The effect of FK506 on glucose metabolism was studied in five cynomolgus monkeys after pancreatic transplantation and in 10 nontransplanted cynomolgus monkeys. We have clearly demonstrated that FK506 can induce hyperglycemia in these animals. In the orally treated nontransplanted animals the hyperglycemia was usually very mild (4.5-6.0 mmol/L). In one of the five transplanted animals, hyperglycemia was induced by the FK506 treatment, since histological signs of rejection were absent and since plasma glucose levels normalized on dose reduction. The glucose disappearance rates, as indicated by the K-values, decreased from a mean of 3.0 +/- 0.5%/min before FK506 treatment to 2.4 +/- 0.6%/min at one month and 1.5 +/- 0.4%/min at three months in the nontransplanted animals. In the transplant group, the K values decreased significantly from 4.2 +/- 0.6%/min in the donor animals to 1.4 +/- 0.4%/min at day 10 posttransplantation (P < 0.02). At one and three months postoperatively, the mean K-values were 1.4 +/- 0.2%/min and 1.2 +/- 0.6%/min, respectively. We conclude that FK506 is diabetogenic in the cynomolgus monkey. This side effect, however, was found to be reversible on dose reduction.