We read with interest the study by Lefrandt et al. (1) in which they analyzed the association between baroreflex sensitivity (BRS) and blood glucose levels in healthy subjects. They observed a negative relationship between BRS and glucose levels that was independent from other risk factors and that had no glycemic thresholds. Some years ago, we evaluated the effects of acute hyperglycemia (15 mmol/l) on autonomic function in 12 healthy male volunteers (2). Heart rate variations during the squatting maneuver (3) were significantly reduced in hyperglycemic condition, suggesting a reduced baroreflex activation. The ratio between the baseline R-R interval and the longest R-R interval during squatting (SqT vagal) represents the bradicardia secondary to baroreflex activation triggered by the raised arterial pressure after squatting. The ratio between the baseline R-R interval and the shortest R-R interval during standing up from squatting is a measure of the tachicardia after the increased sympathetic drive brought about by the fall in blood pressure (SqT sympathetic). Exogenous glutathione (600 mg as an intravenous bolus followed by a 5-mg/min infusion) completely prevented the baroreflex alterations, suggesting the mediation of hyperglycemia-induced free radical generation (4).

Among the possible mechanisms, Lefrandt et al. (1) hypothesized that high normal glucose levels may influence signal transmission through the neuronal pathway of the baroreflex arc, affecting the cardiac autonomic function at the myocyte level or diminishing normal endothelium function. A unifying link across these mechanisms might be the increased free radical generation evoked by high glucose. First, one of the earliest known events after exposure of cells to free radicals is the impairment of Na+-K+ ATPase, which may reduce nervous conduction velocity (5). Second, increased free radical generation is able to raise cytosolic free calcium at the myocyte level (6). Last, free radicals quench nitric oxide (NO), diminishing NO availability (7). On the other hand, all of these findings are observed, both in vitro and in vivo, with glucose concentrations that are well above those reported as being in the high normal glucose range (maximum 7 mmol/l). We ignore if, at this glucose concentration, the pathogenetic mechanisms are the same as those hypothesized during acute hyperglycemia (15 mmol/l).

Lefrandt JD, Mulder MC, Bosma E, Smit AJ, Hoogenberg K: Inverse relationship between blood glucose and autonomic function in healthy subjects.
Diabetes Care
Marfella R, Verrazzo G, Acampora R, La Marca C, Giunta R, Lucarelli C, Paolisso G, Ceriello A, Giugliano D: Glutathione reverses systemic hemodynamic changes induced by acute hyperglycaemia in health subjects.
Am J Physiol
2: E1167–E1171, 1995
Marfella R, Giugliano D, Di Maro G, Acampora R, Giunta R, D’Onofrio F: The squatting test: a useful test tool to asses both parasympathetic and sympathetic involvement of the cardiovascular autonomic neuropathy in diabetes.
Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, Creager MA: Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.
Gupta S, Sussman I, Mc Arthur CS, Tornheim K, Cohen RA, Ruderman NB: Endothelium-dependent inhibition of Na+-K+ATPase activity in rabbit aorta by hyperglycemia: possible role of endothelium-derived nitric oxide.
J Clin Invest
Levy J, Gavin JR 3rd, Sowers JR: Diabetes mellitus: A disease of abnormal cellular calcium metabolism?
Ann Intern Med
Tesfamarian B: Free radicals in diabetic endothelial cell dysfunction.
Free Radical Riot Med

Address correspondence to Raffaele Marfella, MD, PHD, Via Emilio Scaglione, 141, I-80145 Naples, Italy. E-mail: raffaele.marfella@unina2.it.