Evaluation of Clinical Metrics for Identifying Defective Physiologic Responses to Hypoglycemia in Long-Standing Type 1 Diabetes

Abstract

Repeated hypoglycemia exposure leads to impaired awareness of hypoglycemia (IAH) and the development of defective counterregulatory responses. To date, only pancreas or islet transplantation has demonstrated normalization of hypoglycemia awareness and the endogenous glucose production (EGP) response to defend against insulin-induced hypoglycemia in long-standing type 1 diabetes (T1D). This study aims to validate clinical metrics of IAH (Clarke score), hypoglycemia severity (HYPO score), glycemic lability (lability index), and continuous glucose monitoring (CGM) as predictors of absent autonomic symptom (AS) recognition and defective glucose counterregulation during insulin-induced hypoglycemia, thus enabling early identification of individuals with compromised physiologic defense against clinically significant hypoglycemia. Forty-three subjects with mean ± standard deviation age 43 ± 13 years and T1D duration 28 ± 13 years, including 32 with IAH and 11 with hypoglycemia awareness (Aware), and 12 nondiabetic control subjects, underwent single-blinded randomized-paired hyperinsulinemic-euglycemic and hypoglycemic clamp experiments. Receiver operating characteristic (ROC) curves and sensitivity analyses were performed to assess metric prediction of absent AS recognition and defective EGP responses to hypoglycemia. Clarke score and CGM measures of hypoglycemia exposure demonstrated good ability to predict absent AS recognition (area under the curve ≥0.80). A composite threshold of IAH-Clarke ≥4 with ROC curve-derived thresholds for CGM measures of hypoglycemia exposure showed high specificity and predictive value in identifying an absent AS response during the hypoglycemic clamp. Metrics demonstrated poor ability to predict defective glucose counterregulation by the EGP response, which was impaired even in the Aware group. Screening for IAH alongside assessment of CGM data can increase the specificity for identifying individuals with absent hypoglycemia symptom recognition who may benefit from further intervention.

Keywords: Autonomic symptoms; Continuous glucose monitoring; Glucose counterregulation; Hypoglycemia unawareness.

FIG. 1.

Plasma insulin (A) and glucose (B) during the hyperinsulinemic–hypoglycemic clamp experiments. Data presented as mean ± SEM of (▴) IAH-Cohort 1; () IAH-Cohort 2; () Aware group; and () Nondiabetic control group. The shaded area represents the 95% CI for data from the hyperinsulinemic–euglycemic clamp control experiments (n = 54). CI, confidence interval; IAH, impaired awareness of hypoglycemia; SEM, standard error of the mean.

FIG. 2.

Delta AS score and EGP over time (A, B) and by glucose (C, D) during the hypoglycemic clamp experiments. Data presented as mean ± SEM of (▴) IAH-Cohort 1; () IAH-Cohort 2; () Aware group; and () Nondiabetic control group responses. The shaded area represents the 95% CI for data from the hyperinsulinemic–euglycemic clamp control experiments (n = 54). Dashed line marks glucose of 54 mg/dL (3.0 mmol/L) the International Hypoglycemia Study Group consensus of clinically significant hypoglycemia. AS, autonomic symptoms; EGP, endogenous glucose production.

FIG. 3.

ROC curves demonstrating the ability of metrics to predict absent AS (A–F) or defective glucose counterregulation response (EGP) (G, H) to hyperinsulinemic–hypoglycemic clamp testing. (A) Clarke score; (B, G) HYPO severity score; (C) % Total time spent <70 mg/dL; (D) LBGI; (E) % Total time spent <54 mg/dL; (F) % Total time spent <60 mg/dL; (H) LI. HYPO, hypoglycemia severity score; LBGI, low blood glucose index; LI, lability index; ROC, receiver operating characteristic.