A Paradigm Shift and New Therapeutic Options for the Metabolic Syndrome

Abstract

The metabolic syndrome, characterized by obesity, dyslipidemia, insulin resistance and hypertension, increases the risk of cardiovascular morbidity and mortality. In recent years, the convergence of evidence from several studies has resulted in a major shift both in the understanding of the pathophysiology and the treatment options for this disease. Shunning away from the glucocentric hypothesis, this is now based on a unified ‘lipotoxicity’ hypothesis, according to which metabolic syndrome and type 2 diabetes mellitus can be caused by the ectopic accumulation of triglycerides and long-chain fatty acids in liver, muscle and pancreatic islets. This lipocentric approach is integrated with the analysis of inflammatory reactions associated with end-organ damage, including the vascular wall. Transcription factors and coactivators, including peroxisome proliferator-activated receptor coactivator-1 are crucial in mediating insulin resistance and accelerating vascular wall inflammation, and represent promising therapeutic targets. This new integrated view of the metabolic syndrome also takes into account the genetic differences among individuals and consequent variant response to therapy.