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

Not Applicable

Completed

• Conditions: Maturity-Onset Diabetes of the Young, Type 3
• Interventions: Drug: Glucagon-like Peptide-1; Drug: Glimepiride 1Mg Tablet; Drug: Glucose-Dependent Insulinotropic Polypeptide; Drug: Placebo Oral Tablet; Drug: Placebo infusion

• Registration Number: NCT03081676
• Lead Sponsor: University Hospital, Gentofte, Copenhagen

Brief Summary

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.

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 Timeline

• Study Start: 2017-03-08
• Study First Submitted: 2017-03-10
• Study First Submitted QC: 2017-03-15
• Study First Posted: 2017-03-16
• Primary Completion: 2018-06-01
• Study Completion: 2018-06-01
• Status Verified: 2019-06
• Last Update Submitted: 2019-06-25
• Last Update Posted: 2019-06-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + GLP-1	Glucagon-like Peptide-1	Placebo tablet + infusion of GLP-1
Glimepiride + GLP-1	Glimepiride 1Mg Tablet	Glimepiride + infusion of GLP-1
Placebo + GLP-1	Placebo Oral Tablet	Placebo tablet + infusion of GLP-1
Glimepiride + Placebo	Glimepiride 1Mg Tablet	Glimepiride + infusion of placebo (saline)
Glimepiride + GIP	Glimepiride 1Mg Tablet	Tablet Glimepiride + infusion of GIP
Glimepiride + Placebo	Placebo infusion	Glimepiride + infusion of placebo (saline)
Placebo + Placebo	Placebo infusion	Placebo tablet + infusion of placebo (saline)
Placebo + GIP	Glucose-Dependent Insulinotropic Polypeptide	Placebo tablet + infusion of GIP
Placebo + GIP	Placebo Oral Tablet	Placebo tablet + infusion of GIP
Glimepiride + GLP-1	Glucagon-like Peptide-1	Glimepiride + infusion of GLP-1
Placebo + Placebo	Placebo Oral Tablet	Placebo tablet + infusion of placebo (saline)
Glimepiride + GIP	Glucose-Dependent Insulinotropic Polypeptide	Tablet Glimepiride + infusion of GIP

Primary Outcome Measures

Name	Time	Method
Insulin secretion	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

Secondary Outcome Measures

Name	Time	Method
Amount glucose used to maintain the glucose clamp	0-120 minutes
Maximal insulin secretion	120-125 minutes	Arginine maximal insulin secretion test.
Glucagon secretion	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
Maximal glucagon secretion	120-125 minutes	Arginine maximal glucagon secretion test.

Trial Locations

Locations (1)

Center for Diabetes Research, Gentofte Hospital; 🇩🇰 Hellerup, Denmark