Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study

Airani Sathananthan, Chiara Dalla Man, Francesco Micheletto, Alan R Zinsmeister, Michael Camilleri, Paula D Giesler, Jeanette M Laugen, Gianna Toffolo, Robert A Rizza, Claudio Cobelli, Adrian Vella, Airani Sathananthan, Chiara Dalla Man, Francesco Micheletto, Alan R Zinsmeister, Michael Camilleri, Paula D Giesler, Jeanette M Laugen, Gianna Toffolo, Robert A Rizza, Claudio Cobelli, Adrian Vella

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). beta-Cell responsivity (Phi(Total)) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on Phi(Total) was examined.

Results: Two SNPs (rs6923761 and rs3765467) were nominally associated with altered beta-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.

Figures

Figure 1
Figure 1
Effect of rs6923761, analyzed with the general model (A), and with the recessive model (B), and of rs3765467 (C) on ΦTotal in the presence and absence of GLP-1. *P < 0.05.

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