The Role of Endogenous Glucagon-like Peptide 1 (GLP-1) in Type 2 Diabetes Mellitus (T2DM) (DFG_5)

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)

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).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: exendin(9-39)amide; Drug: saline; Other: duodenal meal; Other: duodenal saline

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Munich, Germany, 81377
    • Clinical Research unit, Dept. of Internal Medicine II - Großhadern, University of Munich
  • Munich, Germany, 80999
    • Ludwig Maximilians-University, Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Investigators: Principal Investigator: Joerg Schirra, MD, Clinical Research Unit (CRU), Department of Internal Medicine, Campus Großhadern, Clinical Center of Ludwig-Maximilians-University of Munich

Publications and helpful links

General Publications

• Woerle HJ, Carneiro L, Derani A, Goke B, Schirra J. The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes. Diabetes. 2012 Sep;61(9):2349-58. doi: 10.2337/db11-1701. Epub 2012 Jun 20.

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): August 1, 2007
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: October 2, 2011
• First Submitted That Met QC Criteria: October 5, 2011
• First Posted (Estimate): October 7, 2011

Study Record Updates

• Last Update Posted (Estimate): October 7, 2011
• Last Update Submitted That Met QC Criteria: October 5, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: Insulin; GLP-1; T2DM; incretin effect; Glucagon; Exendin(9-39); human physiology
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: DPI