TFP5, a Peptide Derived From Cdk5 Activator p35, Protects Pancreatic β-Cells From Glucose Toxicity

Abstract

Type 2 diabetes mellitus (T2DM) is among the most important public health challenges. The pathological hyperactivity of multifunctional cyclin-dependent kinase 5 (Cdk5) contributes to the pathogenesis of T2DM. P5, a peptide derived from the Cdk5 activator p35, shows potential as a Cdk5 activity inhibitor. However, its inhibitory effect and functional regulation of Cdk5 activity need to be confirmed. In this study, we conjugated P5 with a Fluorescein Isothiocyanate (FITC) tag at the N-terminus and a TAT protein transduction domain containing an 11 amino acid peptide at the C-terminus to synthesize TFP5, which we used to inhibit Cdk5 activity. We then evaluated the efficiency of TFP5 in treating T2DM. We demonstrated that TFP5 effectively penetrated pancreatic β-cells, inhibited the pathological hyperactivity of Cdk5, enhanced insulin secretion, and protected MIN6 cells from apoptosis in pancreatic tissues of db/db mice (Type II diabetes mice). Furthermore, we found that TFP5 reduced inflammation in pancreatic islets by reducing the expression of inflammatory cytokines (including TGF-β, TNF-α, and IL-1β). These data indicate that the TFP5 peptide is a promising candidate for T2DM treatment.