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Antecedent Adrenaline Attenuates the Responsiveness to But Not the Release of Counterregulatory Hormones during Subsequent Hypoglycemia

Departments of Medicine (B.E.d.G., S.J.R., C.J.T., J.W.M.L., P.S.), Medical Psychology (S.P.v.d.W.), Chemical Endocrinology (C.G.J.S.), and Pharmacology-Toxicology (P.S.), University Medical Center Nijmegen, Nijmegen 6500HB, The Netherlands

Address all correspondence and requests for reprints to: Paul Smits, M.D., Ph.D., Professor of Pharmacology, Department of Pharmacology-Toxicology 233, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: p.smits{at}pharmtox.umcn.nl.

Hypoglycemia unawareness is thought to be the consequence of recurrent hypoglycemia, yet the underlying mechanism is still incompletely understood. The aim of the present study was to determine the role of antecedent elevated adrenaline in the pathogenesis of hypoglycemia unawareness. Sixteen healthy volunteers (eight of either sex) participated in two experiments, performed in random order and at least 3 wk apart. During the morning, three consecutive doses of 0.04, 0.06, and 0.08 µg·kg^-1·min^-1 of adrenaline or matching placebo (normal saline) were infused for the total duration of 1 h. Three hours later, a hyperinsulinemic (360 pmol·m^-2·min^-1) two-step hypoglycemic (5.0–3.5–2.5 mmol·liter^-1) clamp study was performed. During hypoglycemia, hypoglycemic symptoms, counterregulatory hormones, cardiovascular responses, and cognitive function were monitored. Hypoglycemia induced similar responses of autonomic and neuroglycopenic symptoms, counterregulatory hormones, and lengthening in reaction time on the choice reaction time task, irrespective of antecedent infusions. However, prior adrenaline was associated with higher exogenous glucose requirements at hypoglycemic nadir (10.1 ± 1.3 vs. 7.3 ± 1.3 µmol·kg^-1·min^-1, P = 0.017), an attenuated hypoglycemia-induced fall in blood pressure (mean arterial pressure, -13 ± 2 vs. -8 ± 2 mm Hg, P = 0.006), and preserved cognitive function as assessed by the symbol digit test during hypoglycemia, when compared with prior placebo. We conclude that elevated adrenaline attenuates the responsiveness to, but not the release of counterregulatory hormones during subsequent hypoglycemia. As such, adrenaline’s role in the development of hypoglycemia unawareness is limited.

Abbreviations: CRT, Choice reaction time task; CV, coefficient of variation; dBP, diastolic blood pressure; GIR, glucose infusion rate; MAP, mean arterial pressure; sBP, systolic blood pressure; SDT, symbol digit test.

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