1,25-Dihydroxyvitamin D3 and 24,25-Dihydroxyvitamin D3 Production by Isolated Renal Slices is Modulated by Diabetes and Insulin in the Rat

Abstract

The alterations of mineral homeostasis observed in the streptozotocin-induced diabetic rat have been attributed to low circulating levels of 1,25-dihydroxyvitamin D3 [1,25-(OH)2-D3], the biologically active metabolite of vitamin D3. However, the effect of diabetes and subsequent insulin repletion on production of 1,25-(OH)2-D3 and 24,25-(OH)2-D3 by the kidney has not been investigated. We studied the renal production of 1,25-(OH)2-D3 and 24,25-(OH)2-D3 in diabetic and insulin-treated diabetic rats using the renal slice technique. In rats made diabetic with streptozotocin, the renal production of 1,25-(OH)2-D3 was markedly reduced (0.195 ± 0.011 pg/min/mg) compared with controls (0.685 ± 0.107 pg/min/ mg, P < 0.05). The renal production of 24,25-(OH)2-D3 in diabetic rats was markedly increased (0.529 ± 0.052 pg/min/mg) compared with controls (0.233 ± 0.035 pg/min/mg, P < 0.05). Treatment of diabetic rats with insulin for 12 days resulted in a significant increase in 1,25-(OH)2-D3 production (0.331 ± 0.053 pg/min/mg) and decrease in 24,25-(OH)2-D3 production (0.329 ± 0.054 pg/min/mg). The possibility that diabetes decreased renal 1,25-(OH)2-D3 production by decreasing parathyroid hormone (PTH) secretion or depressing the action of PTH on the kidney was also studied. Diabetes caused no decrease in serum PTH levels relative to the control group and urinary cyclic AMP excretion in the diabetic group was not depressed. The cyclic AMP content of diabetic rat kidney slices in response to PTH was similar to controls (39.8 ± 3.3 versus 39.7 ±4.6 pmol/mg wet weight). Serum immunoreactive calcitonin (iCT) was significantly depressed in diabetic rats compared with controls. Insulin treatment of diabetic rats resulted in a marked increase in serum iCT. These data suggest the impairment of renal 1,25-(OH)2-D3 production was not related to impairment of the PTH activation of adenylate cyclase in the diabetic State.