The metabolic syndrome associates central adiposity, insulin resistance, hypertension, and dyslipidemia, and represents a high-risk factor for cardiovascular disease and type 2 diabetes. The lipotoxicity hypothesis proposes that ectopic accumulation of fat in nonadipose tissue is a central pathogenic process in the metabolic syndrome and plays a major role in muscle and liver insulin resistance, diabetic cardiomyopathy, and pancreatic-cell dysfunction (1). Whereas most individuals are capable of compensating for insulin resistance by increasing insulin secretion and thus maintain normal glucose levels, patients predisposed to developing type 2 diabetes fail to adequately compensate, resulting in-cell failure and chronic hyperglycemia. Once-cell failure has occurred, the convergent effects of chronic hyperglycemia and hyperlipidemia adversely affect-cell function (2), leading to the inexorable deterioration of insulin secretion observed during the course of type 2 diabetes (3). A number of in vivo and in vitro studies have shown that under conditions of elevated glucose levels (ie above the normoglycemic level of 5.6 mM), prolonged exposure to pathological levels of fatty acids results in accumulation of triglycerides in-cells and impairment of insulin secretion, insulin gene expression, and cell viability (reviewed in Ref. 4). However, the mechanisms whereby fat accumulation in-cells impairs insulin secretion are poorly understood. A report in this issue of Endocrinology (5) provides new evidence for a link between lipogenesis and the expression of uncoupling protein-2 (UCP-2), shedding new light onto the mechanisms of lipotoxicity in the-cell.