Islet Blood Flow in Multiple Low Dose Streptozotocin-Treated Wild-Type and Inducible Nitric Oxide Synthase-Deficient Mice.

Abstract

The present study tested the hypothesis that changes in islet blood perfusion occur during the development of diabetes in the multiple low dose streptozotocin-treated mouse. Streptozotocin (40 mg/kg) or citrate buffer was given ip once daily for 5 consecutive days to wild-type and inducible nitric oxide synthase (iNOS)-deficient C57BL/6 x 129 SvEv hybrid mice. The blood flows were then determined by a microsphere technique. The islet blood perfusion was almost 2-fold higher in wild-type mice treated with streptozotocin than in those given vehicle. Whole pancreatic blood flow was also increased in the streptozotocin-treated wild-type mice. In iNOS-deficient mice, neither islet blood flow nor whole pancreatic blood flow was affected by repeated streptozotocin treatment. These combined findings suggest an increased islet blood perfusion in the prediabetic stage mediated by an iNOS-dependent mechanism. In combination with increased vasopermeability and expression of adhesion molecules on the islet endothelium, as previously described, this increased islet blood flow may be of crucial importance for the recruitment of inflammatory cells into the islets during the development of diabetes in this animal model. Indeed, an increased degree of insulitis was observed in wild-type mice compared with mice deficient in iNOS as well as a more rapid decrease in islet volume and an earlier debut of manifest diabetes. We also describe altered islet blood perfusion in the iNOS-deficient mice during basal conditions due to a compensatory increase in constitutive NOS activity.