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

Ludwig Maximilian University of Munich

Status and phase

Completed

Phase 1

Conditions

Hyperglycemia

Treatments

Drug: GLP-1 and Exendin(9-39) 900

Drug: saline control

Drug: GLP-1 and Exendin(9-39) 1200

Drug: GLP-1 and Exendin(9-39) 300

Drug: GLP-1 and Exendin(9-39) 600

Drug: GLP-1 control

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00393445

DFG Schi 527/1-2

DOF-Ex

Details and patient eligibility

About

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%.

Full 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%.

Enrollment

6 patients

Sex

All

Ages

18 to 65 years old

Volunteers

Accepts Healthy Volunteers

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.