ANTIHYPERGLYCEMIC EFFECTS OF M16209, A NOVEL ALDOSE REDUCTASE INHIBITOR, IN NORMAL AND DIABETIC RATS

The effect of a single oral administration of M16209 (1-(3-bromobenzo[ b]furan-2-yl-sulfonyl)hydantoin), a novel aldose reductase inhibitor, on serum glucose was investigated. In normal rats, M16209 (100 mg/kg) had a weak hypoglycemic effect but markedly stimulated the disappearan ce of serum glucose in intravenous glucose tolerance tests. In diabeti c rats, M16209 (100 mg/kg) significantly suppressed the hyperglycemia of streptozotocin-induced, mildly diabetic rats and stimulated serum g lucose disappearance in neonatally streptozotocin-induced, non-insulin -dependent diabetes mellitus (NIDDM) rats in glucose tolerance tests. Additionally, M16209 augmented insulin secretion in glucose loaded, no rmal and NIDDM rats and restored the reduced serum insulin in streptoz otocin-induced, mildly diabetic rats. M16209, however, showed no hypog lycemic effect in severely diabetic rats. In contrast, gliclazide, a s ulfonylurea, showed a much more potent hypoglycemic effect in normal r ats than in mildly diabetic rats. These results suggest that M16209 su ppresses hyperglycemia through augmentation of glucose-stimulated insu lin secretion. The antihyperglycemic activity of M16209, combined with its potent aldose reductase inhibiting activity, is expected to be be neficial in the treatment of diabetic complications.