Chronic desensitization of the glucose-dependent insulinotropic polypeptide (gip) receptor in diabetic rats. Tseng, Chi-Chuan, Michael O. Boylan, Linda A. Jarboe, Ted B. Usdin, and M. Michael Wolfe. Harvard Digestive Disease Center, Division of Gastroenterology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115; and Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, Maryland 20892
APStracts 2:0249E, 1995.
Rats were rendered diabetic by streptozotocin, after which serum GIP levels, duodenal mucosal GIP content, and GIP mRNA levels were nine times, 50% and 80%, respectively, greater than in control rats. To determine whether an increase in GIP gene expression might induce chronic desensitization of its receptor, normal rats were subjected to continuous IV GIP infusion. Serum GIP levels increased gradually in GIP-infused rats, and by 4 h, a 3-fold increase was detected. In response to GIP infusion, the serum insulin concentration increased at 30 min followed by a gradual decrease, and at 4 h, no increase in insulin levels was detected despite sustained elevated serum GIP level. The response to glucagon-like peptide (GLP-1) was preserved indicating that desensitization was ligand-specific. To determine the mechanisms governing desensitization of this receptor, a reporter cell line (LGIPR2) stably transfected with rat GIP receptor cDNA was studied. GIP stimulated cAMP production in LGIPR2 cells, which was first detected after 1 h of stimulation, reached maximum level at 4 h, and returned to basal concentrations by 16 h. Additional stimulation with GIP at 16 h did not affect cAMP generation, indicating desensitization of the GIP receptor by the ligand. In contrast, a response to prostaglandin E1 or forskolin in GIP -desensitized LGIPR2 cells was unchanged, suggesting that desensitization was a receptor-specific process. The results of these studies indicate that GIP gene expression is enhanced in diabetic animals and that elevated serum GIP level induces chronic desensitization of the GIP receptor in vivo and in a stably transfected cell line. 

Received 8 August 1995; accepted in final form 27 November 1995.
APS Manuscript Number E374-5.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 12 December 95