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

Abstract

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.

Carvedilol prevents impairment of the counterregulatory response in recurrently hypoglycaemic diabetic rats

“…Importantly, Beverly and colleagues previously showed that release of norepinephrine in the VMH was not impacted by antecedent hypoglycaemia, despite loss of the sympathoadrenal response 12,13 . Taken together, the data suggest that moderate activation of the sympathoadrenal system may be beneficial for the recovery from hypoglycaemia,however, repeated robust activation of the adrenergic system may lead to the development of HAAF as reported by Yimagou and colleagues 8 . This suggests that mild adrenergic blockade may be suitable for preventing the development of HAAF.…”

“…While numerous mechanisms have been proposed to explain the pathophysiology of HAAF, we and others have shown that repeated activation of the adrenergic system may also contribute to the development of HAAF 4–6 . Both repeated administration of epinephrine to healthy human subjects in the absence of hypoglycaemia and the administration of beta‐adrenergic blockers to type 1 diabetic patients during antecedent episodes of hypoglycaemia have supported this notion 7,8 …”

“…[4][5][6] Both repeated administration of epinephrine to healthy human subjects in the absence of hypoglycaemia and the administration of beta-adrenergic blockers to type 1 diabetic patients during antecedent episodes of hypoglycaemia have supported this notion. 7,8 While the activation of adrenergic receptors in the ventromedial hypothalamus (VMH) appears to be important for augmenting the epinephrine response to an acute bout of hypoglycaemia, [9][10][11] repeated activation of VMH adrenergic receptors during antecedent episodes of hypoglycaemia may in fact be detrimental to the counterregulatory response. 4,5 Importantly, Beverly and colleagues previously showed that release of norepinephrine in the VMH was not impacted by antecedent hypoglycaemia, despite loss of the sympathoadrenal response.…”

“…12,13 Taken together, the data suggest that moderate activation of the sympathoadrenal system may be beneficial for the recovery from hypoglycaemia,however, repeated robust activation of the adrenergic system may lead to the development of HAAF as reported by Yimagou and colleagues. 8 This suggests that mild adrenergic blockade may be suitable for preventing the development of HAAF. We previously demonstrated that low doses of the non-specific beta-adrenergic blocker, carvedilol, was not only effective at improving the sympathoadrenal response in non-diabetic rats subjected to recurring episodes of hypoglycaemia, but it also improved hypoglycaemia awareness in animals with impaired awareness of hypoglycaemia.…”

Heterogeneity in Epinephrine Response to Experimental Hypoglycemia in Type 1 Diabetes and Controls

“…Years ago, Ramanathan and Cryer [ 5 ] demonstrated that adrenergic blockade with nonselective α- and β-adrenergic antagonists during the first episode of hypoglycemia prevented the expected blunting of the epinephrine response that occurred during a second episode of hypoglycemia, suggesting that the epinephrine released during hypoglycemia may itself be causing impaired awareness of hypoglycemia. More recently, Lontchi-Yimagou and colleagues [ 6 ] demonstrated that healthy volunteers who met the standard criteria for HAAF during the third exposure to hypoglycemia demonstrated higher levels of hypoglycemia-induced epinephrine response during the first exposure to hypoglycemia in our preinduction protocol, although they did find marked interindividual variability in the responses to hypoglycemia. They hypothesized that this variability may explain an individual’s susceptibility to developing impaired awareness.…”