The Effect of GIP and GLP-1 on Insulin and Glucagon Secretion in Patients With HNF1A-diabetes Treated With or Without Sulphonylurea (HNF1A-Clamp)

June 25, 2019 updated by: Alexander Christensen, University Hospital, Gentofte, Copenhagen
The most prevalent monogenetic diabetic subtype is named maturity onset diabetes of the young type (MODY3) or hepatocyte nuclear factor 1α (HNF1A)-diabetes. The aim of this study is to evaluate the effects of supra-physiological levels of GIP and GLP-1, respectively, on insulin and glucagon secretion at fasting plasma glucose (FPG) and "post-prandial" PG levels (1.5 × FPG) in patients with HNF1A-diabetes and matched healthy controls treated with or without a low dose of glimepiride (sulphonylurea). In addition, we will evaluate the maximal insulin and glucagon secretory capacity in both groups.

Study Overview

Detailed Description

A total of 6 experimental days will be performed. The following is an outline of an experimental day:

Participants will meet after a 10-hour fast. A tablet of glimepiride 1.0 mg or placebo will be administered 90 minutes before the initiation of the experiment (-90 minutes) The mean FPG will be calculated from blood samples -105, -100 and -90 minutes. Two intravenous cannulas will be inserted in a cubital vein of each arm. One intravenous cannula will be used for infusions of glucose, arginine and GIP and the other will be used to collect venous blood. The forearm from which blood samples are drawn will be placed in a heating pad (50°C) throughout the experiment for arterialisation of venous blood.

At time 0 minutes, a glucose clamp will be established at the FPG level for 60 minutes and hereafter a post-prandial clamp period of 1.5 × FPG for another 60 minutes. At time 120 minutes, a bolus of 5g of L-arginine (given as 50% arginine HCl) will be infused during 30 seconds. The post-prandial clamp will be maintained for another 10 minutes until time 130 minutes to prevent reactive hypoglycaemia. Throughout the experiment (0-130 minutes) a continuous infusion of either GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min) or placebo (saline) will be administered.

During the experiment PG will be kept stable by a continuous 20%-glucose infusion. The rate of infusion will be regulated according to PG determined by bed-site measurements every 5 minutes. After 60 minutes, a post-prandial clamp will be established by a bolus infusion over one minute using 50%-glucose to target 1.5 × FPG (the amount of glucose to be administered will calculated as follows: (1.5 × FPG - FPG) × 35 mg glucose × weight in kilogram).

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Hellerup, Denmark, 2900
        • Center for Diabetes Research, Gentofte Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Participants

Ten patients with HNF1A-diabetes and ten matched healthy controls will be recruited. Different inclusion and exclusion criteria applies for the two groups:

Inclusion criteria for HNF1A-patients

  • Patients with HNF1A-diabetes verified by genetic testing
  • Patients treated with diet or sulphonylurea monotherapy
  • Normal haemoglobin (males 8.3-10.5 mmol/l, females 7.3-9.5 mmol/l)
  • Informed consent

Exclusion criteria for HNF1A-patients

  • Nephropathy (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 and/or albuminuria)
  • Liver disease (serum alanine aminotransferase (ALT) and/or serum aspartate aminotransferase (AST) above 2 × normal values)
  • Pregnancy or breastfeeding

Inclusion criteria for healthy controls

  • FPG ≤6 mmol/l and glycated haemoglobin (HbA1c) ≤43 mmol/mol
  • Normal haemoglobin as defined above
  • Age ≥18 years
  • Informed consent

Exclusion criteria for healthy controls

  • No family history of type 1 or type 2 diabetes
  • Nephropathy (defined above)
  • Liver disease (defined above)
  • Pregnancy or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Glimepiride + GIP
Tablet Glimepiride + infusion of GIP
Glimepiride
GIP-infusion
ACTIVE_COMPARATOR: Placebo + GIP
Placebo tablet + infusion of GIP
Placebo
GIP-infusion
ACTIVE_COMPARATOR: Glimepiride + GLP-1
Glimepiride + infusion of GLP-1
Glimepiride
GLP-1 infusion
ACTIVE_COMPARATOR: Placebo + GLP-1
Placebo tablet + infusion of GLP-1
Placebo
GLP-1 infusion
ACTIVE_COMPARATOR: Glimepiride + Placebo
Glimepiride + infusion of placebo (saline)
Glimepiride
Placebo (saline)
PLACEBO_COMPARATOR: Placebo + Placebo
Placebo tablet + infusion of placebo (saline)
Placebo
Placebo (saline)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Insulin secretion
Time Frame: 0-120 minutes
Incremental area under the curve (iAUC) for insulin (measured as C-peptide) at time 0-60 minutes, time 60-120 minutes and time 0-120 minutes
0-120 minutes

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Glucagon secretion
Time Frame: 0-120 minutes
Incremental area under the curve (iAUC) for plasma glucagon at time 0-60 minutes, time 60-120 minutes and time 0-120 minutes
0-120 minutes
Maximal insulin secretion
Time Frame: 120-125 minutes
Arginine maximal insulin secretion test.
120-125 minutes
Maximal glucagon secretion
Time Frame: 120-125 minutes
Arginine maximal glucagon secretion test.
120-125 minutes
Amount glucose used to maintain the glucose clamp
Time Frame: 0-120 minutes
0-120 minutes

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 8, 2017

Primary Completion (ACTUAL)

June 1, 2018

Study Completion (ACTUAL)

June 1, 2018

Study Registration Dates

First Submitted

March 10, 2017

First Submitted That Met QC Criteria

March 15, 2017

First Posted (ACTUAL)

March 16, 2017

Study Record Updates

Last Update Posted (ACTUAL)

June 27, 2019

Last Update Submitted That Met QC Criteria

June 25, 2019

Last Verified

June 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Maturity-Onset Diabetes of the Young, Type 3

Clinical Trials on Placebo Oral Tablet

3
Subscribe