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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 (HNF1A-Clamp)

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ClinicalTrials.gov Identifier: NCT03081676
Recruitment Status : Completed
First Posted : March 16, 2017
Last Update Posted : October 11, 2018
Sponsor:
Information provided by (Responsible Party):
Alexander Christensen, 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.

Condition or disease Intervention/treatment Phase
Maturity-Onset Diabetes of the Young, Type 3 Drug: Glimepiride 1Mg Tablet Drug: Glucagon-like Peptide-1 Drug: Glucose-Dependent Insulinotropic Polypeptide Drug: Placebo Oral Tablet Drug: Placebo infusion Not Applicable

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  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: The Effect of GIP and GLP-1 on Insulin and Glucagon Secretion in Patients With HNF1A-diabetes Treated With or Without Sulphonylurea
Actual Study Start Date : March 8, 2017
Actual Primary Completion Date : June 1, 2018
Actual Study Completion Date : June 1, 2018


Arm Intervention/treatment
Active Comparator: Glimepiride + GIP
Tablet Glimepiride + infusion of GIP
Drug: Glimepiride 1Mg Tablet
Glimepiride

Drug: Glucose-Dependent Insulinotropic Polypeptide
GIP-infusion

Active Comparator: Placebo + GIP
Placebo tablet + infusion of GIP
Drug: Glucose-Dependent Insulinotropic Polypeptide
GIP-infusion

Drug: Placebo Oral Tablet
Placebo

Active Comparator: Glimepiride + GLP-1
Glimepiride + infusion of GLP-1
Drug: Glimepiride 1Mg Tablet
Glimepiride

Drug: Glucagon-like Peptide-1
GLP-1 infusion

Active Comparator: Placebo + GLP-1
Placebo tablet + infusion of GLP-1
Drug: Glucagon-like Peptide-1
GLP-1 infusion

Drug: Placebo Oral Tablet
Placebo

Active Comparator: Glimepiride + Placebo
Glimepiride + infusion of placebo (saline)
Drug: Glimepiride 1Mg Tablet
Glimepiride

Drug: Placebo infusion
Placebo (saline)

Placebo Comparator: Placebo + Placebo
Placebo tablel + infusion of placebo (saline)
Drug: Placebo Oral Tablet
Placebo

Drug: Placebo infusion
Placebo (saline)




Primary Outcome Measures :
  1. Insulin secretion [ Time Frame: 0-120 minutes ]
    Incremental area under the curve (iAUC) for plasma insulin at time 0-60 minutes, time 60-120 minutes and time 0-120 minutes


Secondary Outcome Measures :
  1. 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

  2. Maximal insulin secretion [ Time Frame: 120-125 minutes ]
    Arginine maximal insulin secretion test.

  3. Maximal glucagon secretion [ Time Frame: 120-125 minutes ]
    Arginine maximal glucagon secretion test.

  4. DPP-4 activity [ Time Frame: 0-120 minutes ]
  5. Amount glucose used to maintain the glucose clamp [ Time Frame: 0-130 minutes ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03081676


Locations
Denmark
Center for Diabetes Research, Gentofte Hospital
Hellerup, Denmark, 2900
Sponsors and Collaborators
University Hospital, Gentofte, Copenhagen

Responsible Party: Alexander Christensen, MD, PhD student, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier: NCT03081676     History of Changes
Other Study ID Numbers: H-16038140
First Posted: March 16, 2017    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alexander Christensen, University Hospital, Gentofte, Copenhagen:
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

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glucagon
Gastric Inhibitory Polypeptide
Glucagon-Like Peptide 1
Glimepiride
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Incretins
Anti-Arrhythmia Agents
Hypoglycemic Agents
Immunosuppressive Agents
Immunologic Factors