The Reduced Insulinotropic Effect of a Continuous Infusion Relative to a Bolus Injection of GIP

The Reduced Insulinotropic Effect of a Continuous Infusion Relative to a Bolus Injection of Glucose-dependent Insulinotropic Polypeptide (GIP) in Patients With Type 2 Diabetes is Not Caused by Rapid Tachyphylaxis

In patients with type 2 diabetes, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) has lost its insulinotropic activity, but more so after continuous versus bolus administration. The design was a two-way crossover design comparing repeated bolus injection and continuous infusion of GIP under hyperglycaemic clamp conditions. Patients were age- gender- and weight-matched with type 2 diabetes, first degree relatives of such patients, and healthy subjects. Investigators performed a:

1. Oral glucose challenge;
2. hyperglycemic clamp (8.5 mmol/l) with two repeated GIP bolus administrations (50 pmol/kg body weight at 30 and 120 min); and
3. hyperglycemic clamp with continuous administration of GIP (2 pmol.kg-1.min-1 from 30-180 min).

To answer the question, whether rapid tachyphylaxis occurs with regard to the insulinotropic action of GIP, investigators studied type 2-diabetic patients, their first-degree relatives, and healthy controls under hyperglycaemic clamp conditions with two GIP bolus injections 90 min apart, and compared this to a continued intravenous infusion of GIP.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Procedure: Oral glucose tolerance test (OGTT); Drug: GIP Bolus; Procedure: hyperglycemic clamp; Drug: GIP Clamp

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Exclusion of pregnancy
• Exclusion of impaired glucose tolerance or type 2 diabetes in metabolical healthy subjects
• current diagnosis of type 2 diabetes according to the guidelines of the German Diabetes Association (DDG) ( Kerner et al . 2001) in subjects of diabetes group
• fasting glucose ≤ 150 mg/dl
• Body-mass-index ≥ 20 kg/m²
• Written consent

Exclusion Criteria:

• Type 1 diabetes
• Impaired glucose tolerance or Type 2 diabetes in metabolical healthy subjects
• Ketone bodies urine diagnostics at least ++
• Acidosis
• Fasting blood glucose > 150 mg/dl
• Body-mass-index < 20 kg/m²
• No written consent
• Pregnancy or unsafe contraception in women before menopause
• Active malignancy
• Angina as current, unsolved clinical problem
• Inadequately treated or untreated arterial hypertension ( > 160 mmHg systolic and / or > 95 mmHg diastolic )
• Infection / fever > 37.5 ° C
• Treatment with glucocorticoids
• Insulin therapy within the last three months
• Anemia with a hemoglobin level < 12 g/dl
• Liver function limitations
• Renal impairment ( serum creatinine > 1.5 mg/dl )
• Alcohol or drug abuse
• Participation in clinical trials in the last 3 months
• Inability or unwillingness to comply with the requirements of the Protocol
• Known hypersensitivity to GIP

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral glucose tolerance test; An oral glucose challenge (75 g)	Procedure: Oral glucose tolerance test (OGTT); an oral glucose challenge (75 g)
Active Comparator: GIP Bolus; Hyperglycemic clamp (capillary venous glucose concentration ~ 8.5 mmol/l) with two repeated intravenous bolus injections of synthetic human GIP (50 pmol/kg body weight) administered 30 and 120 min after commencing the hyperglycemic clamp	Drug: GIP Bolus; bolus injections of synthetic human GIP (50 pmol/kg body weight) administered 30 and 120 min after commencing the hyperglycemic clamp; Procedure: hyperglycemic clamp; a hyperglycemic clamp (capillary venous glucose concentration ~ 8.5 mmol/l)
Active Comparator: GIP Infusion; Hyperglycemic clamp with the continuous intravenous infusion of 2 pmol.kg-1.min-1 synthetic human GIP between 30 and 180 min	Procedure: hyperglycemic clamp; a hyperglycemic clamp (capillary venous glucose concentration ~ 8.5 mmol/l); Drug: GIP Clamp; hyperglycemic clamp with the continuous intravenous infusion of 2 pmol.kg-1.min-1 synthetic human GIP between 30 and 180 min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Insulin secretory response after GIP bolus or infusion.	210 minutes

Collaborators and Investigators

• Sponsor: Diabeteszentrum Bad Lauterberg im Harz
• Investigators: Principal Investigator: Michael A. Nauck, Prof., Diabeteszentrum Bad Lauterberg

Study record dates

Study Major Dates

• Study Start: May 1, 2004
• Primary Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: January 28, 2016
• First Submitted That Met QC Criteria: February 1, 2016
• First Posted (Estimate): February 4, 2016

Study Record Updates

• Last Update Posted (Estimate): February 4, 2016
• Last Update Submitted That Met QC Criteria: February 1, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Tachyphylaxis; Insulin secretion; Incretin; Glucose-dependent Insulinotropic Polypeptide (GIP); Glucagon-Like Peptide 1 (GLP-1)
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: GIP and Tachyphylaxis

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO