Diabetes Research in Children Network (DirecNet)

Protocol: Relationship Between Loss of Beta Cell Function and Loss of the Alpha Cell Response to Hypoglycemia Early in Type 1 Diabetes
Status: Closed
Start Date: 11/01/2008
End Date: 04/23/2012
Clinical Trial ID:  
Public Dataset:  Download

Relationship Between Loss of β-Cell Function and Loss of the α-Cell Response to Hypoglycemia Early in Type 1 Diabetes

Click Here to View Protocol

The Diabetes Research in Children Network (DirecNet) is conducting a study to find out more information about the cells in the pancreas that produce a substance called glucagon in children with type 1 diabetes. Glucagon is released when the blood sugar is becoming low and helps to keep the blood sugar level from falling too far. The purpose of the study is to find out more about the relationship of the cells in the pancreas that produce insulin and the cells that produce glucagon.

The study will include individuals 8 to 18 years old who were diagnosed with type 1 diabetes between 6 week and 12 months ago and non-diabetic individuals 8 to 18 years of age who will serve as controls. The study will include 2 tests within 2 weeks of each other: the Mixed Meal Tolerance Test (or MMTT) and Clamp Test (only completed by T1DM subjects.

To take part in the study, T1DM subjects will need to have:

  1. Clinical diagnosis of type 1 diabetes between 6 weeks and 12 months prior to enrollment in the study.
  2. Subjects must have positive antibody determinations. (For subjects who have not had a prior positive antibody determination, blood will be drawn for antibody measurement (GAD65 and ICA512) and enrollment into the study will be deferred until the results are available.)
  3. Age >8.0 to <19.0 years
  4. Not be taking any oral antidiabetic medication
  5. Not be taking a medication or have another disease that the investigator feels would prevent him or her from completing any aspect of the study.
  6. No expectation that subject will be moving out of the area of the clinical center during the next 18 months, unless the move will be to an area served by another study center.

To take part in the study, control subjects will need to have:

  1. Age >8.0 to <19.0 years
  2. Not be clinically diagnosed with type 1 diabetes

Study Procedures
On the day of enrollment, a hemoglobin A1c level will be obtained, and potential subjects will be evaluated for study eligibility through the elicitation of a medical history and performance of a physical examination by a study investigator. T1DM subjects will be scheduled for both the Mixed Meal Tolerance Test and Clamp Test. Non-diabetic subjects will only be scheduled for the Mixed Meal Tolerance Test.

  • In preparation for the Mixed Meal Tolerance Test (or MMTT), subjects will be asked to consume a drink called “Boost”. Blood samples will be collected and blood sugar levels checked at regular intervals for 4 hours
    • The target glucose level at the start of the test should be between 70 and 200 mg/dL for subjects with T1DM.
    • Control subjects with a fasting blood glucose >110 mg/dL will not be eligible for continuation with the MMTT.
    • Blood will be obtained for measurement of plasma glucose, c-peptide and glucagon at -10, 0, 15, 30, 60, 90, 120, 150, 180, 210 and 240 minutes. A split-duplicate sample for quality control will also be collected.
  • For the Clamp Test in T1DM subjects:
    • The subject will be asked to wear a blinded continuous glucose monitor for 6-7 days before returning to the clinic for this test
    • Subjects will be asked not to eat or drink anything after midnight except water the night prior to the Clamp Test. Liquids that contain only simple sugars can be used to treat or prevent hypoglycemia during the night and morning prior to study.
    • IV lines will be inserted in each arm: one for blood sampling and one for infusion of 10-20% dextrose solution.
    • If possible, the subject will wear a calibrated CGM sensor that had been inserted 2-3 days prior to study.
    • The target glucose level at the start must be at least 90 mg/dL. After resting for 15 min after IV insertions, three baseline plasma glucose levels (-30, -15 and 0 min) will be obtained prior to starting a continuous infusion of regular insulin.
    • A dextrose infusion will be used to clamp the plasma glucose level between 90-100 mg/dl for 60 minutes.
    • Plasma glucose levels will be measured every 5 minutes at the bedside throughout the clamp procedure.
    • At the end of 60 min of euglycemic–hyperinsulinemia, the glucose infusion will be temporarily suspended and the plasma glucose levels will be allowed to fall to ~ 55 mg/dl, where it will be clamped for another 75 min.
    • The insulin infusion will be stopped and euglycemia restored by increasing the intravenous glucose infusion at the end of the study.
    • Blood samples for glucose, glucagon, epinephrine and norepinephrine measurements will be obtained just prior to the start of the clamp between 90-100 mg/dL (0 min), 30, 45 and 60 minutes after starting the euglycemic hyperinsulinemic phase of the study and after 15, 30, 45, 60, and 75 minutes of hypoglycemia. A split-duplicate sample for quality control will also be collected.

For T1DM subjects the tests will be repeated 1 year later and may be done again 6 months after that.



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