Human Glucagon-Like Peptide-1 Receptor Gene: Localization to Chromosome Band 6p21 by Fluorescence In Situ Hybridization and Linkage of a Highly Polymorphic Simple Tandem Repeat DNA Polymorphism to Other Markers on Chromosome 6

Abstract

Glucagon-like peptide-1 is a fragment of proglucagon secreted by intestinal L-cells. It has potent glucose-dependent insulin secretory effects and also suppresses gastric acid secretion in the stomach. The biological actions of GLP-1 are mediated by the GLP-1 receptor, the structure of which has recently been determined. Defects in insulin secretion are a common feature of NIDDM and as such the GLP-1 receptor is a candidate for contributing to the development of this clinically and genetically heterogeneous disorder. As a first step in determining the role of the GLP-1 receptor in the development of NIDDM, we have isolated the human GLP-1 receptor gene and mapped it to chromosome 6, band p21.1, using the technique of fluorescence in situ hybridization. We also identified a simple tandem repeat DNA polymorphism in the human GLP-1 receptor gene of the form (TG)n. This DNA polymorphism has 14 alleles and a heterozygosity of > 0.8. We have used this DNA polymorphism to localize the GLP-1 receptor gene within the genetic map of the short arm of chromosome 6. This DNA polymorphism will facilitate genetic studies of the contribution of the GLP-1 receptor gene to impaired beta-cell function and NIDDM.

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…The rat and human GLP-1Rs exhibit a 95% amino acid homology and are 90% identical (Thorens, 1992;Thorens et al, 1993), differing at 42 amino acid positions (Tibaduiza et al, 2001). The human GLP-1R gene is located on the long arm of chromosome 6p21 (Stoffel et al, 1993). GLP-1R is a 64 kDa protein (Widmann et al, 1995) and although alternate splicing results in two different transcripts for both the rat and the human GLP-1R Thorens, 1992) there has, as yet, been only one functionally distinct GLP-1R described.…”

“…GLP-1R is a 64 kDa protein (Widmann et al, 1995) and although alternate splicing results in two different transcripts for both the rat and the human GLP-1R Thorens, 1992) there has, as yet, been only one functionally distinct GLP-1R described. While various polymorphisms have been associated with the GLP-1R human gene locus (Stoffel et al, 1993), linkage analysis eliminates an association with the majority of T2DM cases, based on the populations studied (Tanizawa et al, 1994;Tokuyama et al, 2004;Yagi et al, 1996;Zhang et al, 1994). One patient diagnosed with T2DM from a Japanese study (Tokuyama et al, 2004) exhibited impairment of insulin secretion, insulin sensitivity and glucose tolerance and had a missense mutation resulting in substitution of threonine 149 with methionine (T149M).…”

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

“…The human GLP-1 receptor gene was localized to the long arm of chromosome 6 (hchr 6p21) (Stoffel et al, 1993). The GLP-1 receptor gene spans 40 kb and consists of at least 7 exons.…”

Structure/Activity Characterization of Glucagon‐Like Peptide‐1

“…This work is dedicated to Werner Creutzfeldt, Professor emeritus of Medicine, Georg-August University of Gottingen, Germany, on the occasion of his 70th birthday. the gene encoding the receptor has been localized in humans [17]. So far, little is known about the structural requirements for glucagon-like peptide-1 binding to its receptor.…”