Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis.
The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that act via the enteroinsular axis to potentiate insulin secretion from the pancreas in a glucose-dependent manner. Both GLP-1 receptor and GIP receptor knockout mice (GLP-1R(-/-) and GIPR(-/-), respectively) have been generated to investigate the physiological importance of this axis. Although reduced GIP action is a component of type 2 diabetes, GIPR-deficient mice exhibit only moderately impaired glucose tolerance. The present study was directed at investigating possible compensatory mechanisms that take place within the enteroinsular axis in the absence of GIP action. Although serum total GLP-1 levels in GIPR knockout mice were unaltered, insulin responses to GLP-1 from pancreas perfusions and static islet incubations were significantly greater (40-60%) in GIPR(-/-) than in wild-type (GIPR(+/+)) mice. Furthermore, GLP-1-induced cAMP production was also elevated twofold in the islets of the knockout animals. Pancreatic insulin content and gene expression were reduced in GIPR(-/-) mice compared with GIPR(+/+) mice. Paradoxically, immunocytochemical studies showed a significant increase in beta-cell area in the GIPR-null mice but with less intense staining for insulin. In conclusion, GIPR(-/-) mice exhibit altered islet structure and topography and increased islet sensitivity to GLP-1 despite a decrease in pancreatic insulin content and gene expression.
Pamir
Nathalie
N
Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T 1Z3.
Lynn
Francis C
FC
Buchan
Alison M J
AM
Ehses
Jan
J
Hinke
Simon A
SA
Pospisilik
J Andrew
JA
Miyawaki
Kazumasa
K
Yamada
Yuichiro
Y
Seino
Yutaka
Y
McIntosh
Christopher H S
CH
Pederson
Raymond A
RA
D000222:Adaptation, Physiological; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D005934:Glucagon / Q000235:genetics / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000502:physiology; D007422:Intestines / Q000502:physiology*; D007425:Intracellular Membranes / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000502:physiology*
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D001120:Arginine; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D005947:Glucose