ABSTRACT
In clinical practice, insulin resistance is defined as a state in which endogenously secreted or exogenously administered insulin has decreased effectiveness in regulating blood glucose. In this sense, ‘‘insulin resistance’’ is the opposite of ‘‘insulin sensitivity.’’ Although insulin has many effects on cellular metabolism and on cell growth and differentiation that are mediated by distinct intracellular signaling pathways, it is a decreased sensitivity and responsiveness to insulin’s action to stimulate glucose uptake in insulin-sensitive tissues such as skeletal muscle and adipose tissue and an impairment of its ability to decrease hepatic glucose output through inhibition of glycogenolysis and gluconeogenesis that constitute the clinical condition of insulin resistance. These effects are mediated by a cascade of phosphorylation reactions involving the insulin receptor, insulin receptor substrates (IRS-1 and IRS-2), and activation of the phosphoinositol 3′ kinase (PI-3′-K) pathway. On the other hand, cell growth and differentiation are regulated primarily by the SHC, GRB-2, and the MAP-kinase pathways, which may or may not be resistant to insulin action and may actually exhibit increased activity as a result of compensatory hyperinsulinemia in insulin-resistant individuals. Thus, differential insulin resistance may exist with decreased insulin action on glucose uptake and metabolism and increased effects of insulin on cell growth and differentiation occurring simultaneously.
