116-OR: Hypoglycemia Leads to a Delayed Increase in Platelet and Coagulation Markers in Subjects with Type 2 Diabetes Treated with Metformin Only—Results from an Experimental Stepwise Hypoglycemic Clamp Study

Objective: Although hypoglycemia is associated with increased risk for subsequent cardiovascular events, experimental data investigating the effect of hypoglycemia on coagulation and platelet activation in type 2 diabetes are limited.

Research Design and Methods: This monocentric, open, single arm, trial included 14 subjects with type 2 diabetes (10 male/4 female, age 55±7 years, HbA1c 51±7 mmol/mol, diabetes duration 5±4 years) and metformin treatment only. A stepwise hyperinsulinemic hypoglycemic clamp was performed, aiming to investigate parameters of platelet function during predefined plateaus of hypoglycemia (at 63 and 45 mg/dl, for 30 minutes respectively), 24 hours and 7 days later. Additionally, all subjects underwent a hyperinsulinemic euglycemic clamp experiment.

Results: While platelet activation assessed by light transmittance aggregometry did not significantly increase following a hypoglycemic clamp, flow cytometry based platelet activation assessment demonstrated a significant increase 24 hours (PAC1CD62PCD63^pos p<0.01 compared to baseline, and p<0.001 for PAC1CD63P^pos, respectively) and 7 days after the hypoglycemic clamp (p<0.001 for PAC1CD62P^pos, and PAC1CD63P^pos, and p<0.01 for PAC1CD62PCD63^pos in comparison to baseline). In addition, coagulation markers like fibrinogen, PAI-1 and factor VIII also increased, with highest levels 24 hours after the hypoglycemic clamp (p<0.001 for fibrinogen and factor VIII and <0.01 for PAI-1). No platelet or coagulation activation was observed during the hyperinsulinemic, euglycemic clamp.

Conclusions: One single event of insulin induced hypoglycemia led to an increase in markers of platelet activation and coagulation, however, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycemia.