Exendin(9-39)Amide as a Glucagon-like Peptide-1 (GLP-1) Receptor Antagonist in Humans
Condition: Hyperglycemia
MeSH terms: Hyperglycemia
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine the dose of the GLP-1 receptor antagonist
      exendin(9-39) which blocks the insulinotropic action of synthetic GLP-1 by at least 95%.
    

Detailed description: 
      Following a meal, gut-produced incretin hormones such as glucagon-like peptide-1 (GLP-1) and
      glucose-dependent insulinotropic polypeptide (GIP) are released into the circulation. GLP-1
      and GIP, the two dominant incretin hormones, are part of a natural endogenous system involved
      in maintaining glucose homeostasis. In the presence of normal or elevated, but not low,
      glucose concentration, both GLP-1 and GIP increase insulin secretion from pancreatic islet
      beta-cells (β-cells). GLP-1 also lowers glucagon secretion from pancreatic alpha-cells and
      delays nutrient delivery from the stomach by inhibiting gastric emptying. This rise in
      insulin concentration enhances glucose clearance in peripheral tissues such as muscle, and
      the lower glucagon concentration combined with the rise in insulin reduces hepatic glucose
      production. By enhancing glucose clearance and lowering hepatic glucose production, the
      post-meal glucose excursion is reduced.

      However, the role that each incretin has in glucoregulation is not fully understood. Use of a
      GLP-1 antagonist, exendin (9-39)NH2, will allow for the assessment of non-GLP-1 incretin's
      role in glucoregulation. Therefore, it is of great interest to examine the role that specific
      incretins have in glucoregulation in patients with T2DM.

      Exendin(9-39) has been shown a specific and reversible antagonist at the human GLP-1 receptor
      in vivo. In initial validation studies intravenous exendin(9-39) dose-dependently reduced the
      insulinotropic action of intravenous GLP-1. The maximal dose of 300 pmol/kg/min used in these
      studies was sufficient to reduce GLP-1 stimulated insulin plasma levels by about 83%.
      However, to quantify the contribution of incretin hormones to the incretin effect as stated
      above a nearly complete inhibition of the GLP-1 action is necessary.

      Therefore the purpose of this pilot study is to characterize the dose-response
      characteristics of exendin(9-39) more completely and to find a dosage which inhibits the
      insulinotropic action of GLP-1 by at least 95%.
    

Intervention name(s): GLP-1 control; GLP-1 and Exendin(9-39) 300; saline control; GLP-1 and Exendin(9-39) 600; GLP-1 and Exendin(9-39) 900; GLP-1 and Exendin(9-39) 1200
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): intravenous infusion of GLP-1; intravenous infusion of exendin(9-39) at 300 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min; intravenous infusion of saline; intravenous infusion of exendin(9-39) at 600 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min; intravenous infusion of exendin(9-39) at 900 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min; intravenous infusion of exendin(9-39) at 1200 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min
Other intervention name(s): GLP-1(7-36)amide
Intervention MeSH terms: Glucagon; Glucagon-Like Peptide 1
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Diagnostic
Keywords: GLP-1; Exendin(9-39); Insulin; Glucagon; Human physiology