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      Common Genetic Variation in GLP1R and Insulin Secretion in Response to Exogenous GLP-1 in Nondiabetic Subjects : A pilot study

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          Abstract

          OBJECTIVE

          Glucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects.

          RESEARCH DESIGN AND METHODS

          Eighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (Φ Total) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on Φ Total was examined.

          RESULTS

          Two SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion.

          CONCLUSIONS

          Variation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

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          Oral glucose tolerance test minimal model indexes of beta-cell function and insulin sensitivity.

          E Breda, M Cavaghan, G Toffolo … (2001)
          The simultaneous assessment of quantitative indexes of insulin secretion and action in a single individual is important when quantifying their relative role in the evolution of glucose tolerance in different physiopathological states. Available methods quantify these indexes in relatively nonphysiological conditions, e.g., during glucose clamps or intravenous glucose tolerance tests. Here, we present a method based on a physiological test applicable to large-scale genetic and epidemiologic studies-the oral glucose tolerance test (OGTT). Plasma C-peptide, insulin, and glucose data from a frequently sampled OGTT with 22 samples throughout 300 min (FSOGTT300-22) were analyzed in 11 subjects with various degrees of glucose tolerance. In each individual, two indexes of pancreatic sensitivity to glucose (phis [10(9) min(-1)] and phid [10(9)]) and the insulin sensitivity index (SI) (10(5) dl/kg per min per pmol/l) were estimated by using the minimal model of C-peptide secretion and kinetics originally proposed for intravenous graded glucose infusion and the minimal model approach recently proposed for meal/OGTTs. The indexes obtained from FSOGTT300-22 were used as a reference for internal validation of OGTT protocols with reduced sampling schedules. Our results show that 11 samples in a 300-min period (OGTT300-11) is the test of choice because the indexes it provides (phis = 36 +/- 3 [means +/- SE]; phid = 710 +/- 111; SI = 10.2 +/- 2.4) show excellent correlation and are not statistically different from those of FSOGTT300-22 (phis = 33 +/- 3; phid = 715 +/- 120; SI = 10.1 +/- 2.3). In conclusion, OGTT300-11, interpreted with C-peptide and glucose minimal models, provides a quantitative description of beta-cell function and insulin sensitivity in a single individual while preserving the important clinical classification of glucose tolerance provided by the standard 120-min OGTT.
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            Genomics of type 2 diabetes mellitus: implications for the clinician.

            C. Florez, Elliot Stolerman (2009)
            Our understanding of the genetics of type 2 diabetes mellitus (T2DM) has changed, in part owing to implementation of genome-wide association studies as a method for unraveling the genetic architecture of complex traits. These studies enable a global search throughout the nuclear genome for variants that are associated with specific phenotypes. Currently, single nucleotide polymorphisms in about 24 different genetic loci have been associated with T2DM. Most of these genetic loci are associated with the insulin secretion pathway rather than insulin resistance. Study design, heritability differences and the intrinsic properties of in vivo insulin resistance measures might partially explain why only a few loci associated with insulin resistance have been detected through genome-wide association approaches. Despite the success of these approaches at detecting loci associated with T2DM, currently known associations explain only a small amount of the genetic variance involved in the disease. Compared with previous studies, larger cohorts might be needed to identify variants of smaller effect sizes and lower allele frequencies. Finally, the current list of genetic loci that are related to T2DM does not seem to offer greater predictive value in determining diabetes risk than do commonly used phenotypic risk factors and family history.
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              A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness.

              E. McBride, M. Beinborn, Christine Worrall … (2005)
              Glucagon-like peptide-1 (GLP-1) and its cognate receptor play an important physiological role in maintaining blood glucose homeostasis. A GLP-1 receptor (GLP-1R) polymorphism in which threonine 149 is substituted with a methionine residue has been recently identified in a patient with type 2 diabetes but was not found in non-diabetic control subjects. We have functionally assessed the recombinant GLP-1R variant after transient expression in COS-7 and HEK 293 cells. Compared to the wild type receptor, the variant GLP-1R showed (i) similar expression levels, (ii) 60-and 5-fold reduced binding affinities, respectively, for two GLP-1R full agonists, GLP-1 and exendin-4, and (iii) markedly decreased potencies of these peptides in triggering cAMP-mediated signaling (despite conserved efficacies). In contrast to full agonists, the efficacy of the primary GLP-1 metabolite/GLP-1R partial agonist, GLP-1 (9-36) amide, was essentially abolished by the T149M substitution. By hydropathy analysis, the polymorphism localizes to transmembrane domain 1, suggesting this receptor segment as a novel determinant of agonist affinity/efficacy. These findings reveal that naturally occurring sequence variability of the GLP-1R within the human population can result in substantial loss-of-function. A genetic link between the T149M variant and increased susceptibility to type 2 diabetes remains to be established.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Care
                Journal ID (hwp): diacare
                Journal ID (pmc): dcare
                Journal ID (publisher-id): Diabetes Care
                Title: Diabetes Care
                Publisher: American Diabetes Association
                ISSN (Print): 0149-5992
                ISSN (Electronic): 1935-5548
                Publication date (Print): September 2010
                Volume: 33
                Issue: 9
                Pages: 2074-2076
                Affiliations
                [1] 1Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota;
                [2] 2Department of Information Engineering, University of Padua, Padua, Italy;
                [3] 3Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota;
                [4] 4Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
                Author notes
                Corresponding author: Adrian Vella, vella.adrian@ 123456mayo.edu .

                C.D.M. and F.M. contributed equally to this work.

                Article
                Publisher ID: 0200
                DOI: 10.2337/dc10-0200
                PMC ID: 2928367
                PubMed ID: 20805279
                SO-VID: 61b098e5-3729-418f-a7be-7db2cb16d743
                Copyright © © 2010 by the American Diabetes Association.
                License:

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                Date received : 1 February 2010
                Date accepted : 12 May 2010
                Categories
                Subject: Original Research
                Subject: Pathophysiology/Complications

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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