IN THE fasted state, glucose homeostasis depends upon the balance between hepatic glucose production and glucose utilization by the major insulin-dependent tissues, such as liver, adipose, and muscle, and by insulin-independent tissues, such as brain and kidney. This balance is tightly regulated by pancreatic hormones. Thus, in normal individuals, the response to increased plasma glucose levels is an increase in secretion of insulin from β-cells of the pancreatic islets. This increase in circulating insulin levels stimulates glucose transport into peripheral tissues and inhibits hepatic gluconeogenesis. In type II diabetes there are at least two fundamental defects: one is a decrease in the ability of peripheral tissues to respond to insulin (insulin resistance), and the second is impaired β-cell function, which results from long-term hyperglycemia. It appears that both genetic and environmental factors are responsible for the progression from normal glucose tolerance to type II diabetes (1–4).

In addition to its primary effects on glucose homeostasis, insulin also promotes a number of other cellular events including regulation of ion and amino acid transport, lipid metabolism, glycogen synthesis, gene transcription and mRNA turnover, protein synthesis and degradation, and DNA synthesis (Fig. 1). Thus the actions of insulin play key roles in the normal storage of ingested fuels and in normal cellular growth and differentiation. The biological importance of these effects of insulin are most obvious in the uncontrolled type I diabetic in ketoacidosis (1, 3–5). To fully understand the events leading to insulin-resistant states and the pathophysiology of insulin deficiency, it is necessary to identify, at the molecular level, the key components in the insulin-signaling pathway.