This article provides an overview of the role of metabolite toxicity, low-grade inflammation and disturbed cellular signaling in obesity, glucose intolerance and diabetes. It also highlights links between this continuum of deteriorating glucose tolerance and atherosclerosis. Obesity, diabetes mellitus, and cardiovascular disease are all related to diet and to the level of physical activity. They have reached epidemic proportions worldwide. Glucose intolerance and diabetes increase the risk of atherosclerotic events. Moreover, obesity, and glucose intolerance or diabetes, are components of the metabolic syndrome, which also imparts an increased cardiovascular risk. There is increasing recognition that common mechanisms contribute to diabetes and cardiovascular disease. Following increased calorie intake and/or decreased physical activity, fuel metabolism generates excess of ‘toxic’ metabolites, particularly glucose and fatty acids. Homeostasis is affected by the endocrine output from the adipose tissue. Reactive oxygen species are generated, creating oxidative stress, which exerts major effects on signaling pathways, further affecting cellular metabolism and triggering low-grade inflammatory reaction. This perspective on the diabetic syndrome has been reflected in the approach to its treatment, which integrates maintenance of glycemic control with primary and secondary cardiovascular prevention. Laboratory medicine should support diabetes care with an integrated package of tests which, in addition to glycemic control, enable assessment and monitoring of the risk of microvascular complications as well as cardiovascular disease.