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

Abstract

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 1st vs. 3rd episode: HAAF subjects 1072±156 vs. 530±87pg/ml, p<0.001). Importantly, peak EPI levels during the 1st 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. Disclosure E. Lontchi Yimagou: None. S. Aleksic: None. L. Upadhyay: None. S. Sharma: None. M. Carey: None. A. Goyal: None. J. You: None. R. Hulkower: None. S. Murthi: None. W.G. Mitchell: None. H. Shamoon: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc. Funding American Diabetes Association (1-18-PMF-024 to E.L.Y.); National Institutes of Health (R01DK079974)

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

“…Hence, a mild tempering of adrenergic stimulation is likely sufficient to improve the sympathoadrenal response and complete adrenergic blockade is not necessary. Our findings are similar to those reported by Yimagou and colleagues who reported that HAAF was elicited in healthy human subjects who exhibited larger epinephrine responses to hypoglycaemia, whereas those with smaller epinephrine responses, retained hypoglycaemia awareness, again suggesting that more profound adrenergic activation during antecedent episodes of hypoglycaemia may contribute to the development of HAAF 6 …”

“…Moreover, Ramanathan and colleagues reported that in healthy human subjects, adrenergic blockade during day 1 hypoglycaemia prevented suppression of the sympathoadrenal response during day 2 hypoglycaemia. These results are similar to those reported by Yimagou and colleagues who conducted the converse study where healthy human subjects were administered intravenous epinephrine repeatedly in the absence of hypoglycaemia on day 1 and this recapitulated the HAAF phenotype the following day 6 . Taken together, these data support the notion that repeated adrenergic activation during antecedent bouts of hypoglycaemia plays a fundamental role in suppressing the sympathoadrenal response to subsequent episodes of hypoglycaemia and that β‐adrenergic receptor blockers may be a useful therapeutic strategy to prevent the development of HAAF and improve hypoglycaemia awareness in patients with T1D.…”

“…Unfortunately, prior antecedent exposure to hypoglycaemia dramatically reduces this response and awareness of hypoglycaemia. 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 …”

“…Additionally, exposure to hypoglycaemia reduces awareness of hypoglycaemia due to loss of the sympathoadrenal response 18 . While the mechanisms underlying the development of HAAF are not clear, repeated activation of the adrenergic system may be one contributing factor 5,6 …”

“…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][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.…”