Discovery of amino acid variants in the human glucose-dependent insulinotropic polypeptide (GIP) receptor: the impact on the pancreatic beta cell responses and functional expression studies in Chinese hamster fibroblast cells.

Details

Serval ID
serval:BIB_2CB01B8B0DF9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Discovery of amino acid variants in the human glucose-dependent insulinotropic polypeptide (GIP) receptor: the impact on the pancreatic beta cell responses and functional expression studies in Chinese hamster fibroblast cells.
Journal
Diabetologia
Author(s)
Almind K., Ambye L., Urhammer S.A., Hansen T., Echwald S.M., Holst J.J., Gromada J., Thorens B., Pedersen O.
ISSN
0012-186X[print], 0012-186X[linking]
Publication state
Published
Issued date
10/1998
Volume
41
Number
10
Pages
1194-1198
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are insulinotropic factors released from the small intestine to the blood stream in response to oral glucose ingestion. The insulinotropic effect of GLP-1 is maintained in patients with Type II (non-insulin-dependent) diabetes mellitus, whereas, for unknown reasons, the effect of GIP is diminished or lacking. We defined the exon-intron boundaries of the human GIP receptor, made a mutational analysis of the gene and identified two amino acid substitutions, A207 V and E354Q. In an association study of 227 Caucasian Type II diabetic patients and 224 matched glucose tolerant control subjects, the allelic frequency of the A207 V polymorphism was 1.1% in Type II diabetic patients and 0.7% in control subjects (p = 0.48), whereas the allelic frequency of the codon 354 polymorphism was 24.9% in Type II diabetic patients versus 23.2% in control subjects. Interestingly, the glucose tolerant subjects (6% of the population) who were homozygous for the codon 354 variant had on average a 14% decrease in fasting serum C-peptide concentration (p = 0.01) and an 11% decrease in the same variable 30 min after an oral glucose load (p = 0.03) compared with subjects with the wild-type receptor. Investigation of the function of the two GIP receptor variants in Chinese hamster fibroblasts showed, however, that the GIP-induced cAMP formation and the binding of GIP to cells expressing the variant receptors were not different from the findings in cells expressing the wildtype GIP receptor. In conclusion, amino acid variants in the GIP receptor are not associated with random Type II diabetes in patients of Danish Caucasian origin or with altered GIP binding and GIP-induced cAMP production when stably transfected in Chinese hamster fibroblasts. The finding of an association between homozygosity for the codon 354 variant and reduced fasting and post oral glucose tolerance test (OGTT) serum C-peptide concentrations, however, calls for further investigations and could suggest that GIP even in the fasting state regulates the beta-cell secretory response.
Keywords
Alleles, Animals, C-Peptide/blood, Cell Line, Cricetinae, Cricetulus, Cyclic AMP/biosynthesis, DNA Mutational Analysis, Diabetes Mellitus, Type 2/genetics, Gastric Inhibitory Polypeptide/metabolism, Gastric Inhibitory Polypeptide/pharmacology, Gene Expression, Gene Frequency, Glucose Tolerance Test, Homozygote, Humans, Islets of Langerhans/drug effects, Islets of Langerhans/physiology, Mutation, Polymorphism, Single-Stranded Conformational, Receptors, Gastrointestinal Hormone/chemistry, Receptors, Gastrointestinal Hormone/genetics, Transfection
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 13:41
Last modification date
20/08/2019 13:11
Usage data