Physiologic Response to Glucagon at Varying Insulin Levels
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      The purpose of this research study is to test how different levels of insulin block the
      effect of glucagon. Insulin is a hormone that lowers blood glucose. Glucagon raises blood
      glucose. Both are natural hormones made by people without diabetes. Sensor-based blood
      glucose control studies have been done by our research group using glucagon in small doses to
      prevent hypoglycemia (low blood sugar). However, sometimes glucagon does not work to raise
      blood sugar. The investigators believe this is because of too much insulin in the body. This
      study will help determine how different levels of insulin in the body affect the ability of
      glucagon to raise blood sugar.
    

Detailed description: 
      We investigators have been working on the development of a closed loop (artificial endocrine
      pancreas) insulin and glucagon infusion system since 2005 and are part of the Juvenile
      Diabetes Research Foundation Artificial Pancreas Consortium. As part of our studies, we give
      small doses of glucagon to prevent hypoglycemia. As we assessed the success and failure of
      glucagon administration during these studies, we found the use of glucagon reduced the
      frequency of hypoglycemia by about 75%. However, the fact that approximately 25% of
      administrations of glucagon are ineffective remains a concern.

      The primary question to be addressed by this study is, in the setting of low dose
      subcutaneous glucagon administration, how do plasma glucagon and plasma insulin
      quantitatively interact? In other words, as the rate of insulin administration is increased,
      how much more glucagon is necessary to overcome the effect of insulin to prevent
      hypoglycemia? This study is designed to address this question. Subjects will be brought in to
      a Legacy Hospital for four 10 hour experiments on each of four separate days. On each study
      day, there will be a continuous infusion of a different rate of IV Regular insulin in order
      to achieve different steady state free insulin levels. At each insulin level, there will be
      four subcutaneous glucagon doses given. Octreotide will be infused by IV at a constant rate
      to suppress endogenous production of glucagon. A stable glucose isotope will also be infused
      to allow for measurement of hepatic glucose production and glucose turnover. Arterialized
      venous blood glucose will be measured by the HemoCue Glucose 201 Analyzer.
    

Intervention name(s): Glucagon; Insulin
Intervention type(s): Drug; Drug
Intervention description(s): The first dose of glucagon will be delivered approximately one hour after infusion of IV insulin has started. The subsequent three doses will be delivered every two hours. The dosage will depend on the IV insulin infusion (50 units regular insulin in 499.5 mL 0.9% saline): Study 1) insulin 0.01 units/kg/hour and glucagon doses (ug): 10,25,45,70; Study 2) insulin 0.02 units/kg/hr and glucagon doses (ug): 25,45,70,100; Study 3) insulin 0.04 units/kg/hr and glucagon doses (ug): 45,70,100,135; Study 4) insulin 0.08 units/kg/hr and glucagon doses (ug): 70,100,135,175. Insulin levels and glucagon doses will be randomized. Glucagon will be reconstituted with 10 mL of sterile water and administered subcutaneously.; Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.
Other intervention name(s): GlucaGen; Regular insulin
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Glucagon
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: diabetes; glucagon; insulin; dideuterated glucose