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

NCT ID: NCT03081676

Last Updated: 2019-06-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-08
• Study Completion Date: 2018-06-01

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).

Conditions

Maturity-Onset Diabetes of the Young, Type 3

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Glimepiride + GIP

Tablet Glimepiride + infusion of GIP

Group Type: ACTIVE_COMPARATOR

Glimepiride 1Mg Tablet

Intervention Type: DRUG

Glimepiride

Glucose-Dependent Insulinotropic Polypeptide

Intervention Type: DRUG

GIP-infusion

Placebo + GIP

Placebo tablet + infusion of GIP

Group Type: ACTIVE_COMPARATOR

Glucose-Dependent Insulinotropic Polypeptide

Intervention Type: DRUG

GIP-infusion

Placebo Oral Tablet

Intervention Type: DRUG

Placebo

Glimepiride + GLP-1

Glimepiride + infusion of GLP-1

Group Type: ACTIVE_COMPARATOR

Glimepiride 1Mg Tablet

Intervention Type: DRUG

Glimepiride

Glucagon-like Peptide-1

Intervention Type: DRUG

GLP-1 infusion

Placebo + GLP-1

Placebo tablet + infusion of GLP-1

Group Type: ACTIVE_COMPARATOR

Glucagon-like Peptide-1

Intervention Type: DRUG

GLP-1 infusion

Placebo Oral Tablet

Intervention Type: DRUG

Placebo

Glimepiride + Placebo

Glimepiride + infusion of placebo (saline)

Group Type: ACTIVE_COMPARATOR

Glimepiride 1Mg Tablet

Intervention Type: DRUG

Glimepiride

Placebo infusion

Intervention Type: DRUG

Placebo (saline)

Placebo + Placebo

Placebo tablet + infusion of placebo (saline)

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

Placebo

Placebo infusion

Intervention Type: DRUG

Placebo (saline)

Interventions

Glimepiride 1Mg Tablet

Glimepiride

Intervention Type: DRUG

Glucagon-like Peptide-1

GLP-1 infusion

Intervention Type: DRUG

Glucose-Dependent Insulinotropic Polypeptide

GIP-infusion

Intervention Type: DRUG

Placebo Oral Tablet

Placebo

Intervention Type: DRUG

Placebo infusion

Placebo (saline)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

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

Exclusion Criteria

• 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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University Hospital, Gentofte, Copenhagen

OTHER

Sponsor Role: lead

Responsible Party

Alexander Christensen

MD, PhD student

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Center for Diabetes Research, Gentofte Hospital

Hellerup, , Denmark

Countries

Denmark

References

Christensen AS, Haedersdal S, Storgaard H, Rose K, Hansen NL, Holst JJ, Hansen T, Knop FK, Vilsboll T. GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1alpha Mutation Carriers. Diabetes. 2020 Sep;69(9):1989-2002. doi: 10.2337/db20-0074. Epub 2020 Jun 9.

Reference Type: DERIVED

PMID: 32518064 (View on PubMed)

Other Identifiers

H-16038140

Identifier Type: -

Identifier Source: org_study_id