Evaluation of Counter-regulatory Hormone Responses During Hypoglycemia and the Accuracy of Continuous Glucose Monitors in Children With T1DM

The present study is being undertaken to compare counterregulatory hormone responses to a mild and gradual reduction in plasma glucose in young children with T1DM versus responses in adolescents. The studies will be performed under the close supervision of the professional staff of each DirecNet center and frequent bedside monitoring of plasma glucose concentrations will ensure that clinically significant hypoglycemia is prevented from developing. All subjects will be admitted to the CRC and have an IV line for blood sampling inserted on the evening prior to study to reduce stress on the morning of the study. The study procedure will be simplified and made less invasive in comparison to a clamp or standard insulin infusion study (i.e. only the one IV for blood sampling will be needed) by limiting enrollment to insulin pump-treated subjects who will have their basal rates modestly increased to produce the hypoglycemic stimulus. Monsod and colleagues used the same procedure of increasing the basal insulin infusion dose to induce a gradual fall in plasma glucose in youth with type 1 diabetes in a study that compared the ability of injections of glucagon and epinephrine to treat mild hypoglycemia. It is particularly important to note that once the blood glucose level falls below 60 mg/dl, a blood sample will be obtained and hypoglycemia will then be immediately corrected by intravenous administration of exogenous glucose. In our recent DirecNet study, ~25% of children and adolescents had plasma glucose levels below 60 mg/dl during a typical night and this rose to ~50% of subjects when there was antecedent exercise in the late afternoon. Moreover, the frequency of mild as well as severe hypoglycemia is substantially higher in pre-school children than in children and adolescents. This safe and rigorously designed study will provide important new information regarding the role of inadequate counter-regulation on the increased risk of hypoglycemia in very young children with T1DM.

Real-time continuous glucose sensing systems offer the potential to markedly lower the risk of hypoglycemia in youth with T1DM. However, the DirecNet inpatient accuracy study demonstrated that the first generation of these devices was inaccurate when blood glucose was lowered to less than 70 mg/dl. In that study, children with T1DM between 3-17 years of age were admitted to the CRC for approximately 26 hours during which they wore 1-2 Medtronic MiniMed CGMS and 1-2 Cygnus GlucoWatch G2 Biographer continuous glucose monitors. In every subject in that study, blood samples were obtained every 30-60 minutes from an indwelling intravenous catheter for measurement of reference plasma glucose levels in the DirecNet Central Laboratory. The Guardian-RT continuous glucose monitoring systems is a real-time continuous glucose monitor that has considerable promise for use in children with diabetes. Therefore, a secondary aim of this study is to obtain very important data regarding the accuracy of this system during hypoglycemia in young children, as well as adolescents.

The Guardian-RT has been approved by the FDA for detecting trends and tracking patterns in adults (18 and older) and are indicated for adjunctive rather than replacement of standard home glucose monitoring devices. The sensor has been approved by the FDA for use for up to 72 hours but can function for a longer period of time.

The primary objective of this study will be to compare the glucose level at which counter-regulatory hormone responses occur during hypoglycemia in young children with diabetes, with the glucose level counter regulatory hormone responses that occur in older children with diabetes. We hypothesize that the children in the younger age group will not have a counterregulatory response until a lower glucose level is reached compared with children in the older age group.

Secondary objectives will be: