Effects of Acute and Antecedent Hypoglycemia on Endothelial Function and Markers of Atherothrombotic Balance in Healthy Humans

Abstract

The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, proinflammatory biomarkers, proatherothrombotic mechanisms, and endothelial function. Twenty healthy individuals (12 male and 8 female) were studied during separate 2-day randomized protocols. Day 1 consisted of either two 2-h hyperinsulinemic (812 ± 50 pmol/L)-euglycemic (5 ± 0.1 mmol/L) or hyperinsulinemic (812 ± 50 pmol/L)-hypoglycemic (2.9 ± 0.1 mmol/L) clamps. Day 2 consisted of a single 2-h hyperinsulinemic-hypoglycemic clamp. Two-dimensional Doppler ultrasound was used to determine brachial arterial endothelial function. Plasminogen activator inhibitor 1, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, E-selectin, P-selectin, TAT (thrombin/antithrombin complex), tumor necrosis factor-α, and interleukin-6 responses were increased (P < 0.05) during single or repeated hypoglycemia compared with euglycemia. Endogenous and exogenous nitric oxide (NO)-mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (P < 0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance; increases proinflammatory responses, platelet activation, and coagulation biomarkers; and reduces NO-mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO-mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased proatherothrombotic state compared with a single acute episode of hypoglycemia.

Hypoglycaemia, thrombosis and vascular events in diabetes

“…Acute hypoglycemia triggers the release of counter-regulatory catecholamines, and these have been implicated in increased platelet activation [27][28][29]. Recent studies of acute, insulin-induced hypoglycemia have yielded variable results in relation to platelet activation with no difference observed in markers of platelet aggregation between hypoglycemia and euglycemia in control and T1DM patients in some studies [17,19] and increased aggregation in healthy controls after repeated hypoglycemia in one study [18]. This discrepancy in the data may be related to the methodologies used and the difficulties encountered in accurately measuring platelet activation or simply due to chronic activation of platelets in hyperglycemic states making the 'additional' effects of hypoglycemia difficult to measure.…”

“…Increased levels of the antifibrinolytic agent PAI-1 have been demonstrated following acute [17] and repeated [18] hypoglycemia. Moreover, hypoglycemia is associated with increased thrombin generation [18] and plasma levels of clotting factor VIII [30], thereby enhancing thrombus formation.…”

“…Increased levels of the antifibrinolytic agent PAI-1 have been demonstrated following acute [17] and repeated [18] hypoglycemia. Moreover, hypoglycemia is associated with increased thrombin generation [18] and plasma levels of clotting factor VIII [30], thereby enhancing thrombus formation. Contrary to hyperglycemia which can persist beyond the acute episode, hypoglycemic attacks are generally terminated quickly by patients in everyday life, except in those with hypoglycemia unawareness where hypoglycemic can persist for longer periods.…”

“…Acute, insulin-induced hypoglycemia has been shown in numerous studies to induce a proinflammatory state. Increased levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), reactive oxygen species, and adhesion molecules have detrimental effects on the vascular endothelium leading to increased atherosclerotic plaque formation [17][18][19]. Numerous changes are also observed in hemostatic proteins leading to a prothrombotic environment, which are further detailed later.…”

“…There is evidence to support a proinflammatory state associated with hypoglycemia with increased inflammatory cytokines such as IL-6 and TNF-α [17,18,33], along with markers of endothelial dysfunction such as vascular adhesion molecules and reduced nitric oxide-induced vasodilation [18,19] and increased oxidative stress [33]. For reasons cited earlier, it is unclear to what extent brief episodes of hypoglycemia have on the development of atherosclerotic plaque formation as opposed to the more prolonged hyperglycemia, and studies in this area are urgently needed.…”