GLP1R Polymorphisms and Response to GLP1

A Pilot Study Examining How Common Genetic Variation in GLP1R Alters Response to GLP1 Infusion

Glucagon-like Peptide-1 (GLP-1) is an important incretin hormone which acts as a powerful insulin secretagogue. Defects in GLP-1 synthesis and secretion are thought to be part of the pathogenesis of type 2 diabetes. Furthermore GLP-1 based therapy is an important part of the therapeutic armamentarium for the treatment of type 2 diabetes. The GLP-1 receptor (GLP1R) is the principal site of action of GLP-1 and GLP-1 receptor agonists like exenatide and liraglutide. The gene coding for this receptor, GLP1R, is highly polymorphic and contains numerous non-synonymous Single Nucleotide Polymorphisms (nsSNPs) which could potentially alter response to endogenous or exogenous GLP-1 or GLP-1R agonists. Indeed there is some in vitro data to support this concept. We propose to utilize a hyperglycemic clamp to test the insulin secretory response to infused GLP-1 in healthy volunteers to determine the effect of genetic variation in GLP1R on response to GLP-1.

Inclusion Criteria:

• Aged 18-40
• fasting glucose concentration of less than 95 mg/dl.

Exclusion Criteria:

• Individuals with a BMI < 19 or > 40 kg/m^2
• active systemic illness
• medication that can alter gastric emptying, insulin secretion & action
• history of abdominal surgery (other than appendectomy or tubal ligation).