Clinical trial NCT01483651
Conditions: Type 1 Diabetes Mellitus
Keywords: diabetes glucagon insulin dideuterated glucose
Sponsor: Legacy Health System
Start date: 2011-11-01; Completion date: 2013-03-01
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief 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.

Arms: arm 1: All study subjects in this arm were randomized as follows:

First study is regular insulin infused at lowest level with glucagon administration.

Second study is regular insulin infused at medium level with glucagon adminstration.

Third study is regular insulin infused at highest level with glucagon administration. arm 2: All study subjects in this arm were randomized as follows:

First study is regular insulin infused at lowest level with glucagon administration.

Second study is regular insulin infused at highest level with glucagon adminstration.

Third study is regular insulin infused at medium level with glucagon administration. arm 3: All study subjects in this arm were randomized as follows:

First study is regular insulin infused at medium level with glucagon administration.

Second study is regular insulin infused at lowest level with glucagon adminstration.

Third study is regular insulin infused at highest level with glucagon administration. arm 4: All study subjects in this arm were randomized as follows:

First study is regular insulin infused at medium level with glucagon administration.

Second study is regular insulin infused at highest level with glucagon adminstration.

Third study is regular insulin infused at lowest level with glucagon administration. arm 5: All study subjects in this arm were randomized as follows:

First study is regular insulin infused at highest level with glucagon administration.

Second study is regular insulin infused at lowest level with glucagon adminstration.

Third study is regular insulin infused at medium level with glucagon administration. arm 6: All study subjects in this arm were randomized as follows:

First study is regular insulin infused at highest level with glucagon administration.

Second study is regular insulin infused at medium level with glucagon adminstration.

Third study is regular insulin infused at lowest level with glucagon administration.
Interventions: intervention 1: Glucagon intervention 2: Insulin
Intervention descriptions: intervention 1: 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. intervention 2: Insulin was administered at a low, medium or high infusion rate. The intervention sequence was randomly pre-determined for all participants.

Protocol documents: