Tightly co-ordinated control of both insulin action and secretion is required in order to maintain glucose homeostasis. Gene knockout experiments have helped to define key signalling molecules that affect insulin action, including insulin and insulin-like growth factor-1 (IGF-1) receptors, insulin receptor substrate (IRS) proteins and various downstream effector proteins. beta-cell function is also a tightly regulated process, with numerous factors (including certain signalling molecules) having an impact on insulin production, insulin secretion and beta-cell mass. While signalling molecules play important roles in insulin action and secretion under normal circumstances, abnormal insulin signalling in muscle, adipose tissue, liver and pancreas leads to insulin resistance and beta-cell dysfunction. In particular, the signalling protein IRS-2 may have a central role in linking these abnormalities, although other factors are likely to be involved.