Comparative effects of acute hypoglycemia and hyperglycemia on pro-atherothrombotic biomarkers and endothelial function in non-diabetic humans

Abstract

Background The comparative effects of acute moderate hyperglycemia and hypoglycemia on in-vivo endothelial function together with pro-inflammatory and pro-atherothrombotic responses in healthy individuals have not been determined. Methods To investigate this question 45 healthy subjects were compared during glucose clamp studies consisting of euinsulinemic hyperglycemia and hyperinsulinemic hyperglycemia (plasma glucose 11.1 mmol/L, both with pancreatic clamps) and hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia (plasma glucose 5.1 and 2.9 mmol/L, respectively). Two D doppler ultrasound was used to determine brachial artery endothelial function. Results Insulin levels during euinsulinemia hyperglycemia were 194±23 and (850±49–988±114) pmol/L during all hyperinsulinemic protocols. Responses of VCAM-1, ICAM-1, E-Selectin, P-selectin, PAI-1, and IL-6 were increased (p<0.05-0.0001) during euinsulinemic hyperglycemia or hypoglycemia as compared to hyperinsulinemic euglycemia or hyperinsulinemic hyperglycemia. PAI-1 was increased (p<0.04) during hypoglycemia as compared to euinsulinemic hyperglycemia, TNF-α responses were also increased during hypoglycemia as compared to hyperinsulinemic euglycemia or hyperinsulinemic hyperglycemia (p<0.05). In vivo endothelial function was similarly blunted by acute moderate hyperglycemia or hypoglycemia. Conclusion In summary, acute moderate hypoglycemia and euinsulinemic hyperglycemia can result in similar endothelial dysfunction and pro-atherothrombotic responses. Fibrinolytic balance was reduced by a greater extent by hypoglycemia as compared to moderate hyperglycemia. Acutely, hyperinsulinemia can prevent the acute pro-atherothrombotic and pro-inflammatory effects of moderate hyperglycemia but not hypoglycemia.

Early Endothelial Dysfunction in Type 1 Diabetes Is Accompanied by an Impairment of Vascular Smooth Muscle Function: A Meta-Analysis

“…An increased magnitude of glycemic variability would generate more reactive oxygen species (including nitrotyrosine) in complications-prone cells compared to stable hyperglycemia and preliminary data suggest that protective adaptations induced by constant exposure to hyperglycemia are inadequately activated with intermittent exposure, allowing for more pronounced toxicity (92). Besides, in accordance with other reports (96,97), Pena et al (48) showed that an index of hypoglycaemic risk (i.e., Glycemic Risk Assessment Diabetes Equation-Hypoglycemia), measured over the 48 preceding hours, was a negative predictor of FMD but not of NMD. Noteworthy, hypoglycemia may induce vascular damages in the short and long terms: the hypoglycaemia-induced acute hemodynamic changes may precipitate and aggravate a vascular event during an acute episode (99), while repetition of hypoglycemic events could trigger abnormalities of coagulation, fibrinolysis, and inflammation.…”

“…These 2 studies, in children with type 1 diabetes, failed to detect significant correlation between FMD and glycemic variability, as assessed using 2-week, seven-point, self-monitored blood glucose logs (14) or 48-h continuous glucose monitoring (48). However, as previous in vitro (92) and in vivo (21,(93)(94)(95)(96)(97)(98), studies suggested a possible deleterious impact of glycemic variability on vascular function, further studies are needed to better explore the strength, conditions and mechanisms of this impact. An increased magnitude of glycemic variability would generate more reactive oxygen species (including nitrotyrosine) in complications-prone cells compared to stable hyperglycemia and preliminary data suggest that protective adaptations induced by constant exposure to hyperglycemia are inadequately activated with intermittent exposure, allowing for more pronounced toxicity (92).…”

Exposure to hypoglycemia and risk of stroke

“…Another study observed increased CD40 expression and platelet–monocyte aggregation during acute hypoglycemia in both nondiabetic and T1D subjects . A recent study on 45 healthy subjects compared inflammatory and proatherosclerotic biomarkers released during euinsulinemic hyperglycemia observed an increase in plasminogen activator inhibitor‐1 (PAI‐1) and TNF‐α levels during hypoglycemia . PAI‐1 is a protein that inhibits activators of plasminogen and fibrinolysis like tissue plasminogen activator, while TNF‐α has been shown to facilitate activation of the coagulation cascade .…”

“…55 A recent study on 45 healthy subjects compared inflammatory and proatherosclerotic biomarkers released during euinsulinemic hyperglycemia observed an increase in plasminogen activator inhibitor-1 (PAI-1) and TNF-␣ levels during hypoglycemia. 56 PAI-1 is a protein that inhibits activators of plasminogen and fibrinolysis like tissue plasminogen activator, while TNF-␣ has been shown to facilitate activation of the coagulation cascade. 57 These studies demonstrate activation of hemostatic mechanisms by exposure to hypoglycemia.…”

Insulin Increases The Central-To-Peripheral Arterial Stiffness Gradient in Response To Hyperglycemia in Healthy Humans: A Randomized Four-Way Crossover Study

“…Norepinephrine causes vasoconstriction in most arteries and also transiently increases heart rate, resulting in increased sympathetic tone [40]. The primary source of circulating norepinephrine is spillover from sympathetic nerves innervating blood vessels, and recent work has shown that hyperglycemic-hyperinsulinemia signi cantly increases circulating norepinephrine (but not epinephrine) in healthy humans [41]. In contrast, insulin has vasodilatory effects, with insulinmediated vasodilation and glucose uptake being functionally linked in humans [42].…”