Antidiabetic in vitro and in vivo evaluation of cyclodipeptides isolated from Pseudomonas fluorescens IB-MR-66e

Abstract

Three cyclodipeptides [cyclo(L-Pro-L-Leu), 1; cyclo(L-Pro-L-Val), 2; and cyclo(L-Pro-L-Phe), 3] were isolated from Pseudomonas fluorescens IB-MR-66e. The structures were established by spectral means and corroborated by synthesis. The antidiabetic potential of compounds 1–3 was explored in vivo, in vitro and in silico. The three peptides showed important inhibitory activity against the α-glucosidase enzyme. Further analysis in vivo using a sucrose tolerance test corroborated that compounds 1 and 3 (1–30 mg kg⁻¹) significantly reduced the postprandial state. Peptide 1 (1–30 mg kg⁻¹) also reduced the postprandial peak after a glucose challenge and exhibited significant hypoglycemia during an insulin tolerance test; thus, its antidiabetic action involved also an improvement of insulin utilization not related to Akt phosphorylation nor to an increment in mitochondrial bioenergetics nor insulin secretion.