已发表论文

一种新型选择性 VPAC2 激动剂肽缀合的、壳聚糖修饰的硒纳米颗粒具有增强的抗 2 型糖尿病的协同作用

 

Authors Zhao SJ, Wang DH, Li YW, Han L, Xiao X, Ma M, Wan DC, Hong A, Ma Y

Received 18 December 2016

Accepted for publication 13 February 2017

Published 20 March 2017 Volume 2017:12 Pages 2143—2160

DOI https://doi.org/10.2147/IJN.S130566

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Jiang Yang

Peer reviewer comments 3

Editor who approved publication: Dr Linlin Sun

Abstract: A novel neuroendocrine peptide, pituitary adenylate cyclase activating peptide (PACAP), was found to have an important role in carbohydrate or lipid metabolism and was susceptible to dipeptidyl peptidase IV degradation. It can not only mediate glucose-dependent insulin secretion and lower blood glucose by activating VPAC2 receptor, but also raise blood glucose by promoting glucagon production by VPAC1 receptor activation. Therefore, its therapeutic application is restricted by the exceedingly short-acting half-life and the stimulatory function for glycogenolysis. Herein, we generated novel peptide-conjugated selenium nanoparticles (SeNPs; named as SCD), comprising a 32-amino acid PACAP-derived peptide DBAYL that selectively binds to VPAC2, and chitosan-modified SeNPs (SeNPs-CTS, SC) as slow-release carrier. The circulating half-life of SCD is 14.12 h in mice, which is 168.4- and 7.1-fold longer than wild PACAP (~5 min) and DBAYL (~1.98 h), respectively. SCD (10 nmol/L) significantly promotes INS-1 cell proliferation, glucose uptake, insulin secretion, insulin receptor expression and also obviously reduces intracellular reactive oxygen species levels in H2O2-injured INS-1 cells. Furthermore, the biological effects of SCD are stronger than Exendin-4 (a clinically approved drug through its insulinotropic effect), DBAYL, SeNPs or SC. A single injection of SCD (20 nmol/kg) into db/db mice with type 2 diabetes leads to enhanced insulin secretion and sustained hypoglycemic effect, and the effectiveness and duration of SCD in enhancing insulin secretion and reducing blood glucose levels are much stronger than Exendin-4, SeNPs or SC. In db/db mice, chronic administration of SCD by daily injection for 12 weeks markedly improved glucose and lipid profiles, insulin sensitivity and the structures of pancreatic and adipose tissue. The results indicate that SC can play a role as a carrier for the slow release of bioactive peptides and SCD could be a hopeful therapeutic against type 2 diabetes through the synergy effects of DBAYL and SeNPs.
Keywords: pituitary adenylate cyclase activating peptide (PACAP)-derived peptide, nano-selenium, VPAC2 receptor, synergy effect, type 2 diabetes (T2D)