The Role of Endogenous Glucagon-like Peptide 1 (GLP-1) in Type 2 Diabetes Mellitus (T2DM)

Study Overview
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Brief Summary
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The purpose of the study is to determine the contribution of endogenous Glucagon-like peptide 1 (GLP-1) to the postprandial secretion of insulin and glucagon and the incretin effect in healthy subjects and patients with type 2 diabetes mellitus (T2DM).

Official Title
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The Contribution of Glucagon-like Peptide 1 (GLP-1) to the Entero-insulinar Axis in Healthy Subjects and Patients With Type 2 Diabetes Mellitus (T2DM)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: exendin(9-39)amide
* Drug: saline
* Other: duodenal meal
* Other: duodenal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male or female (postmenopausal, surgically sterile or using double-barrier method of contraception) healthy subjects and patients with type 2 diabetes mellitus (T2DM) must be able to complete a 1 week wash-out of current anti-diabetic medications Age 30-70 years HbA1c (Hemoglobin A1c) ≤11% at screening Body mass index (BMI) <40 kg/m2 Patients with type 2 diabetes mellitus (T2DM): Must have a fasting blood glucose of ≤12.2 mmol/L (240 mg/dL) at screening 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: Patients with type 1 diabetes mellitus (T1DM), diabetes as a result of pancreatic injury, or secondary forms of diabetes (eg Cushing, acromegaly) Need for insulin within the previous 3 months Use of Thiazolidinediones in the previous 4 weeks Significant concomitant disease or complications of diabetes (i.e. nephropathy, autonomic dysfunction, orthostasis). Treatment with systemic steroids and thyroid hormone (unstable dosage). 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 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. 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 val-ues 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. History of immunocompromise. Evidence of liver disease as indicated by abnormal transaminases and alkaline phosphatase exceeding twice the upper limit of the normal range, and serum bilirubin should not exceed the value of 27 µmol/L (1.6 mg/dL).

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: intravenous infusion<br> | Drug: exendin(9-39)amide<br>* intravenous infusion of exendin(9-39)<br>Drug: saline<br>* intravenous infusion of saline<br>|
| Experimental: intraduodenal perfusion<br> | Other: duodenal meal<br>* duodenal perfusion of a meal<br>Other: duodenal saline<br>* duodenal perfusion of saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incretin effect | The incretin effect is the difference between postprandial plasma concentrations of insulin and C-peptide, respectively, and those during the isoglycemic fasting control experiment. The AUC is calculated after priming intravenous infusion (saline or exendin(9-39)) and under steady state duodenal meal perfusion. | Area Under Curve (AUC) Time Frame: from 0 to 90 minutes under duodenal meal perfusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of glucagon | The AUC is calculated after priming intravenous infusion (saline or exendin(9-39)) and under steady state duodenal meal perfusion. | Area Under Curve (AUC) Time Frame: from 0 to 90 minutes under duodenal meal perfusion | 
| Plasma concentrations of insulin | The AUC is calculated after priming intravenous infusion (saline or exendin(9-39)) and under steady state duodenal meal perfusion. | Area Under Curve (AUC) Time Frame: from 0 to 90 minutes under duodenal meal perfusion | 
| Plasma concentrations of C-peptide | The AUC is calculated after priming intravenous infusion (saline or exendin(9-39)) and under steady state duodenal meal perfusion. | Area Under Curve (AUC) Time Frame: from 0 to 90 minutes under duodenal meal perfusion | 
| Plasma concentrations of Glucagon-like peptide-1(7-36) (GLP-1(7-36)) | The AUC is calculated after priming intravenous infusion (saline or exendin(9-39)) and under steady state duodenal meal perfusion. | Area Under Curve (AUC) Time Frame: from 0 to 90 minutes under duodenal meal perfusion | 
| Plasma concentrations of Glucose-dependent insulinotropic polpypeptide (GIP) | The AUC is calculated after priming intravenous infusion (saline or exendin(9-39)) and under steady state duodenal meal perfusion. | Area Under Curve (AUC) Time Frame: from 0 to 90 minutes under duodenal meal perfusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-1, Exendin(9-39), Insulin, Glucagon, T2DM, incretin effect, human physiology