OBJECTIVE To test the hypothesis that because of sustained glycemic actions, bedtime administration of the glucagon-releasing amino acid alanine or the epinephrine-simulating beta2-adrenergic agonist terbutaline more effectively prevents nocturnal hypoglycemia than a conventional bedtime snack, we studied 15 patients with IDDM. METHODS On each of four occasions, the same individualized dose of NPH insulin (0.1-0.2 U/kg) was administered with either no treatment (control) or, in random sequence, oral treatment with a snack (240 ml of 2% milk plus one slice of toast, approximately 200 kcal), alanine (40 g, plus 10 g of glucose, approximately 200 kcal), or terbutaline (5.0 mg) at 2200. RESULTS During the first half of the night (2315-0300), mean plasma glucose concentrations were higher after the snack (P < 0.02), alanine plus glucose (P < 0.01), or terbutaline (P < 0.001), compared with no treatment. During the second half of the night, mean plasma glucose levels were no different from control values (73 +/- 5 mg/dl, 4.1 +/- 0.3 mmol/l) after the snack (73 +/- 7 mg/dl, 4.1 +/- 0.4 mmol/l), tended to be higher after alanine plus glucose (96 +/- 16 mg/dl, 5.3 +/- 0.9 mmol/l), and were significantly higher after terbutaline (124 +/- 15 mg/dl, 6.9 +/- 0.8 mmol/l, P < 0.01). Nocturnal plasma glucose levels of 40 mg/dl (2.2 mmol/l) or less (which were treated with intravenous glucose) occurred on 13 occasions in seven patients in the control arm and 10 occasions in six patients in the snack arm (not significantly different from the control arm), but on only 1 occasion in the alanine-plus-glucose arm (P < 0.02) and the terbutaline arm (P < 0.02). CONCLUSIONS In patients with IDDM given an evening dose of NPH insulin, a conventional bedtime snack exerts an inconsistent glycemic effect only during the first half of the night, and bedtime administration of the glucagon-releasing amino acid alanine or the epinephrine-simulating beta2-adrenergic agonist terbutaline more effectively prevents nocturnal hypoglycemia than a conventional bedtime snack.