Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction

Obesity is a major public health problem worldwide, and it is associated with an increased risk of developing type 2 diabetes. It is now commonly accepted that chronic inflammation associated with obesity induces insulin resistance and beta-cell dysfunction in diabetic patients. Obesity-associated inflammation is characterized by increased abundance of macrophages and enhanced production of inflammatory cytokines in adipose tissue. Adipose tissue macrophages are suggested to be the major source of local and systemic inflammatory mediators such as tumor necrosis factor alpha, interleukin (IL)-1 beta, and IL-6. These cytokines induce insulin resistance in insulin target tissues by activating the suppressors of cytokine signaling proteins, several kinases such as c-Jun N-terminal kinase, I kappa B kinase beta, and protein kinase C, inducible nitric oxide synthase, extracellular signal-regulated kinase, and protein tyrosine phosphatases such as protein tyrosine phosphatase 1B. These activated factors impair the insulin signaling at the insulin receptor and the insulin receptor substrates levels. The same process most likely occurs in the pancreas as it contains a pool of tissue-resident macrophages. High concentrations of glucose or palmitate via the chemokine production promote further immune cell migration and infiltration into the islets. These events ultimately induce inflammatory responses leading to the apoptosis of the pancreatic beta cells. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation are discussed, with particular attention being placed on the roles of the molecular players linking inflammation to insulin resistance and beta-cell dysfunction.