Calcium Insufficiency Accelerates Type 1 Diabetes in Vitamin D Receptor-Deficient Nonobese Diabetic (NOD) Mice

Vitamin D exerts important regulatory effects on the endocrine and immune systems. Autoimmune type 1 diabetes (T1D) development in the inbred NOD mouse strain can be accelerated by vitamin D insufficiency or suppressed by chronic treatment with high levels of 1 alpha,25-dihydroxyvitamin D-3. Consequently, a report that T1D development was unaffected in NOD mice genetically lacking the vitamin D receptor (VDR) was unexpected. To further assess this result, the mutant stock was imported to The Jackson Laboratory, backcrossed once to NOD/ShiLtJ, and progeny rederived through embryo transfer. VDR-deficient NOD mice of both sexes showed significant acceleration of T1D. This acceleration was not associated with alterations in immune cells targeting pancreatic beta-cells. Rather, the capacity of beta-cells to produce and/or secrete insulin was severely impaired by the hypocalcaemia developing in VDR-deficient NOD mice fed a standard rodent chow diet. Feeding a high-lactose calcium rescue diet that circumvents a VDR requirement for calcium absorption from the intestine normalized serum calcium levels, restored beta-cell insulin secretion, corrected glucose intolerance, and eliminated accelerated T1D in VDR-deficient NOD mice. These findings suggest that calcium and/or vitamin D supplementation may improve disease outcomes in some T1D-prone individuals that are calcium deficient. (Endocrinology 152: 4620-4629, 2011)