Automated Insulin Delivery for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes with Hypoglycemia Unawareness

Abstract

Objective: Automated insulin delivery (AID) may benefit individuals with long-standing type 1 diabetes where frequent exposure to hypoglycemia impairs counterregulatory responses. This study assessed the effect of 18 months AID on hypoglycemia avoidance and glucose counterregulatory responses to insulin-induced hypoglycemia in long-standing type 1 diabetes complicated by impaired awareness of hypoglycemia. Methods: Ten participants mean ± standard deviation age 49 ± 16 and diabetes duration 34 ± 16 years were initiated on AID. Continuous glucose monitoring was paired with actigraphy to assess awake- and sleep-associated hypoglycemia exposure every 3 months. Hyperinsulinemic hypoglycemic clamp experiments were performed at baseline, 6, and 18 months postintervention. Hypoglycemia exposure was reduced by 3 months, especially during sleep, with effects sustained through 18 months (P ≤ 0.001) together with reduced glucose variability (P < 0.01). Results: Hypoglycemia awareness and severity scores improved (P < 0.01) with severe hypoglycemia events reduced from median (interquartile range) 3 (3-10) at baseline to 0 (0-1) events/person·year postintervention (P = 0.005). During the hypoglycemic clamp experiments, no change was seen in the endogenous glucose production (EGP) response, however, peripheral glucose utilization during hypoglycemia was reduced following intervention [pre: 4.6 ± 0.4, 6 months: 3.8 ± 0.5, 18 months: 3.4 ± 0.3 mg/(kg·min), P < 0.05]. There were increases over time in pancreatic polypeptide (Pre:62 ± 29, 6 months:127 ± 44, 18 months:176 ± 58 pmol/L, P < 0.01), epinephrine (Pre: 199 ± 53, 6 months: 332 ± 91, 18 months: 386 ± 95 pg/mL, P = 0.001), and autonomic symptom (Pre: 6 ± 2, 6 months: 6 ± 2, 18 months: 10 ± 2, P < 0.05) responses. Conclusions: AID led to a sustained reduction of hypoglycemia exposure. EGP in response to insulin-induced hypoglycemia remained defective, however, partial recovery of glucose counterregulation was evidenced by a reduction in peripheral glucose utilization likely mediated by increased epinephrine secretion and, together with improved autonomic symptoms, may contribute to the observed clinical reduction in hypoglycemia.

Keywords: Automated insulin delivery; Glucose counterregulation; Hypoglycemia-associated autonomic failure; Impaired awareness of hypoglycemia; Type 1 diabetes.

FIG. 1.

Continuous glucose monitoring outcomes during time when awake (A) and when asleep (B), before, and throughout intervention with AID. Data presented are median % time spent <70, >180 mg/dL, and in-range 70–180 mg/dL derived from HypoCount software with incorporated actigraphy data. AID, automated insulin delivery.

FIG. 2.

Impaired awareness of hypoglycemia (Clarke score, A); glycemic lability (LI, B); HYPO score (C); and severe hypoglycemia event rate (D) outcomes before and throughout intervention with AID. Data presented as median (IQR) [range] and □ mean. Comparison of baseline and follow-up visits during intervention with AID by Friedman ANOVA. Dotted line represents (A) Clarke score ≥4, the threshold to define impaired awareness of hypoglycemia; (B) LI ≥329 and (C) HYPO score ≥423, the 75th percentiles of a normative group of 100 individuals with type 1 diabetes. ANOVA, analysis of variance; HYPO, hypoglycemia severity; IQR, interquartile range; LI, lability index.

FIG. 3.

Hyperinsulinemic hypoglycemic clamp procedure: plasma (A) insulin and (B) glucose in individuals with type 1 diabetes (T1D) (-■-) before and at (-●-) 6 months and (-▴-) 18 months after intervention with AID. Insulin was infused at a rate of 1 mU/(kg·min) with a variable rate infusion of 20% dextrose adjusted to achieve hourly stepped reductions in plasma glucose targeting 80, 65, 55, and 45 mg/dL. Data presented as mean ± SE. SE, standard error.

FIG. 4.

Glucose counterregulatory fuel utilization and mobilization responses: (A) EGP; (B) glucose infusion rate; (C) peripheral glucose disposal, R_d; and (D) free fatty acids in individuals with type 1 diabetes (-■-) before and at (-●-) 6 months and (-▴-) 18 months after intervention with AID. Data are mean ± SE; Friedman ANOVA comparison of baseline, 6-, and 18-month responses, *P < 0.05. Wilcoxon matched pairs comparison between baseline and 18-month timepoints when ANOVA P ≤ 0.10, ^£P < 0.05; n = 9 for baseline EGP and R_d data. EGP, endogenous glucose production.

FIG. 5.

Counterregulatory hormone and symptom responses to insulin-induced hypoglycemia: (A) glucagon; (B) pancreatic polypeptide; (C) epinephrine; and (D) autonomic symptoms in individuals with type 1 diabetes (T1D) (-■-) before and at (-●-) 6 months and (-▴-) 18 months after intervention with AID. Data are mean ± SE; Friedman ANOVA comparison of baseline, 6- and 18-month responses, *P < 0.05, **P < 0.01; n = 9 for 18-month epinephrine data.