Body weight gain and severe hypoglycemia are the major adverse effects of insulin therapy in type 2 diabetic patients. Metformin has been shown to prevent insulin therapy-induced body weight gain when used in combination with insulin. However, the effects of metformin on hormonal and symptomatic responses to hypoglycemia mediating hypoglycemia awareness have not been assessed to date. Fifteen young healthy men were treated with 850 mg metformin and placebo twice daily for a 16-d period in a double blind, cross-over design. On the last 2 d of the treatment period, the subjects underwent three hypoglycemic clamp experiments, with the first and the last performed with identical patterns of plasma glucose decrease. Differences between the effects of metformin and placebo (effect of metformin) as well as between first and last hypoglycemic clamps (effect of antecedent hypoglycemia) were assessed. Antecedent hypoglycemia significantly reduced epinephrine, ACTH, cortisol, glucagon, GH, and symptomatic responses to hypoglycemia (P < 0.05 for all variables). There was no detectable effect of metformin on epinephrine, norepinephrine, ACTH, cortisol, glucagon, or autonomic symptomatic response to hypoglycemia (P > 0.05 for all comparisons), except that metformin slightly increased the response of GH to hypoglycemia (P = 0.039). The latter finding may be due to an IGF-I-reducing effect of metformin, as after 14 d of metformin treatment baseline levels of IGF-I were significantly lower than in the placebo condition (236.9 +/- 13.9 vs. 263.2 +/- 14.4 microg/liter; P = 0.015). The data indicate that metformin does not adversely affect hormonal and symptomatic responses to hypoglycemia. This finding appears to be relevant with regard to the safety of the combination of metformin with insulin therapy.