Experimental Diabetes in the Rat Causes an Insulin-Reversible Decrease in Renal 25-Hydroxyvitamin D3-lα-Hydroxylase Activity*

Abstract

The decreased intestinal mucosal absorption of calcium observed in the diabetic rat has been attributed to low circulating 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] levels. We investigated the cause of the depressed plasma 1,25-(OH)₂D₃ and the possibility that in diabetes the incorporation of 1,25-(OH)₂D₃ into intestinal mucosa may be defective. In diabetic rats the metabolic clearance of iv [³H]1,25-(OH)₂D₃ was not increased, suggesting that their low plasma 1,25-(OH)₂D₃ levels were due to decreased formation. The in vivo conversion of a standard dose of [³H]25-hydroxyvitamin D₃ ([³H]25OHD₃) to [³H]1,25-(OH)₂D₃ was found to be reduced by 60% in diabetic rats; it returned to normal by insulin treatment. Serum calcium and phosphorus levels were unaffected by diabetes. Since diabetes did not augment 1,25-(OH)₂D₃ catabolism, the decreased conversion of [³H]25OHD₃ to [³H]1,25-(OH)₂D₃ indicates that the activity of the renal 25-OH-D₃-la-hydroxylase is decreased in diabetic rats. Intestinal mucosa of diabetic rats was significantly hypertrophied. However, there was no intrinsic defect in the incorporation of [³H]1,25-(OH)₂D₃. Thus, the depressed intestinal calcium absorption in diabetic rats is due to decreased delivery of 1,25-(OH)₂D₃ to the intestinal mucosa consequent to decreased renal la-hydroxylase activity. Whether the decrease in la-hydroxylase activity is due to insulin deficiency or is a secondary consequence of the diabetic state is unknown.