Approved Research

Physiological and Bioinformatics Analyses of Genetic Variants in the Glucagon Receptor

Lay summary

The worldwide prevalence of obesity is increasing, and so is related diseases such as type 2 diabetes and fatty liver disease. Understanding mechanisms underlying these diseases might lead to new options for prevention and/or treatment. The researchers associated with this study are particularly interested in the hormone glucagon derived from the pancreas and its roles in development of metabolic diseases. Both activation and inhibition of its receptor, the glucagon receptor, is being investigate as potential drugs of obesity and type 2 diabetes, respectively. In the proposed research project, we plan to investigate whether genetic variants of the glucagon receptor with particularly high/low activity are associated to medical conditions. We will explore associations to factors such as BMI, liver fat, and reported diseases.

The project is planned to run for three years.

Scope extension:

Glucagon is secreted from the pancreatic alpha cells and increased glucagon signaling contributes to metabolic diseases. According to the genetic databases GnomAD, variants in the glucagon receptor (GCGR) gene exists by frequencies between 1/150 and 1/15,000 individuals. The aim of this project is to investigate if GCGR variants with altered receptor activity, assessed by golden standard pharmacological in-vitro studies, associate with metabolic diseases such as chronic kidney disease, obesity, type 2 diabetes and non-alcoholic fatty liver disease.

Research questions:

1) Do GCGR gene variants associate with metabolic diseases such as obesity and type 2 diabetes?

2) Do GCGR gene variants associate with increased liver fat estimated by magnetic resonance imaging?

3) Are GCGR gene variants and hepatic fat associated with plasma concentrations of amino acids controlling glucagon secretion (e.g. alanine)?

The glucagon receptor family furthermore includes the glucagon-like peptide 1 receptor (GLP-1R), glucagon-like peptide 2 receptor (GLP-2R), and the Glucose-dependent insulinotropic polypeptide receptor (GIPR). We will also investigate if GLP-1R, GLP-2R and GIPR gene variants with altered activity associate with the risk of bone fracture, osteoporosis, and metabolic diseases.

4) Are GLP-1R, GLP-2R, and GIPR gene variants associated with bone fracture, osteoporosis, and metabolic diseases?