HEPARIN ATTENUATES LOW-DOSE STREPTOZOTOCIN-INDUCED IMMUNE DIABETES IN MICE AND INHIBITS THE BETA-CELL BINDING OF T-SPLENOCYTES INVITRO

Five low doses (40 mg.kg-1.day-1) of streptozotocin were given to CD-1 mice to induce "immune" diabetes with insulitis. T-splenocytes (L3T4+ and Lyt 2+) from streptozotocin-treated mice were previously reported to display in vitro an increased binding for Beta cells, preceding the onset of hyperglycaemia and of insulitis. Since heparin inhibits lymphocyte traffic, displays anti-adhesive properties, and attenuates some cell-mediated immune diseases, we have investigated the effects of heparin and N-desulphated heparin: 1) in vivo on low-dose streptozotocin-induced diabetes and insulitis, and 2) in vitro on the increased binding of T-splenocytes from streptozotocin-treated mice to rat insulinoma (RINm5F) cells. Daily subcutaneous low doses (5-mu-g or 10-mu-g) of heparin induced a delay in onset and a reduction of the severity of hyperglycaemia and insulitis (p < 0.01), and reduced the incidence of diabetes (p < 0.01). Similar effects were obtained with 5-mu-g daily doses of N-desulphated heparin devoid of anticoagulant activity. In contrast, lower (1-mu-g) or higher (200-mu-g) doses of heparin were ineffective. Heparin (10-mu-g) did not modify the "toxic" diabetes induced by a single high dose (200 mg/kg) of streptozotocin. On the other hand, heparin dose-dependently (0.1-mu-g/ml to 500.0-mu-g/ml) inhibited the increased binding of splenocytes from streptozotocin-injected mice to RIN cells as compared to splenocytes from control mice. This in vitro anti-adhesive effect was detected when either splenocytes or RIN cells were pretreated with heparin before their co-incubation, and was also obtained with N-desulphated heparin. Heparinoids display anti-adhesive and immunomodulatory properties that are of therapeutic potential in this model of Type 1 (insulin-dependent) diabetes mellitus.