The term "metabolic syndrome" refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is thought to be related to insulin resistance. Since the term is widely used in research and clinical practice, we undertook an extensive review of the literature in relation to the syndrome's definition, underlying pathogenesis, and association with CVD and to the goals and impact of treatment. While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a "syndrome." Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the "metabolic syndrome." Diabetes Care 28:2289 -2304, 2005F or most of the 20th century, cardiovascular disease (CVD) was identified as the major cause of morbidity and mortality in the developed world. During this period there was considerable effort to understand the underlying biology of the disease and to identify the contributing risk factors. As risk factors were identified, it became apparent that more than one were often present in the same individual. Toward the end of the century, the clustering of CVD risk factors was first described, most notably the simultaneous presence of obesity, type 2 diabetes, hyperlipidemia, and hypertension (1-3). Although insulin resistance (i.e., resistance to insulin-stimulated glucose uptake) as a feature of type 2 diabetes was first described many years earlier (4), hyperinsulinemia was also found to be a key feature of type 2 diabetes (5,6), as well as hyperlipidemia (7-9), obesity (10 -13), and hypertension (12)(13)(14). In addition, a cluster of heart disease risk factors seemed clearly related to type 2 diabetes (15).This risk factor clustering, and its association with insulin resistance, led investigators to propose the existence of a unique pathophysiological condition, called the "metabolic" (1-3) or "insulin resistance" (11) syndrome. This concept was unified and extended with the landmark publication of Reaven's 1988 Banting Medal award lecture (16). Reaven postulated that insulin resistance and its compensatory hyperinsulinemia predisposed patients to hypertension, hyperlipidemia, and diabetes and thus was the underlying cause of much CVD. Although obesity was not included in Reaven's primary list of disorders caused by insulin resistance, he acknowledged that it, too, was correlated with insulin resistance or hyperinsulinemia, and that the obvious "treatment" for what he termed "syndrome X" was weight maintenance (or weight loss) and physical activity.Reaven's seminal paper was followed by many studies documenting the clustering of CVD risk factors and their relatio...

ATP, the principal energy currency of the cell, fuels most biosynthetic reactions in the cytoplasm by its hydrolysis into ADP and inorganic phosphate. Because resynthesis of ATP occurs in the mitochondrial matrix, ATP is exported into the cytoplasm while ADP is imported into the matrix. The exchange is accomplished by a single protein, the ADP/ATP carrier. Here we have solved the bovine carrier structure at a resolution of 2.2 A by X-ray crystallography in complex with an inhibitor, carboxyatractyloside. Six alpha-helices form a compact transmembrane domain, which, at the surface towards the space between inner and outer mitochondrial membranes, reveals a deep depression. At its bottom, a hexapeptide carrying the signature of nucleotide carriers (RRRMMM) is located. Our structure, together with earlier biochemical results, suggests that transport substrates bind to the bottom of the cavity and that translocation results from a transient transition from a 'pit' to a 'channel' conformation.