115-OR: Epinephrine Contributes to Hypoglycemia-Associated Autonomic Failure (HAAF)

Recurrent hypoglycemia leads to HAAF, with blunted counterregulatory hormone responses to subsequent hypoglycemic episodes. A recent report suggested inter-individual differences in susceptibility to HAAF (JCEM 102:3571, 2017). Since adrenergic receptor blockade prevents HAAF (Diabetes 60:602, 2011), we investigated to what extent the rises in plasma epinephrine (EPI) associated with hypoglycemia predict the development of HAAF.

Healthy non-diabetic subjects (n=18, age 43±2years, BMI 25±1 kg/m²) underwent two 2-hour hypoglycemic clamp studies (nadir 54mg/dl; 0-2h and 4-6 h) on Day 1 followed by a third 2-hour hypoglycemic clamp on Day 2. Twelve subjects (67%) developed HAAF by the third episode, as defined by at least 20% reductions in peak EPI levels (peak EPI 1^st vs. 3^rd episode: HAAF subjects 1072±156 vs. 530±87pg/ml, p<0.001). Importantly, peak EPI levels during the 1^st hypoglycemic episode were ∼83% higher in the subjects who developed HAAF compared to those who did not (p=0.02).

To specifically define the role of EPI in the pathogenesis of HAAF, we challenged an additional seven non-diabetic subjects (age 32±4 years, BMI 25±1 kg/m²) with two 2-hour infusions of EPI (0.03 μg/kg/min;0-2h and 4-6 h) on Day 1 followed by 200-minute stepped hypoglycemic clamps (90, 80, 70 and 60 mg/dl, each for 50 minutes) on Day 2. Compared to saline, EPI infusion on Day 1 induced 40% and 28% reductions in epinephrine response to hypoglycemia at the 70 and 60 mg/dl glucose steps on Day 2, respectively (all p<0.05). There were parallel reductions in hypoglycemic symptoms (all p<0.05). Furthermore, the rate of glucose infusion was higher at all steps after EPI infusion (all p<0.05), consistent with a trend towards lower endogenous glucose production (6,6-D2-glucose).

Thus, rises in EPI similar to those seen with hypoglycemia reproduce key features of HAAF in non-diabetic subjects. Marked inter-individual variability in EPI levels in response to hypoglycemia may explain why some people are more prone to develop HAAF.