Partial protection of 1α-hydroxyvitamin D 3 against the development of diabetes induced by multiple low-dose streptozotocin injection in CD-1 mice

Abstract

1α-Hydroxyvitamin D 3 (1α-OH-D 3), a precursor of active vitamin D 3, 1α,25-dihydroxyvitamin D 3, was tested in CD-1 mice for its in vivo effect against the development of diabetes induced by administering multiple low doses of streptozotocin (STZ). Daily intraperitoneal (IP) injections of 35 mg/kg body weight of STZ administered for 5 consecutive days to mice from 7 weeks of age induced a delayed-onset hyperglycemia, insulitis, and β-cell degranulation in 26 of 28 mice. Only 12 of 29 mice developed diabetes when treated with simultaneous daily IP injections of 1α-OH-D 3 for 14 consecutive days, with diabetes defined as a plasma glucose level greater than 200 mg/dL. A daily dose of 0.3 μg/kg 1α-OH-D 3 also protected against the development of hyperglycemia in five of 13 mice, whereas 0.2 μg/kg 1α-OH-D 3 was ineffective, indicating a dose-related effect. Histological study showed that, among the 1α-OH-D 3-treated mice, the pancreatic islets of euglycemic mice showed neither massive islet infiltration nor β-cell degranulation, whereas those of the hyperglycemic mice showed insulitis. However, when diabetes was chemically induced with a single high dose of STZ, the simultaneous administration of 1α-OH-D 3 to mice failed to protect against the development of hyperglycemia; all five mice so treated developed hyperglycemia. Their pancreatic islets did not show insulitis. Therefore, it is suggested that 1α-OH-D 3 may protect against the development of diabetes following administration of multiple low doses of STZ, probably via an immune mechanism.