Metabolic , Endocrine and Genitourinary Pathobiology RhoB Loss Prevents Streptozotocin-Induced Diabetes and Ameliorates Diabetic Complications in Mice

RhoB is an early-response gene whose expression is elevated by multiple cellular stresses; this gene plays an important role in cancer, macrophage motility, and apoptosis. These factors are essential for the onset of type 1 diabetes mellitus and related complications. This study explores the role of RhoB in -cell depletion and hyperglycemia-associated complications and tests whether the pleiotropic effect of statins on glycemic control is RhoB dependent. We induced -cell depletion in RhoB / , RhoB / , and RhoB / mice with streptozotocin (STZ). Diabetic status was assessed by glucose tolerance and pancreatic islet loss. RhoB / mice showed a significant reduction in the severity of STZ-induced diabetes; only 13% of the STZ-treated RhoB-null animals became hyperglycemic, as opposed to 61% of the wild-type controls. Diabetes-related complications, such as wound healing rate and onset of nephropathy, were also assessed. Hyperglycemic RhoB / mice had fewer signs of nephropathy and showed faster wound healing than RhoB / animals. After assessing the diabetic status of mice treated simultaneously with STZ and simvastatin, we conclude that the effect of statins in improving glycemic control is RhoB independent. We propose that RhoB is a modifier of diabetes, important for the induction of -cell loss. Suppression of RhoB expression may have potential application in the treatment of diabetes and associated complications. (Am J Pathol 2011, 178:245–252; DOI: 10.1016/j.ajpath.2010.11.040) RhoB is an early-response gene whose expression is elevated by cellular stresses, including UV irradiation and hypoxia. The RhoB gene encodes a small GTPase that regulates vascular sprouting and intracellular trafficking of v-akt murine thymoma viral oncogene homolog 1 (AKT) in endothelial cells. This protein has also been implicated in a variety of cellular processes, such as migration and adhesion in macrophages, endocytosis, epidermal growth factor signaling, actin organization, intracellular trafficking, and DNA damage–induced apoptosis. All of these are important processes for type 1 diabetes mellitus onset and for the complications associated with hyperglycemia, such as delayed wound healing and nephropathy. However, to our knowledge, RhoB has not been examined in the context of diabetes and hyperglycemia. Rho GTPases can be found in two forms: the active GTP-bound form, generated by guanine nucleotide exchange factors; and the inactive form, bound to GDP by the GTPase-activating proteins. Both can be post-translationally modified by cysteine prenylation. Although RhoB can be prenylated by either a farnesyl group or a geranylgeranyl group, RhoA and RhoC can only be geranylgeranylated. The method of prenylation of the Rho GTPases determines its cellular localization. Statins have been shown in previous studies to prevent hyperglycemia in nonobese diabetic mice and streptozotocin (STZ)–treated mice. The mechanism by which this is achieved is still unclear. Statins are HMGCoA reductase inhibitors broadly used to control cholesterol levels and mitigate cardiovascular disease. This inhibition affects the mevalonate pathway, inhibiting Rho prenylation by preventing the formation of farnesyl and geranylgeranyl isoprenoids. We tested the effect of the