Decoding insulin resistance and metabolic syndrome for promising therapeutic intervention.

Metabolic syndrome, also known as insulin resistance syndrome, has become a major public health problem worldwide. It consists of obesity, hyperglycemia, hyperinsulinemia, dyslipidemia, and hypertension. Metabolic syndrome is a major risk factor for the development of type 2 diabetes mellitus, which currently afflicts 22 million Americans and over 100 million Chinese (Alberti et al. 2005, Cornier et al. 2008, Roger et al. 2011). Importantly, metabolic syndrome is also a significant risk factor for the development of cardiovascular disease, and two-thirds of patients with diabetes mellitus die of heart failure (Roger et al. 2011). In 2011, an estimated 366 million people around the world had diabetes, and this number is predicted to rise to 522 million by 2030 (Whiting et al. 2011). The estimated costs of diagnosed diabetes in the USA have risen from $174 billion in 2007 to $245 billion in 2012 (Herman 2013). Obviously, understanding and controlling metabolic syndrome and associated cardiovascular disorders have far-reaching impacts on our healthcare and economic systems that affect the quality of our daily life. As a first step, understanding the mechanisms responsible for insulin action and resistance is critical for developing therapeutic interventions and, thereby controlling metabolic syndrome. In this special issue of Journal of Endocrinology, we provide four thematic review articles, which combine discussion of the disease mechanism behind metabolic syndrome with the most recent research from cell-based and animal studies. These reviews address how insulin resistance in different organs contributes to metabolic syndrome at the molecular, biochemical, and physiological levels. In particular, we largely focus on studies using genetically engineered mouse models, which have provided detailed information with respect to the inactivation of the insulin signaling cascade in the brain, adipose tissue, pancreas, muscle, and liver, as well as other tissues. Thus, we can determine the insulin resistance contribution of each organ to the clinical features of metabolic syndrome. In the first review of the series, Dr S Guo updates our understanding of the insulin signaling cascade, with an emphasis on the role of phosphatidylinositide-3-kinase (PI3K) in metabolic control (Guo 2014). A key action of insulin on metabolic regulation involves activation of PI3K by association with the insulin receptor substrate 1 (IRS1) and IRS2, and subsequent phosphorylation of Akt/Foxo1. This pathway has a central role in the control of nutrient homeostasis and organ survival. A large amount of evidence suggests that inactivation of Akt and subsequent activation of the forkhead/winged helix family transcription factor Foxo1, through the suppression of IRS1 and IRS2 in organs following hyperinsulinemia, metabolic inflammation, and overnutrition, may form key mechanisms for metabolic syndrome in humans. Thus, targeting the IRS/Akt/Foxo1 signaling cascade will probably provide a strategy for therapeutic intervention in the treatment of type 2 diabetes mellitus and its complications. Recent studies carried out in Dr Guo’s laboratory have further demonstrated that suppression of IRS1 and IRS2 expression and functionality occurs in the liver and heart of animals with insulin resistance and/or type 2 diabetes, suggesting that loss of IRS1 and IRS2 not only contributes to the occurrence of hyperglycemia, but also promotes heart failure and death