Functional, molecular, and biochemical characterization of Streptozotocin-induced diabetes

Altered divalent cation homeostasis with bone mineral loss, hypercalciuria, and hypomagnesemia have been associated consistently with human diabetes m ellitus. This study investigated functional, molecular, and biochemical det erminants that accompany this condition in chronically (2 wk) streptozotoci n (STZ)-diabetic rats. Catheterized, conscious, diabetic rats on servo-cont rolled fluid replacement exhibited an increased GFR (+70%) and a substantia lly raised urinary calcium output (+568%) when compared with control rats. In addition, fractional calcium reabsorption was reduced, indicating that t he hypercalciuria was not due solely to an osmotic effect but may involve a n actual tubular defect. The expression of proteins involved in renal dista l Ca2+ and water transport in STZ-diabetic rats were then studied by Wester n analysis and immunofluorescence microscopy to investigate the molecular b asis of the hypercalciuria. Extracellular Ca2+-sensing receptor abundance w as reduced to 52% of control in STZ-diabetes, whereas thiazide-sensitive Na Cl cotransporter expression was increased by 192%. Subcutaneous insulin imp lant rectified both functional and molecular parameters. The levels of calb indin D-28k plasma membrane Ca2+ ATPase, and aquaporin 1 in whole kidney an d of aquaporin 2 in inner medulla were unchanged in diabetic and/or insulin replacement. Blood levels of 1,25(OH)(2)D-3 were reduced in diabetes as we re levels of osteocalcin, a marker of bone formation. It is concluded that diabetic hypercalciuria in rats involves elevated GFR with raised urinary o utput, reduced Ca2+ reabsorption, and impaired bone deposition. Changes in Ca2+-sensing receptor and NaCl cotransporter protein expression could accou nt: for the altered divalent cation homeostasis seen during diabetes mellit us.