3 - Cellular Models for the Study of Type 2 Diabetes

Abstract

Type 2 diabetes mellitus is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signaling. Both genetic and environmental factors can contribute to the development of insulin resistance. This review provides new insights into the molecular mechanisms of insulin action and resistance in several cell lines developed in our laboratory derived from deficient mouse models. These cells are unique tools that delineate the tissue specificity of the distinct components of the insulin signaling cascade, as well as the different pathways that lead to the insulin effects in target tissues. There is a consistent association between central obesity and the development of type 2 diabetes. Several factors secreted from adipose tissue, including cytokines, growth factors and free fatty acids, can impair insulin signaling, altering insulin-mediated processes including glucose homeostasis and lipid metabolism. Among them, TNF-α has been proposed as a link between adiposity and the development of insulin resistance. We have recently explored in depth the mechanism by which TNF-α produces insulin resistance to glucose uptake in two physiological models: primary cultures of neonatal myocytes and fetal brown adipocytes. Furthermore, these models can be useful for investigating the mechanism by which thicizolidinediones, drugs that have been recently introduced for the treatment of type 2 diabetes, increase insulin sensitivity in situations that mimic insulin resistance.