The protective effect of simvastatin against low dose streptozotocin induced type 1 diabetes in mice is independent of inhibition of HMG-CoA reductase.

Besides a cholesterol-lowering effect, simvastatin possesses anti-inflammatory properties attributed to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and/or direct binding to, and inhibition of, the integrin lymphocyte function associated antigen-1 (LFA-1). We have shown that simvastatin protects against multiple low dose streptozotocin (MLDS) induced type 1 diabetes in mice. Presently, we examined if this effect could be abolished by co-administration of mevalonic acid, thus determining if the protective effect is dependent or independent of inhibition of HMG-CoA reductase. Mevalonic acid did not affect the protective effect of simvastatin against MLDS diabetes. Moreover, spleens from these mice did not show any signs of toxic side-effects, thus excluding the possibility that the protective effect is secondary to a general inflammatory response. We suggest that simvastatin's protective effect mainly is independent of HMG-CoA reductase inhibition. This implies that inhibition of LFA-1 activation is important for the protective effect exerted by simvastatin.