Pituitary adenylate cyclase-activating peptide (PACAP): assessment of dipeptidyl peptidase IV degradation, insulin-releasing activity and antidiabetic potential.
Pituitary adenylate cyclase-activating peptide (PACAP) is a member of the glucagon family of peptides. Like other members, most notably glucagon-like peptide-1 (GLP-1), PACAP is rapidly degraded by dipeptidylpeptidase IV (DPP IV). This study investigated how degradation by DPP IV affected the insulinotropic activity of PACAP, and whether PACAP exerted acute antihyperglycemic properties in normal or ob/ob mice. DPP IV degradation of PACAP(1-27) over 18 h led to the formation of PACAP(3-27), PACAP(5-27) and ultimately PACAP(6-27). In contrast to 1.4-1.8-fold concentration-dependent stimulation of insulin secretion by PACAP(1-27), these peptide fragments lacked insulinotropic activity. While PACAP(1-27) and PACAP(1-38) generated significant insulin responses when given alone or together with glucose in ob/ob and normal mice, they also elevated plasma glucose. These actions were eliminated following degradation of the peptide by incubation with DPP IV. The hyperglycemic effects may be explained at least partly by a potent glucagon-releasing action in ob/ob and normal mice. In conclusion, PACAP is inactivated by DPP IV and despite insulin-releasing effects, its actions on glucagon secretion and glucose homeostasis do not make it a good therapeutic tool for the treatment of type 2 diabetes.
Green
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BD
School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, United Kingdom. b.green@ulster.ac.uk
Irwin
N
N
Flatt
P R
PR
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D008820:Mice, Obese; D008969:Molecular Sequence Data; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism / Q000502:physiology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4