Long-term administration of PACAP receptor antagonist, PACAP(6-27), impairs glucose tolerance and insulin sensitivity in obese diabetic ob/ob mice.
Pituitary adenylate cyclase-activating peptide (PACAP) is a ubiquitous peptide of the glucagon superfamily that is involved in glucose homeostasis and regulation of insulin secretion. This study employed the PACAP receptor antagonist, PACAP(6-27) to evaluate the role of endogenous PACAP in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob mice. Acute in vivo antagonistic potency of PACAP(6-27) was confirmed in ob/ob mice by blockade of the insulin-releasing action but not hyperglycaemia. In longer-term studies, ob/ob mice were given once daily injections of PACAP(6-27) or vehicle for 14 days. Feeding activity, body weight, basal plasma glucose and plasma insulin concentrations were not significantly affected by chronic PACAP(6-27) treatment. However, PACAP(6-27) treatment impaired glucose tolerance, insulin sensitivity and the glycaemic response to feeding. Plasma glucagon and lipids were unchanged. These observations indicate a role of endogenous PACAP for normal glucose homeostasis, but indicate a minor involvement in the regulation of insulin secretion in ob/ob mice.
Green
Brian D
BD
School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, United Kingdom. b.green@qub.ac.uk
Irwin
Nigel
N
Cassidy
Roslyn S
RS
Gault
Victor A
VA
Flatt
Peter R
PR
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood* / Q000209:etiology / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D018149:Glucose Intolerance / Q000097:blood*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000494:pharmacology*; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D007328:Insulin; D008055:Lipids; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; C106317:pituitary adenylate-cyclase-activating peptide (6-27); D005934:Glucagon