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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Maturity-Onset Diabetes of the Young, Type 3

Intervention / Treatment
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* Drug: Glimepiride 1Mg Tablet
* Drug: Glucagon-like Peptide-1
* Drug: Glucose-Dependent Insulinotropic Polypeptide
* Drug: Placebo Oral Tablet
* Drug: Placebo infusion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glimepiride + GIP<br>Tablet Glimepiride + infusion of GIP | Drug: Glimepiride 1Mg Tablet<br>* Glimepiride<br>Drug: Glucose-Dependent Insulinotropic Polypeptide<br>* GIP-infusion<br>|
| Active Comparator: Placebo + GIP<br>Placebo tablet + infusion of GIP | Drug: Glucose-Dependent Insulinotropic Polypeptide<br>* GIP-infusion<br>Drug: Placebo Oral Tablet<br>* Placebo<br>|
| Active Comparator: Glimepiride + GLP-1<br>Glimepiride + infusion of GLP-1 | Drug: Glimepiride 1Mg Tablet<br>* Glimepiride<br>Drug: Glucagon-like Peptide-1<br>* GLP-1 infusion<br>|
| Active Comparator: Placebo + GLP-1<br>Placebo tablet + infusion of GLP-1 | Drug: Glucagon-like Peptide-1<br>* GLP-1 infusion<br>Drug: Placebo Oral Tablet<br>* Placebo<br>|
| Active Comparator: Glimepiride + Placebo<br>Glimepiride + infusion of placebo (saline) | Drug: Glimepiride 1Mg Tablet<br>* Glimepiride<br>Drug: Placebo infusion<br>* Placebo (saline)<br>|
| Placebo Comparator: Placebo + Placebo<br>Placebo tablet + infusion of placebo (saline) | Drug: Placebo Oral Tablet<br>* Placebo<br>Drug: Placebo infusion<br>* Placebo (saline)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin secretion | 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 | 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 | Arginine maximal insulin secretion test. | 120-125 minutes | 
| Maximal glucagon secretion | Arginine maximal glucagon secretion test. | 120-125 minutes | 
| Amount glucose used to maintain the glucose clamp |  | 0-120 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Maturity-Onset Diabetes of the Young, Type 3, Glucose-dependent insulinotropic peptide, Glucagon-like-peptide 1, Dipeptidyl peptidase 4, Glimepiride, Sulphonylurea, Glucose clamp, Hepatocyte nuclear factor 1 alpha