NMDA receptor blockade by memantine increases hormonal counterregulation during hypoglycaemia

Objectives: Hormonal counterregulation during hypoglycaemia is essential for preventing severe hypoglycaemic effects in patients with diabetes mellitus. Although animal studies have yielded evidence for the involvement of the glutamatergic system, it is not known to which extent NMDA receptor mediated signalling contributes to the hormonal counterregulation during hypoglycaemia in humans. We assessed the effects of the NMDA receptor antagonist memantine on hypoglycaemia induced counterregulation in healthy humans.

Methods: We performed two clamp experiments in 10 healthy men. Subjects were pretreated with an oral dose of 20mg memantine or placebo in a randomized, double-blind order. Plasma glucose was decreased to 2.3 mmol/l during a 50-min hypoglycaemic clamp and counterregulatory hormones (epinephrine, norepinephrine, ACTH, cortisol, glucagon, growth hormone) were determined. In addition, rated symptoms related to glycaemic changes (e.g., well-being, hunger) and neurocognitive functions (i.e., short-term memory and attention) were assessed during the baseline period and the hypoglycaemic plateau.

Results: Counterregulatory hormones significantly increased during hypoglycaemia in both conditions. Memantine treatment further enhanced the cortisol response to hypoglycaemia compared to placebo, while baseline levels of cortisol and other hormonal parameters remained unchanged. Also, rated symptoms and cognitive functions were not affected by memantine.

Conclusion: We conclude that NMDA receptor blockade enhances the counterregulatory hormonal response to hypoglycaemia. Hence, endogenous glutamate signalling may contribute to the hormonal response to hypoglycaemia, and NMDA receptor antagonisation could ameliorate defective counterregulation and prevent hypoglycaemia unawareness in patients with diabetes mellitus.