Does Hypoglycemia Awareness Status on Gold and Clark Questionnaires Predict Hormonal and Symptomatic Responses to Hypoglycemia (HG) in Type 1 Diabetes (T1D)?

Abstract

Impaired awareness of hypoglycemia (IAH) is characterized by the diminished ability to perceive symptoms of HG. Gold and Clark questionnaires are commonly used in research to identify patients with IAH. However, the relationship between IAH status on questionnaires and the symptom and counterregulatory (CR) hormone responses to HG are not well understood. In this study, we examined data from 51 research subjects with T1D who completed both questionnaires and underwent a hyperinsulinemic hypoglycemic clamp (target glucose 50 mg/dL) on the same day. Clarke and Gold scores were highly correlated with one another (r = 0.78) and each had a similar relationship with epinephrine (EPI) response during HG (Clarke: r = -0.46, Gold: r = -0.53) and symptom response (Clarke: r = -0.60, Gold: r = -0.52). However, Clarke and Gold disagreed on classification of HG awareness status (misclassification=37%, Cohen’s κ=0.54). Clarke classifications were: 26 Aware (A), 13 Indeterminate (I), 12 Unaware (U), whereas Gold classifications were 16 A, 15 I, and 20 U. A mixture model based clustering identified 3 patterns in joint EPI and symptom responses. Cluster 1 subjects (n=10) had low symptom (<5) and EPI responses (<140) to HG and 8/10 were classified as U by one or both questionnaires. Cluster 3 subjects (n=9) had high symptom (20+) and EPI responses (450+) to HG and 8 of 9 were classified as A by one or both questionnaires. Cluster 2 subjects (n=22) had intermediate symptom and EPI responses to HG but concordance of classification by Clarke and Gold was true for only 11 of the 24. Clarke classified cluster 2 subjects as 12 A, 7 I, and 3 U whereas Gold classified the same subjects into 6 A, 7 I, and 9 U. IAH classification may be discordant between Clark and Gold questionnaires and may not always correlate with the CR responses during experimental HG. To ensure reproducibility, researchers must be rigorous and consistent in defining the awareness status of study subjects. Disclosure N. Rubin: None. A. Moheet: None. L.E. Eberly: None. A. Kumar: None. S. Mangia: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..