Exendin(9-39)Amide as a Glucagon-like Peptide-1 (GLP-1) Receptor Antagonist in Humans
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|ClinicalTrials.gov Identifier: NCT00393445|
Recruitment Status : Completed
First Posted : October 27, 2006
Last Update Posted : October 4, 2011
|Condition or disease||Intervention/treatment||Phase|
|Hyperglycemia||Drug: GLP-1 control Drug: GLP-1 and Exendin(9-39) 300 Drug: saline control Drug: GLP-1 and Exendin(9-39) 600 Drug: GLP-1 and Exendin(9-39) 900 Drug: GLP-1 and Exendin(9-39) 1200||Phase 1|
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%.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||6 participants|
|Intervention Model:||Crossover Assignment|
|Official Title:||Effect of GLP-1 on Glucose Metabolism in Healthy Subjects and Patients With T2DM. Part 1: A Pilot Study to Assess the Efficacy of Exendin(9-39)Amide as a GLP-1 Receptor Antagonist in Healthy Subjects|
|Study Start Date :||November 2006|
|Actual Study Completion Date :||May 2007|
Experimental: Intravenous infusion
intravenous infusion of test substances
Drug: GLP-1 control
intravenous infusion of GLP-1
Other Name: GLP-1(7-36)amide
Drug: GLP-1 and Exendin(9-39) 300
intravenous infusion of exendin(9-39) at 300 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min
Drug: saline control
intravenous infusion of saline
Drug: GLP-1 and Exendin(9-39) 600
intravenous infusion of exendin(9-39) at 600 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min
Drug: GLP-1 and Exendin(9-39) 900
intravenous infusion of exendin(9-39) at 900 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min
Drug: GLP-1 and Exendin(9-39) 1200
intravenous infusion of exendin(9-39) at 1200 pmol/kg/min during GLP-1 at 0.3 and 0.9 pmol/kg/min
- To assess the effect of increasing doses of exendin(9-39) on first and second phase insulin secretion stimulated by intravenous GLP-1 during hyperglycemia [ Time Frame: within the actual study period ]
- To assess the effect of increasing doses of exendin(9-39) on plasma glucagon levels decreased by intravenous GLP-1 during hyperglycemia [ Time Frame: within the actual study period ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00393445
|Ludwig Maximilians University, Clinical Research Unit|
|Munich, Germany, D-81377|
|Study Chair:||Joerg Schirra, MD||Clinical Research Unit (CRU), Department of Internal Medicine II-Grosshadern, Ludwig-Maximilans-University of Munich|