title: A novel selective VPAC2 agonist peptide-conjugated chitosan modified selenium nanoparticles with enhanced anti-type 2 diabetes synergy effects.
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.
authors.affiliation: Institute of Biomedicine, Department of Cellular Biology, Jinan University; National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University.
authors.forename: Shao-Jun
authors.initials: SJ
authors.lastname: Zhao
authors.affiliation: Institute of Biomedicine, Department of Cellular Biology, Jinan University; National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University.
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Wang
authors.affiliation: Institute of Biomedicine, Department of Cellular Biology, Jinan University; National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University.
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Li
authors.affiliation: Institute of Biomedicine, Department of Cellular Biology, Jinan University; National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Institute of Biomedicine, Department of Cellular Biology, Jinan University; National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University.
authors.forename: Xing
authors.initials: X
authors.lastname: Xiao
authors.affiliation: College of traditional Chinese Medicine, Institute of Integrated Traditional Chinese and Western Medicine, Jinan University, Guangdong.
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People's Republic of China.
authors.forename: David Chi-Cheong
authors.initials: DC
authors.lastname: Wan
authors.affiliation: Institute of Biomedicine, Department of Cellular Biology, Jinan University; National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University.
authors.forename: An
authors.initials: A
authors.lastname: Hong
authors.affiliation: Institute of Biomedicine, Department of Cellular Biology, Jinan University; National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D065546:Drug Liberation; D000077270:Exenatide; D005215:Fasting / Q000097:blood; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006207:Half-Life; D006861:Hydrogen Peroxide / Q000633:toxicity; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists*; D012643:Selenium / Q000737:chemistry*; D014688:Venoms / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D014688:Venoms; D048271:Chitosan; D000077270:Exenatide; D006861:Hydrogen Peroxide; D011972:Receptor, Insulin; D012643:Selenium; D005947:Glucose
keywords: VPAC2 receptor; nano-selenium; pituitary adenylate cyclase activating peptide (PACAP)-derived peptide; synergy effect; type 2 diabetes (T2D)