Tseng C C, Boylan M O, Jarboe L A, Usdin T B, Wolfe M M
Harvard Digestive Disease Center, Division of Gastroenterology, Harvard Medical School, Boston, Massachusetts, USA.
Am J Physiol. 1996 Apr;270(4 Pt 1):E661-6. doi: 10.1152/ajpendo.1996.270.4.E661.
Rats were rendered diabetic by streptozotocin, after which serum glucose-dependent insulinotropic polypeptide (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 intravenous GIP infusion. Serum GIP levels increased gradually in GIP-infused rats, and by 4 h a threefold 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 a sustained elevated serum GIP level. The response to glucagon-like peptide-1 (GLP-1) was preserved, a reporter cell line (LGIPR2) stably transfected with rat GIP receptor cDNA was studied. GIP stimulated adenosine 3', 5'-cyclic monophosphate (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-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.
用链脲佐菌素使大鼠患糖尿病，之后血清葡萄糖依赖性促胰岛素多肽（GIP）水平、十二指肠黏膜GIP含量和GIP mRNA水平分别比对照大鼠高9倍、50%和80%。为了确定GIP基因表达增加是否会诱导其受体慢性脱敏，对正常大鼠进行持续静脉输注GIP。在输注GIP的大鼠中，血清GIP水平逐渐升高，4小时时检测到增加了3倍。响应GIP输注，血清胰岛素浓度在30分钟时升高，随后逐渐下降，4小时时，尽管血清GIP水平持续升高，但未检测到胰岛素水平增加。对胰高血糖素样肽-1（GLP-1）的反应得以保留，研究了稳定转染大鼠GIP受体cDNA的报告细胞系（LGIPR2）。GIP刺激LGIPR2细胞中3',5'-环磷酸腺苷（cAMP）的产生，刺激1小时后首次检测到，4小时时达到最高水平，16小时时恢复到基础浓度。16小时时用GIP额外刺激不影响cAMP的生成，表明配体使GIP受体脱敏。相比之下，GIP脱敏中对前列腺素E1或福斯可林的反应是受体特异性过程。这些研究结果表明，糖尿病动物中GIP基因表达增强，血清GIP水平升高会在体内和稳定转染的细胞系中诱导GIP受体慢性脱敏。
