Islet function phenotype in gastrin-releasing peptide receptor gene-deficient mice.
Gastrin-releasing peptide (GRP) is an islet neuropeptide that stimulates insulin secretion. To explore whether islet GRP contributes to neurally mediated insulin secretion, we studied GRP receptor (GRPR)-deleted mice. By using RT-PCR we showed that GRPR mRNA is expressed in islets of wild-type mice, but is lost in GRPR-deleted mice. Functional studies revealed that GRP potentiates glucose-stimulated insulin secretion in wild-type animals, but not in GRPR-deleted mice. This shows that GRPR is the receptor subtype mediating GRP-induced insulin secretion and that GRPR-deleted mice are tools for studying the physiological role of islet GRP. We found that GRPR-deleted mice display 1) augmentation of the insulin response to glucose by a mechanism inhibited by ganglionic blockade; 2) increased insulin responsiveness also to the cholinergic agonist carbachol, but not to arginine; 3) impaired insulin and glucagon responses to autonomic nerve activation by 2-deoxyglucose; 4) normal islet adaptation to high fat-induced insulin resistance and fasting; and 5) normal islet cytoarchitecture, as revealed by immunocytochemistry of insulin and glucagon. In conclusion, 1) GRPR is the receptor subtype mediating the islet effects of GRP; 2) GRP contributes to insulin secretion induced by activation of the autonomic nerves; and 3) deletion of GRPR is compensated by increased cholinergic sensitivity.
Persson
Kristin
K
Department of Medicine, Lund University, Sweden. kristin.persson@med.lu.se
Pacini
Giovanni
G
Sundler
Frank
F
Ahrén
Bo
B
D000222:Adaptation, Physiological; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology; D005215:Fasting / Q000502:physiology; D019886:Gastrin-Releasing Peptide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010641:Phenotype; D018004:Receptors, Bombesin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D007328:Insulin; D018004:Receptors, Bombesin; D019886:Gastrin-Releasing Peptide; D005947:Glucose