The Effect of GLP-1 on the Inhibition of Glucagon Secretion

Study Overview
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Brief Summary
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Diabetes(both types) are recognized by high levels of glucagon in the circulation. Glucagon is known to increase blood glucose, and might therefore contribute to the respective diseases. Under some circumstances the gut hormone GLP-1 inhibits the glucagon secretion. The investigators aim to identify the impact of GLP-1 on the glucagon secretion, at increasing blood glucose levels in healthy subjects, in patients with type 2 diabetes, and in patients with type 1 diabetes. The investigators think that the effect of GLP-1 on the glucagon secretion might be dependent of blood glucose levels.

Conditions
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Type 2 Diabetes, Type 1 Diabetes

Intervention / Treatment
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* Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))
* Drug: NaCl
* Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))
* Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with T2DM Above the age of 35 years, treatment with diet or oral anti-diabetic medication. Diagnosed with T2DM in at leat three months in advance(WHO criterion) Normal hemoglobin Informed content Patients with T1DM T1DM (WHO criterion) Plasma-C-peptid negative due to arginin-test Normal hemoglobin age> 18 years Informed content Healthy subjects Normal fasting plasma glucose and normal glucose tolerance (WHO criterion) Normal hemoglobin Age >18 years Informed content Exclusion Criteria: Patients with T2DM Treatment with glitazones and/or gliptins Inflammatory bowels disease previous bowel resection with or without stomy Nephropathy (serum creatinin >150 µM and/or albuminuria) Liver disease (serum alanine-aminotransferase (ALAT) and/or serum aspartate-aminotransferase (ASAT) >2×normal values) Medical treatment impossible to break for 12h. Age >80 years Patients with T1DM Overweight (BMI >30 kg/m2) Inflammatory bowels disease previous bowel resection with or without stomy Nephropathy (serum creatinin >150 µM and/or albuminuria) Liver disease (serum alanine-aminotransferase (ALAT) and/or serum aspartate-aminotransferase (ASAT) >2×normal values) Medical treatment impossible to break for 12h (except treatment with insulin). Age >80 years Healthy subjects Diabetes Prediabetes (impaired glucose tolerance and/or impaired fasting plasma glucose) First order relatives with diabetes Overweight (BMI >30 kg/m2) Inflammatory bowels disease previous bowel resection with or without stomy Nephropathy (serum creatinin >150 µM and/or albuminuria) Liver disease (serum alanine-aminotransferase (ALAT) and/or serum aspartate-aminotransferase (ASAT) >2×normal values) Medical treatment impossible to break for 12h. Age >80 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy Subjects<br> | Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.2 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: NaCl<br>* Continuous iv. saline infusion (NaCl Isotonic) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.4 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.8 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>|
| Other: T2DM<br> | Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.2 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: NaCl<br>* Continuous iv. saline infusion (NaCl Isotonic) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.4 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.8 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>|
| Other: T1DM<br> | Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.2 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: NaCl<br>* Continuous iv. saline infusion (NaCl Isotonic) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.4 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36))<br>* Continuous iv. infusion of the native gut hormone GLP-1 (0.8 pmol/kg/min) for 210 minutes. Combined with a step wise glucose clamp using 20% w/w glucose iv. infusion reaching plasma glucose value of 15 mM starting at fasting plasma glucose (30 min per step)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Glucagon response to the GLP-1 infusion / glucose clamp | The collection of blood samples will be done during the 210 min GLP-1 infusion / glucose clamp-session | At 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210 min | 
| Plasma GLP-1 response to the GLP-1 infusion / glucose clamp | The collection of blood samples will be done during the 210 min GLP-1 infusion / glucose clamp-session | At 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210 min | 
| Plasma Glucose response to the GLP-1 infusion / glucose clamp | The collection of blood samples will be done during the 210 min GLP-1 infusion / glucose clamp-session | At 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210 min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting Metabolic Rate response to the GLP-1 infusion / glucose clamp | Assessed by indirect calorimetry during the GLP-1 infusion / glucose clamp-session | at 0, 120, and 180 min | 
| Hunger scores response to the GLP-1 infusion / glucose clamp | Assessed by VAS during the 210 min GLP-1 infusion / glucose clamp-session | At 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210 min | 
| plasma Insulin response to the GLP-1 infusion / glucose clamp | The collection of blood samples will be done during the 210 min GLP-1 infusion / glucose clamp-session | At 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210 min | 
| plasma GIP response to the GLP-1 infusion / glucose clamp | The collection of blood samples will be done during the 210 min GLP-1 infusion / glucose clamp-session | At 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210 min | 
| Food Intake | Assessed by ad'libitum meal after the 210 min GLP-1 infusion / glucose clamp. | at 210 min | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucagon-like peptide-1, Normal physiology, T2DM, T1DM, Glucagon