CONCENTRATION-DEPENDENT GLUCOSE-LOWERING EFFECTS OF ORAL VANADYL ARE MAINTAINED FOLLOWING TREATMENT WITHDRAWAL IN STREPTOZOTOCIN-DIABETIC RATS

We have recently reported that treatment with vanadyl sulfate 0.75 mg/ mL in drinking water eliminates hyperglycemia in a subset of streptozo tocin (STZ)-diabetic rats, with some rats remaining unresponsive to su ch treatment. In the present study, we demonstrate that unresponsive d iabetic animals become normoglycemic when given higher concentrations of vanadyl. Since the subset of rats that require higher concentration s ([HC] 1.25 to 1.50 mg/mL) were found to be more severely diabetic be fore treatment than those that responded to lower concentrations ([LC] 0.75 to 1.00 mg/mL), the relative amount of residual circulating insu lin (LC 36.0 +/- 2.2 v HC 25.6 +/- 3.3 mu U/mL) appeared to be a key e lement in achievement of a normoglycemic effect to a given dose of van adyl. Similarly, STZ-diabetic animals that responded to euglycemia wit h a more potent organic vanadyl compound (naglivan) had higher pretrea tment plasma insulin levels than unresponsive animals (DT-R) (35.5 +/- 1.9 v 24.2 +/- 3.6 mu U/mL). Vanadyl treatment over 10 weeks resulted in a period of normalized glucose levels and glucose tolerance after treatment was stopped. At 20 weeks after withdrawal from treatment wit h vanadyl sulfate, 13 of 19 animals remained euglycemic, whereas four of seven naglivan-treated animals also maintained normal glucose level s after a 30 week withdrawal period. At 3 weeks after withdrawal, main tenance of normal glucose homeostasis appeared to be independent of al tered insulin levels, whereas at 20 weeks an improved insulin secretio n, albeit 50% that of age-matched controls both in the fed state and i n response to a glucose dose, was sufficient to return plasma glucose levels to the normal range. In conclusion, the results suggest that in diabetic animals vanadyl and endogenous insulin work in an interdepen dent and complementary manner, and that maintenance of normal glucose homeostasis after withdrawal appears to be due to a continued enhancem ent of insulin sensitivity in the short term, whereas it may depend mo re critically on an improved pancreatic function in the long term. Cop yright (C) 1995 by W.B. Saunders Company