OBJECTIVE - To test the hypothesis that the amino acid Ala and the β2- adrenergic agonist terbutaline raise plasma glucose concentrations substantially, and do so through different mechanisms, in IDDM patients. RESEARCH DESIGN AND METHODS - We administered these (Ala: 20 and 40 g, orally; terbutaline: 2.5 and 5.0 mg orally and 0.25 mg subcutaneously) and placebos in random sequence to 6 nondiabetic subjects and 6 insulin-infused, initially euglycemic IDDM patients, each studied on six different occasions. Inhaled terbutaline, 0.4 mg, was also tested on a seventh occasion in IDDM patients. RESULTS - Ala administration raised plasma glucagon (P = 0.0219), C-peptide (P = 0.0014), and insulin (P = 0.0094), with no significant change in plasma glucose, in nondiabetic subjects. In patients with IDDM it raised glucagon (P = 0.0001), but not C-peptide or insulin, and plasma glucose rose to 8.3 ± 0.3 (Ala 20 g, P = 0.0006) and 10.0 ± 1.0 mM (Ala 40 g, P = 0.0094). Catecholamine levels were unchanged. Terbutaline ingestion raised plasma glucose minimally (e.g., to 6.3 ± 0.3 mM, P = 0.0133) in nondiabetic subjects but substantially, to 10.2 ± 1.0 (terbutaline 2.5 mg, P = 0.0078) and 14.0 ± 0.6 mM (terbutaline 5.0 mg, P = 0.0001), in IDDM patients; subcutaneous terbutaline raised plasma glucose (to a peak of 10.3 ± 0.7 mM, P = 0.0017) with an initial effect within 10 min, but inhaled terbutaline did so more slowly. In addition to its direct glycemic actions, terbutaline stimulated sympathetic neural norepinephrine release (P = 0.0151) and increased nonesterified fatty acid levels (P = 0.0104), potential indirect glycemic actions. Glucagon levels were unchanged, insulin levels increased in the nondiabetic subjects. CONCLUSIONS - These data demonstrate substantial glycemic responses to Ala and terbutaline, through different mechanisms, in IDDM patients. Thus, Ala and terbutaline represent potential new approaches to the treatment, and perhaps the prevention, of iatrogenic hypoglycemia in IDDM.