IMPROVEMENT OF GLUCOSE-TOLERANCE WITH IMMUNOMODULATORS IN TYPE-2 DIABETIC ANIMALS

Cytokine-inducers prevent insulin-dependent diabetes mellitus (IDDM) i n animal models. We extended this therapy to non-insulin-dependent dia betes mellitus (NIDDM), because it was reported that diabetes of KK-Ay mice, a model for NIDDM, was recovered by allogenic bone-marrow trans plantation that also prevented IDDM in animal models. An i.p. or i.v. injection of streptococcal preparation (OK-432) lowered fasting blood glucose (FBG) levels and markedly improved glucose tolerance test (GTT ) in KK-Ay mice for more than 32 h regardless of the glucose loading r outes (oral, i.v. or i.p.), while an i.v. injection of BCG improved FB G and GTT for more than 4 wks without body weight loss. The improvemen t of FBG and GTT with OK-432 was brought about in other NIDDM animals, GK rats and Wistar fatty rats. Among various cytokines possibly induc ed by OK-432 and BCG, IL-1 alpha, TNF alpha and lymphotoxin significan tly improved FBG and GTT in KK-Ay mice, whereas IL-2 and IFNgamma did not. There were no differences between the OK-432-treated KK-Ay mice a nd control in histology of the pancreas, degree of insulin-induced dec rease in blood glucose levels, and muscle glycogen synthase activities . As to insulin secretion, there is a tendency that the OK-432-treatme nt less than I week did not affect insulin levels during GTT, whereas the treatment more than 2 weeks increased the insulin levels. Thus, cy tokine-inducers improved FBG and glucose tolerance of NIDDM animals pr obably via cytokines. The results imply a role of the cytokines in glu cose tolerance of NIDDM, although precise immune and metabolic mechani sms remain to be elucidated.