Duodenal calcium absorption and a vitamin D-dependent duodenal calcium-binding protein are depressed in rats with alloxan- or streptozotocin-induced diabetes. To test for possible abnormal vitamin D metabolism in diabetes we measured serum concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in control, streptozotocin diabetic, and insulin-treated diabetic rats. The serum concentration of 1,25-dihydroxyvitamin D was depressed in untreated diabetic rats to one-eighth of the level in controls and was restored to control levels by insulin treatment. The serum concentration of 25-hydroxyvitamin D was the same in all three groups. Hence, effects of diabetes on duodenal calcium transport can be explained by reduced concentrations of 1,25-dihydroxyvitamin D resulting either from failure of renal 1alpha-hydroxylation of 25-hydroxyvitamin D or increased catabolism of 1,25-dihydroxyvitamin D.

No abstract

We tested the hypothesis that depressed duodenal calcium absorption in the streptozotocin diabetic rat is the consequence of diabetes rather than nephrotoxicity of the diabetogenic agent causing abnormal renal vitamin D metabolism. We treated streptozotocin diabetic rats with insulin and compared their duodenal calcium transport response with that of untreated diabetics and matched controls. Insulin treatment restored depressed calcium transport of diabetics to control levels in in vivo studies and significantly increased calcium transport in vitro. Previous studies showed that even in uncontrolled diabetes the mucosa retains the ability to respond to an end organ stimulus enhancing calcium transport: 1,25-dihydroxycholecalciferol corrects the defect, but vitamin D and 25-hydroxycholecalciferol are ineffective. Since 1,25-dihydroxycholecalciferol is synthesized in the kidney, these findings, in conjunction with the current study, are consistent with the association of experimental diabetes with a renal defect depressing synthesis of 1,25-dihydroxycholecalciferol. Since insulin treatment restores duodenal calcium transport, the renal defects is unlikely to be caused by streptozotocin nephrotoxicity.

We studied diabetic rats, 5 days after streptozotocin injection, and matched controls to determine whether depressed duodenal calcium absorption associated with uncontrolled diabetes in the rat would respond to vitamin D or its metabolites. At the appropriate time following the intravenous injection of 0.25 mug of either vitamin D3, 25-hydroxycholecalciferol (25-OHD3), 1,25-dihydroxycholecalciferol (1,25-OH)2D3), or 1alpha-hydroxycholecalciferol (1alpha-OHD3) to half of each diabetic and control group, calcium transport was evaluated using everted duodenal sacs with 0.4 mM40Ca and tracer 45Ca on both mucosal and serosal surfaces. All agents stimulated duodenal calcium absorption in controls. Diabetics responded only to 1,25-(OH)2D3, the metabolite that acts directly on the duodenum, and to its synthetic analog, 1alpha-OHD3. 1alpha-OHD3 is activated to 1,25-(OH)2D3 by 25-hydroxylation in the liver; 25-OHD3 must be 1alpha-hydroxylated in the kidney to be active. The stimulation of duodenal calcium absorption in diabetic rats by 1alpha-OHD3, but not by either vitamin D3 or 25-OHD3, is most consistent with a defect in vitamin D metabolism at the 1alpha-hydroxylation step in the kidney.