Glucose-6-phosphatase catalyzes the final step of glucose production by liver and kidney. Though its strategic position has sparked interest in its regulation, difficulty with isolating a pure, stable enzyme has slowed progress. Virtually all previous work examining the physiologic regulation of this enzyme has relied on estimates of glucose-6-phosphatase activity in crude microsome preparations. The recent cloning of human and murine glucose-6-phosphatase cDNAs has now allowed study of its mRNA expression. We studied the effect of acute, streptozotocin-induced diabetes on hepatic microsomal glucose-6-phosphatase activity and mRNA expression in young (89 +/- 3 g), juvenile (304 +/- 4 g) and adult (512 +/- 10 g) rats. In control rats, mRNA expression and enzyme activity was similar among the three age groups. Streptozotocin-induced diabetes significantly increased the enzyme activities in both intact and triton-treated microsomes in all groups of rats (p < 0.001). Glucose-6-phosphatase mRNA expression was increased in the diabetic rats as well (p < 0.0001). Blood glucose concentrations correlated significantly with glucose-6-phosphatase mRNA level (p < 0.005) and both intact (p < 0.002) and triton-treated (p < 0.001) microsomal glucose-6-phosphatase activity. Both intact and triton-treated microsomal glucose-6-phosphatase activity correlated with mRNA level (p < 0.001, for each). We conclude that acute streptozotocin-diabetes increase expression of glucose-6-phosphatase mRNA and this contributes to the increased glucose-6-phosphatase activity seen with diabetes mellitus.