title: A recombinant slow-release PACAP-derived peptide alleviates diabetes by promoting both insulin secretion and actions.
abstract: Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuroendocrine factor that activates both the receptor VPAC1 and VPAC2. Although PACAP possesses insulinotropic activity, its therapeutic application is limited by the extremely short acting half-life and the stimulatory effects on glucagon production via a VPAC1-dependent mechanism. Here we have generated a recombinant PACAP-derived peptide (named as MHDBAY) comprising a 7-mer albumin-binding peptide identified by phage display screening (WQRPSSW), a cleavage peptide for Factor Xa (FXa) and dipeptidyl peptidase IV (DPP IV), and a 31-amino acid PACAP-derived peptide (DBAY) that can specifically bind to the VPAC2 receptor. MHDBAY binds to albumin both in vitro and in animals, thereby leading to an orderly slow release of the active peptide DBAY via the protease cleavage. In db/db mice and New Zealand rabbits, the circulating half-life of MHDBAY is approximately 12.2 h, which is 146-fold longer than DBAY (∼5 min). A single injection of MHDBAY into db/db diabetic mice markedly increases insulin secretion, thereby leading to sustained alleviation of hyperglycemia. The potency and duration of MHDBAY in increasing insulin secretion and decreasing blood glucose levels is much greater than Exendin-4, an anti-diabetic drug via its insulinotropic actions. Furthermore, chronic administration of MHDBAY by daily injection for 8 weeks significantly improves both glucose and lipid profiles and also greatly increases insulin sensitivity in db/db mice. These findings suggest that serum albumin may act as a reservoir for slow-release of small bioactive peptides, and MHDBAY may represent a promising therapeutic peptide for diabetes.
authors.affiliation: Institute of Biomedicine & Dept. Cellular Biology, Jinan University, National Engineering Research Center of Genetic Medicine, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Institute of Biomedicine & Dept. Cellular Biology, Jinan University, National Engineering Research Center of Genetic Medicine, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
authors.forename: Shixiong
authors.initials: S
authors.lastname: Fang
authors.affiliation: Institute of Biomedicine & Dept. Cellular Biology, Jinan University, National Engineering Research Center of Genetic Medicine, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Institute of Biomedicine & Dept. Cellular Biology, Jinan University, National Engineering Research Center of Genetic Medicine, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Biomedicine & Dept. Cellular Biology, Jinan University, National Engineering Research Center of Genetic Medicine, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
authors.forename: Dongbo
authors.initials: D
authors.lastname: Wang
authors.affiliation: School of Medicine of Jinan University, Guangzhou 510632, Guangdong Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.affiliation: Institute of Biomedicine & Dept. Cellular Biology, Jinan University, National Engineering Research Center of Genetic Medicine, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
authors.forename: Tianjie
authors.initials: T
authors.lastname: Luo
authors.affiliation: Institute of Biomedicine & Dept. Cellular Biology, Jinan University, National Engineering Research Center of Genetic Medicine, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China. Electronic address: makesi8866@163.com.
authors.forename: An
authors.initials: A
authors.lastname: Hong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003692:Delayed-Action Preparations; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004926:Escherichia coli / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008055:Lipids / Q000097:blood; D051379:Mice; D008969:Molecular Sequence Data; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D012709:Serum Albumin / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007328:Insulin; D008055:Lipids; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D011994:Recombinant Proteins; D012709:Serum Albumin
keywords: Diabetes; Gene recombination; Insulin; Pituitary adenylate cyclase activating polypeptide (PACAP)-derived peptide; Slow-release; VPAC2 receptor