Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure

Eric Lontchi-Yimagou, Sandra Aleksic, Raphael Hulkower, Rebekah Gospin, Akankasha Goyal, Bryan Kuo, William G. Mitchell, Jee Young You, Laxmi Upadhyay, Michelle Carey, Oana A. Sandu, Ilan Gabriely, Harry Shamoon, Meredith Hawkins

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Background: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. Methods: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 μg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. Results: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006). Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. Conclusions: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual’s susceptibility to developing HAAF.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - Nov 1 2020


  • Adrenergic receptors
  • Counterregulatory responses
  • Epinephrine
  • Hypoglycemia
  • Hypoglycemia-associated autonomic failure

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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