TFP5, a Peptide Derived from Cdk5 Activator p35, Protects Pancreatic β-cells from Glucose Toxicity

Abstract

Type 2 diabetes mellitus (T2DM) is worldwide epidemic, which challenges the health of the public. The pathological hyperactivity of cyclin-dependent kinase 5 (Cdk5) contributes to the pathogenesis of T2DM. P5, a peptide derived from the Cdk5 activator p35, shows excellent performance as a Cdk5 activity inhibitor. However, its inhibitory effect and functional regulation on Cdk5 activity needs 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, an 11-amino acid peptide, at the C-terminus to synthesize TFP5, which was used to inhibits 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 penetrated pancreatic β-cells (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-β1, TNF-α, and IL-1β. These data indicates that the TFP5 peptide is a promising candidate for T2DM treatment.