Chapter 17 - Significance of Organ Crosstalk in Insulin Resistance and Type 2 Diabetes

Abstract

Diabetes mellitus (DM) is a metabolic disorder that affects humans worldwide and is an increasing economic burden on society. The disease has profound implications at the systemic level as a consequence of unregulated high blood glucose levels that lead to serious organ-specific complications. The cause of DM could be either secondary to lack of insulin due to autoimmune destruction of pancreatic β-cells (type 1 diabetes mellitus or T1D), or due to an inability of the pancreatic β-cells to compensate for the ambient insulin resistance in peripheral metabolic tissues (type 2 diabetes mellitus or T2D) [1] ; [2] ; [3] ; [4] ; [5] ; [6] . Insulin resistance is an early determinant of T2D, and a better understanding of the molecular basis underlying insulin resistance is essential for planning the treatment of the human disease [7] . Insulin resistance results from a combination of genetic and environmental factors and is defined as an inability of a given amount of bioactive insulin to adequately lower blood glucose levels [8] ; [9] ; [10] ; [11] ; [12] ; [13] ; [14] ; [15] . From clinical studies in humans, it is evident that defects within the insulin signal transduction machinery occur early and lead to an insulin resistant state. However, the precise molecular alterations that lead to insulin resistance in target tissues that are important for metabolism of the organism are not fully defined. While insulin-mediated reduction in blood glucose levels is achieved mostly by stimulating glucose uptake by muscle and adipose tissues and by suppression of hepatic glucose production, other effects of insulin on non-classical tissues have recently been reported to contribute significantly to the pathogenesis of the disease. In this chapter we will review the inter-relationships between various tissues and how their mutual crosstalk has the potential to alter glucose metabolism and insulin sensitivity in the pathophysiological state. Together, these emerging studies indicate that a better understanding of multi-level organ crosstalk is critical for the long-term goal of developing effective strategies to prevent and/or delay the onset of T2D.