Chapter 331 - IRS-Protein Scaffolds and Insulin/IGF Action in Central and Peripheral Tissues

Abstract

The investigation of the insulin signaling cascade has revealed a broad physiologic role that extends far beyond the classical insulin target tissues—liver, muscle, and fat. The insulin-like signaling system is integrated throughout the body to coordinate systemic growth and development with peripheral and central nutrient homeostasis, fertility, and lifespan. Dysregulated insulin signaling is associated with a cohort of common systemic disorders, including obesity and dyslipidemia, cardiovascular disease and hypertension, infertility, and neurodegeneration. The insulin receptor substrates proteins—mainly Irs1 and Irs2—coordinate insulin and insulin-like growth factor signals in all tissues. The insulin-like signaling cascade through Irs2 is critical for β-cell growth, function, and survival, so similar signaling cascades coordinate insulin secretion and action. The IRS-proteins are adapter molecules that link the insulin-like receptors to common downstream signaling cascades. Recent studies reveal a variety of factors secreted from adipose tissue that inhibit insulin signaling. The tools now available to probe the insulin-like signaling cascades in healthy and diabetic tissues provide a rational platform to develop new strategies to treat insulin resistance and prevent its progression to Type 2 diabetes and neurodegeneration. Future work must better resolve the network of insulin responses that are generated in various tissues, because too much insulin action might also shorten lives.