Metformin does not adversely affect hormonal and symptomatic responses to recurrent hypoglycemia

Body weight gain and severe hypoglycemia are the major adverse effects of i nsulin therapy in type 2 diabetic patients. Metformin has been shown to pre vent insulin therapy-induced body weight gain when used in combination with insulin. However, the effects of metformin on hormonal and symptomatic res ponses to hypoglycemia mediating hypoglycemia awareness have not been asses sed to date. Fifteen young healthy men were treated with 850 mg metformin a nd placebo twice daily for a 16-d period in a double blind, crossover desig n. On the last 2 d of the treatment period, the subjects underwent three hy poglycemic clamp experiments, with the first and the last performed with id entical patterns of plasma glucose decrease. Differences between the effect s of metformin and placebo (effect of metformin) as well as between first a nd last hypoglycemic clamps (effect of antecedent hypoglycemia) were assess ed. Antecedent hypoglycemia significantly reduced epinephrine, ACTH, cortis ol, glucagon, GH, and symptomatic responses to hypoglycemia (P < 0.05 for a ll 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 slig htly increased the response of GH to hypoglycemia (P = 0.039). The latter f inding may be due to an IGF-I-reducing effect of metformin, as after 14 d o f metformin treatment baseline levels of IGF-l were significantly lower tha n in the placebo condition (236.9 +/- 13.9 vs. 263.2 +/- 14.4 mug/liter; P = 0.015). The data indicate that metformin does not adversely affect hormon al and symptomatic responses to hypoglycemia. This finding appears to be re levant with regard to the safety of the combination of metformin with insul in therapy.