Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals

Abstract

Objective: Recent 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 methods: Thirty-five healthy volunteers (19 male and 16 female subjects age 32 +/- 2 years, BMI 26 +/- 2 kg/m(2), 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/m(2), A1C 7.7 +/- 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol x kg(-1) x 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.

Results: Insulin 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.

Conclusions: In 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.

Trial registration: ClinicalTrials.gov NCT00574340.

Figure 1

Effects of hyperinsulinemic euglycemia and hypoglycemia (2.9 mmol/l) in overnight-fasted healthy control subjects (n = 35) and individuals with type 1 diabetes (n = 24) that participated in either one or both of the studies on vascular biological markers. Response of VCAM-1, ICAM-1, E-selectin, and VEGF are significantly increased during hypoglycemia as compared with euglycemia in both healthy control subjects and type 1 diabetic subjects. Statistical difference with two-way ANOVA during the 120-min clamp experiments is marked in each graph panel.

Figure 2

Effects of hyperinsulinemic euglycemia and hypoglycemia (2.9 ± 0.1 mmol/l) in overnight-fasted healthy control subjects (n = 35) and subjects with type 1 diabetes (n = 24) that participated in either one or both of the studies on vascular biological markers. Responses of PAI-1, P-selectin, IL-6, and adiponectin are significantly increased during hypoglycemia as compared with euglycemia in healthy control subjects. Responses of P-selectin, IL-6, and adiponectin are significantly increased during hypoglycemia as compared with euglycemia in type 1 diabetes. Statistical difference with two-way ANOVA during the 120-min clamp experiments is marked in each graph panel.

Figure 3

*Mean individual peak responses of VCAM-1, ICAM-1, E-selectin, VEGF, PAI-1, IL-6, P-selectin, and adiponectin in both healthy control subjects (n = 35) and subjects with type 1 diabetes (n = 24) that participated in either one or both of the studies are significantly increased (P <0.05) compared with baseline. †Mean individual nadir responses of VCAM-1, ICAM-1, E-selectin, VEGF, PAI-1, P-selectin, and adiponectin during hyperinsulinemic euglycemia in both healthy control subjects and type 1 diabetic subjects are significantly decreased (P <0.05) compared with baseline.