We investigated possible alterations in serum alpha 1-protease inhibitor (alpha 1-PI) concentration and activity from insulin-dependent diabetic subjects (IDDs) and in vitro in serum samples containing high glucose concentrations. The in vivo measurements were compared to others taken from normal reference subjects and the in vitro measurements were performed in serum samples containing 0, 10, 20, and 40 mmol/l of glucose. The diabetics had a significantly lower mean alpha 1-PI concentration in their serum than did the reference subjects (1.74 +/- 0.1 g/l vs. 2.1 +/- 0.1 g/l, P less than 0.05), as well as a lower total alpha 1-PI inhibitory activity (201 +/- 0.7 vs. 246.9 +/- 13.5 U/l, P less than 0.02). Addition of glucose to the serum samples in the in vitro study significantly reduced the mean alpha 1-PI concentrations (P less than 0.01 in the case of 10 mmol/l glucose, and P less than 0.001 in the cases of 20 and 40 mmol/l). Added glucose also significantly reduced the mean serum alpha 1-PI activity as determined by the percentage of elastase inhibition in 1, 2, and 3 microliters of reference serum (P less than 0.02 in the case of 10 mmol/l glucose, P less than 0.01 in 20 mmol/l, and P less than 0.001 in 40 mmol/l). Hyperglycaemia thus impaired serum alpha 1-PI concentration and activity both in vivo and in vitro. While the underlying mechanisms and clinical implications of these observations are unknown, the abnormally low alpha 1-PI activity in diabetics may worsen the severity and contribute to the chronicity of their infections.