Effects of Acute Hypoglycemia on Inflammatory and Pro-atherothrombotic Biomarkers in Individuals With Type 1 Diabetes and Healthy Individuals

Abstract

OBJECTIVERecent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals.RESEARCH DESIGN AND METHODSThirty-five healthy volunteers (19 male and 16 female subjects age 32 ± 2 years, BMI 26 ± 2 kg/m2, A1C 5.1 ± 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 ± 3 years, BMI 24 ± 2 kg/m2, A1C 7.7 ± 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol · kg−1 · min−1) euglycemic or hypoglycemic (2.9 ± 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study.RESULTSInsulin levels were similar (602 ± 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 ± 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 ± 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes.CONCLUSIONSIn summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.

The Relationship of Glucokinase Activator–induced Hypoglycemia with Arteriopathy, Neuronal Necrosis, and Peripheral Neuropathy in Nonclinical Studies

“…This hypothesis is substantiated by reports in patients with type 2 diabetes of acute hypoglycemia-related impairment of flowmediated dilatation by nitric oxide (NO)-dependent and NO-independent mechanisms as well as changes in inflammatory and pro-atherothrombotic biomarkers (Chow and Heller 2012;Gogitidze et al 2010). Endothelial dysfunction and Vol.…”

Hypoglycemia in Type 2 Diabetes - More Common Than You Think

“…25,26 Hypoglycemia-induced increases in blood pressure and heart rate, triggering of blood vessel constriction or acute thrombosis are probable explanations of these adverse events. 27,28 However, most studies on GV have been conducted in critical care settings and findings may not extend to T2DM patients in the outpatient setting.…”

Effect of Conversion from ESA with Shorter Half-Life to CERA Once Monthly for Maintaining Hb Concentration in Pre-Dialysis CKD Patients

“…E-selectin and VCAM are upregulated during inflammation and increase the adhesion of leukocytes to injured arterial endothelial cells, which is first step in subsequent atherosclerosis [16]. ESA increased E-selectin levels in healthy volunteers and haemodialysis patients, indicating substantial activation of endothelial cells [8,17,18].…”