Adolescents with type 1 diabetes aged 12–18 years with hypoglycemia unawareness attending Princess Margaret Hospital diabetes clinics were invited to participate. Hypoglycemia unawareness score was determined by the use of modified Clarke's questionnaire (⁸). This questionnaire has been shown to accurately identify patients with impaired awareness of hypoglycemia for both clinical and research purposes (⁹). A score of ≥8 is suggestive of hypoglycemia unawareness. Consent was obtained for all participants.

All subjects underwent a hyperinsulinemic hypoglycemic clamp study at baseline to assess hypoglycemic symptoms and hormonal responses. Subjects were then randomized to either standard therapy (standard group) or to the use of real-time (Medtronic Minimed Paradigm REAL-Time System) CGM (CGM group) for 4 weeks. At the end of the 4-week period, all patients underwent a repeat hypoglycemic clamp study.

Eleven subjects were studied, including five subjects in the standard group (age 15.0 ± 0.8 years, A1C 7.9 ± 0.3% since diagnosis, duration 6.5 ± 1.2 years) and six subjects in the CGM group (age 13.8 ± 0.7 years, A1C 7.7 ± 0.2% since diagnosis, duration 5.2 ± 1.4 years).

At baseline, the epinephrine response to hypoglycemia was blunted, and there was no difference between subjects randomized to standard or CGM groups (percentage change 288 ± 151 vs. 214 ± 72%, standard vs. CGM group, respectively; P = 0.688). Following the intervention, there was a greater epinephrine response in the CGM group (percentage change 114 ± 83 vs. 604 ± 234%, standard vs. CGM group, respectively; P = 0.048). This represents a greater percentage rise in epinephrine concentrations during hypoglycemia following therapy in the CGM group (P = 0.375 vs. 0.031, standard vs. CGM group, respectively) as shown in Fig. 1. Peak adrenaline response during hypoglycemia after the intervention was also greater in the CGM group than in the standard group (1,093 ± 221 vs. 572 ± 162 pmol/l; P = 0.048). Subjects in the CGM group reported higher adrenergic symptoms scores after the intervention than the standard group (5.4 ± 0.4 vs. 3.4 ± 0.2; P < 0.001).

The mean A1C at baseline was 7.9 ± 0.3% for both groups. Following the intervention, there was no deterioration in glycemic control in the standard or CGM group (A1C 7.9 ± 0.4 vs. 8.3 ± 0.3%; P = 0.587).

The glucagon response was absent at baseline and after intervention in both groups. There was no change in cortisol and growth hormone responses to hypoglycemia for both groups.

The epinephrine response to hypoglycemia in patients with type 1 diabetes with hypoglycemia unawareness was greater after the use of real-time CGM with low glucose alarms than with standard medical therapy alone. The use of CGM was not associated with deterioration in A1C. This greater epinephrine response during hypoglycemia suggests that real-time CGM is a useful clinical tool to improve hypoglycemia unawareness in adolescents with type 1 diabetes. The high risk of associated severe hypoglycemia requires that hypoglycemia unawareness be recognized and treated.

This study demonstrates that blunted counterregulatory responses to hypoglycemia do occur in adolescents with a relatively short duration of diabetes. In addition to the blunted epinephrine response, most of these subjects reported no adrenergic symptoms during their baseline hypoglycemic clamp study.

A limitation of this study is the sample size. However, evaluating counterregulatory response with hypoglycemia clamp studies is a robust method, and this technique limits inclusion of a large number of subjects.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

No potential conflicts of interest relevant to this article were reported.

T.T.L. wrote the manuscript and collected and researched data. J.H. reviewed and edited the manuscript, collected data, and contributed to the study design. R.J.D. reviewed and edited the manuscript and contributed to the study design. E.M.L. reviewed and edited the manuscript and researched data. E.A.D. contributed to discussion, researched data, and reviewed and edited the manuscript. T.W.J. contributed to the study design, researched data, and wrote the manuscript.

We thank the families and children of Princess Margaret Hospital Diabetes Clinic for participating in this study.