There is increasing incidence of diabetes mainly driven by the obesity pandemic. Diabetes and obesity are both associated with micro-and macrovascular complications. Diabetic kidney disease is a major health burden often leading to dialysis and/or transplantation and further complicated by accelerated cardiovascular risk. Despite current new treatment options there remains an unmet clinical need for mechanism- based treatments in diabetic kidney disease and other diabetic complications. We have identified the excessive production of reactive oxygen species (ROS) by NADPH oxidase isoforms as a promising new target to reduce oxidative stress, inflammation and fibrosis in diabetes. NADPH oxidases are expressed in several isoforms and there appear to be organ-specific effects with NOX1 promoting atherosclerosis whereas NOX4 being vasculoprotective but deleterious in the kidney in diabetes. We provide new evidence for a critical role of the human isoform NOX5 in diabetic complications using humanised Nox5 transgenic mice, rabbit models of diabetes, 3D kidney organoids and human kidney biopsies. There is a close link between ROS formation and inflammation. Inhibitors of the inflammasome have been proposed as novel therapeutic agents in diabetic complications. Although some studies have shown end-organ protective effects with NLRP3 inflammasome inhibitors in diabetes, this area remains controversial and requires further evaluation in settings of low-grade inflammation such as in diabetic kidney disease.