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

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes; Type 2 Diabetes
• Intervention / Treatment: 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))

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, DK-2900
    • Gentofte University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: Healthy Subjects	Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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); Drug: NaCl; 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); Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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); Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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)
OTHER: T2DM	Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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); Drug: NaCl; 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); Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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); Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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)
OTHER: T1DM	Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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); Drug: NaCl; 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); Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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); Drug: Native human Glucagon-like Peptide-1 ( GLP-1(7-36)); 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen

Publications and helpful links

General Publications

• Bagger JI, Grondahl MFG, Lund A, Holst JJ, Vilsboll T, Knop FK. Glucagonostatic Potency of GLP-1 in Patients With Type 2 Diabetes, Patients With Type 1 Diabetes, and Healthy Control Subjects. Diabetes. 2021 Jun;70(6):1347-1356. doi: 10.2337/db20-0998. Epub 2021 Mar 15.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (ACTUAL): August 1, 2013
• Study Completion (ACTUAL): August 1, 2013

Study Registration Dates

• First Submitted: December 13, 2011
• First Submitted That Met QC Criteria: January 10, 2012
• First Posted (ESTIMATE): January 11, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): December 10, 2013
• Last Update Submitted That Met QC Criteria: December 9, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: T2DM; Glucagon; T1DM; Glucagon-like peptide-1; Normal physiology
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Glucagon; Glucagon-Like Peptide 1
• Other Study ID Numbers: GlukaStase; H-3-2011-088 (OTHER: The Danish National Committee for Research Ethics)