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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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 Summary:

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).


Sponsor: University Hospital, Gentofte, Copenhagen

Current Primary Outcome: 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


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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
  • Maximal insulin secretion [ Time Frame: 120-125 minutes ]
    Arginine maximal insulin secretion test.
  • Maximal glucagon secretion [ Time Frame: 120-125 minutes ]
    Arginine maximal glucagon secretion test.
  • DPP-4 activity [ Time Frame: 0-120 minutes ]
  • Amount glucose used to maintain the glucose clamp [ Time Frame: 0-130 minutes ]


Original Secondary Outcome: Same as current

Information By: University Hospital, Gentofte, Copenhagen

Dates:
Date Received: March 10, 2017
Date Started: March 8, 2017
Date Completion: June 1, 2018
Last Updated: March 16, 2017
Last Verified: March 2017