Exendin(9-39)Amide as a Glucagon-like Peptide-1 (GLP-1) Receptor Antagonist in Humans

• ClinicalTrials.gov Identifier: NCT00393445
• Recruitment Status: Completed
• First Posted: October 27, 2006
• Last Update Posted: October 4, 2011
• Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: German Research Foundation; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Joerg Schirra, Ludwig-Maximilians - University of Munich

Study Description

Brief 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%.

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

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%.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Diagnostic
• 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

Arms and Interventions

Arm

Intervention/treatment

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

Outcome Measures

Primary Outcome Measures :

1. 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 ]

Secondary Outcome Measures :

1. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Male or female (postmenopausal, surgically sterile or using double-barrier method of contraception) healthy volunteers
• Age 18-65 years
• Hemoglobin A1c (HbA1c) < 6%
• Body mass index (BMI) < 30 kg/m2
• Must have a fasting blood glucose below 100 mg/dl at screening and on all study days
• Able to provide written informed consent prior to study participation
• Able to communicate well with the investigator and comply with the requirements of the study

Exclusion Criteria:

• Diabetes mellitus
• Fasting triglycerides > 5.1 mmol/L (> 450 mg/dL) within the past 4 weeks.
• Treatment with systemic steroids and thyroid hormone
• Patients with any history of gastrointestinal surgery, e.g. partial bowel resections, partial gastric resections, etc.
• Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation.
• Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.
• Significant illness within the two weeks prior to dosing.
• Past medical history of clinically significant electrocardiogram (ECG) abnormalities or a family history of a prolonged QT-interval syndrome.
• History of clinically significant drug allergy; history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug.

• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the subject in case of participation in the study. The investigator should be guided by evidence of any of the following:

  • history of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding
  • history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
  • history or clinical evidence of pancreatic injury or pancreatitis
  • history or presence of impaired renal function as indicated by abnormal creatinine or urea values or abnormal urinary constituents (e.g., albuminuria)
  • evidence of urinary obstruction or difficulty in voiding at screening
• Polymorphonuclears < 1500/µL at inclusion or platelet count < 100,000/μL at screening and baseline.
• Evidence of liver disease as indicated by abnormal liver function tests such as SGOT, SGPT, GGT, alkaline phosphatase, or serum bilirubin.
• History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations.

Contacts and Locations

Locations

Germany

Ludwig Maximilians University, Clinical Research Unit

Munich, Germany, D-81377

Sponsors and Collaborators

Ludwig-Maximilians - University of Munich

German Research Foundation

Merck Sharp & Dohme LLC

Investigators

• Study Chair: Joerg Schirra, MD; Clinical Research Unit (CRU), Department of Internal Medicine II-Grosshadern, Ludwig-Maximilans-University of Munich

More Information

Publications of Results:

Schirra J, Sturm K, Leicht P, Arnold R, Göke B, Katschinski M. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998 Apr 1;101(7):1421-30.

Schirra J, Katschinski M, Weidmann C, Schäfer T, Wank U, Arnold R, Göke B. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest. 1996 Jan 1;97(1):92-103.

• Responsible Party: Joerg Schirra, Prof. Dr. med., Ludwig-Maximilians - University of Munich
• ClinicalTrials.gov Identifier: NCT00393445
• Other Study ID Numbers: DOF-Ex; DFG Schi 527/1-2
• First Posted: October 27, 2006
• Last Update Posted: October 4, 2011
• Last Verified: October 2011

Keywords provided by Joerg Schirra, Ludwig-Maximilians - University of Munich:

GLP-1; Exendin(9-39); Insulin; Glucagon; Human physiology

Additional relevant MeSH terms:

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Glucagon; Glucagon-Like Peptide 1; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Gastrointestinal Agents