimulated, and insulin-resistant conditions, respectively. Mechanistically, we found that AGDMP1 could bind to HSP60 to dampen its effects on AKT signaling and pro-inflammatory response, which was reversed in the present of recombinant HSP60 protein. AGDMP1 ameliorated adipose insulin resistance and inflammation by targeting HSP60 and activating the IRS-1/AKT/GLUT4 signaling pathway. These data supported AGDMP1 with therapeutic potential in GDM and associated pathologies.