In previous studies on calcium homeostasis in diabetes, drug-induced diabetic rats have generally been used, and various alterations have been demonstrated in several parameters of the vitamin D-endocrine system. It is, however, still questionable whether the drug-induced diabetic rat is the most appropriate animal model for the investigation of calcium and vitamin D metabolism because of the toxicity of diabetogenic agents toward the principle organs of vitamin D metabolism, such as liver and kidney. Therefore, in the present study, we examined the strain of genetically diabetic mice, C57BL/KsJ db/db, to evaluate 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] receptors in intestine and kidney and to investigate the alterations of calcium and vitamin D metabolism. In both control and diabetic mice, intestinal and renal 1,25-(OH)2D3 receptors were demonstrated; they had a sedimentation coefficient of 3.4S. The number of specific 1,25-(OH)2D3-binding sites in intestine was 118 +/- 11 fmol/mg protein in diabetic mice, significantly lower than the value of 199 +/- 11 fmol/mg protein in controls (P less than 0.01). Moreover, the renal concentration of specific 1,25-(OH)2D3-binding sites of 34.6 +/- 7.1 fmol/mg protein in diabetic mice was also significantly reduced compared to the value of 63.3 +/- 5.7 fmol/mg protein in controls (P less than 0.01). There were no significant differences in the equilibrium dissociation constants (Kd) of intestinal and renal receptors between control and diabetic mice. Significant hypocalcemia was demonstrated in the diabetic mice (P less than 0.01), suggesting the development of a negative calcium balance. Diabetic mice showed a significant decrease in renal 24,25-(OH)2D3 production (P less than 0.02), whereas renal 1,25-(OH)2D3 production was significantly increased in the diabetic group (P less than 0.05) compared to the control value. It is probable from these results that the genetic/endogenous diabetes may be directly associated with the alterations of mineral homeostasis. The altered calcium and vitamin D metabolism in diabetic mice is suggested to be derived, at least in part, from the decreased number of the 1,25-(OH)2D3 receptors in both intestine and kidney in the diabetic state.