TOLBUTAMIDE REDUCES THE INCIDENCE OF DIABETES-MELLITUS, BUT NOT INSULITIS, IN THE NON-OBESE-DIABETIC MOUSE

The functional state of beta cells may influence the rate of their destruction in Type 1 (insulin-dependent) diabetes mellitus. We examined the effect of diazoxide, which inhibits insulin secretion, or tolbutamide, which stimulates insulin secretion, upon the incidence of diabetes in the non-obese-diabetic (NOD) mouse. Female mice were treated from 3-30 weeks of age with diet containing diazoxide 250 mg . kg-1 or tolbutamide 125 mg . kg-1. The cumulative incidence of diabetes at 35 weeks was similar in the diazoxide (16 of 24) and control (18 of 24) groups, but reduced in the tolbutamide group (10 of 23, p < 0.04 vs control group). In a second experiment, treatment was started from 9 weeks of age, by which time insulitis is already present. The cumulative incidence of diabetes at 35 weeks was 16 of 24 in controls, 15 of 24 on diazoxide and 11 of 24 on tolbutamide (p = NS vs control). A third experiment compared the effect of treatment from 3 weeks with control diet or diet containing tolbutamide 125 mg . kg-1 or 500 mg . kg-1. Diabetes was reduced by tolbutamide treatment, with a cumulative incidence of 25 of 31 in controls, 18 of 30 on tolbutamide 125 mg . kg-1 (p < 0.04) and 14 of 32 on 500 mg . kg-1 (p < 0.002), although the difference between the two-treatment groups failed to reach statistical significance. A fourth experiment showed that treatment from 3-12 weeks with diazoxide 1000 mg . kg-1 increased the extent of insulitis compared with controls and animals treated with tolbutamide 500 mg . kg-1. Elucidation of the mechanisms by which tolbutamide reduces the incidence of diabetes in the NOD mouse has implications for human intervention trials.