Hypoglycaemia leads to a delayed increase in platelet and coagulation activation markers in people with type 2 diabetes treated with metformin only: Results from a stepwise hypoglycaemic clamp study

AIMS: To investigate the effect of hypoglycaemia on platelet and coagulation activation in people with type 2 diabetes. MATERIALS AND METHODS: This monocentric, open, single‐arm, mechanistic trial included 14 people with established type 2 diabetes (four women, 10 men, age 55 ± 7 years, glycated haemoglobin concentration 51 ± 7 mmol/mol) receiving metformin monotherapy. A stepwise hyperinsulinaemic‐hypoglycaemic clamp experiment (3.5 and 2.5 mmol/L, for 30 minutes respectively) was performed, aiming to investigate platelet and coagulation activity during predefined plateaus of hypoglycaemia, as well as 1 day and 7 days later. RESULTS: While platelet activation assessed by light transmittance aggregometry did not significantly increase after the hypoglycaemic clamp procedure, the more sensitive flow cytometry‐based measurement of platelet surface activation markers showed hypoglycaemia‐induced activation 24 hours (PAC1(pos)CD62P(pos), PAC1(pos)CD63P(pos) and PAC1(pos)CD62P(pos)CD63(pos); P < .01) and 7 days after the hypoglycaemic clamp (P < .001 for PAC1(pos)CD63(pos); P < .01 for PAC1(pos)CD62P(pos) and PAC1(pos)CD62P(pos)CD63(pos)) in comparison to baseline. Coagulation markers, such as fibrinogen, D‐dimer, plasminogen activator inhibitor‐1, von Willebrand factor activity and factor VIII, were also significantly increased, an effect that was most pronounced 24 hours after the hypoglycaemic clamp. CONCLUSION: A single event of insulin‐induced hypoglycaemia led to an increase in markers of platelet activation and coagulation in people with early stages of type 2 diabetes on metformin therapy. However, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycaemic episode.