-4 HE TERM DIABETES MELLITUS DESCRIBES A HETEROGE-neous group of disorders characterized by elevated blood glucose and metabolic abnormalities. These disorders may result from decreased circulating insulin or ineffective insulin action in target cells. Diabetes is classified as being either insulin-dependent (type I) or noninsulin-dependent (type II) and affects 5% of the US population. Target cell resistance to the action of insulin occurs in both forms of diabetes but is a central feature oftype H diabetes. Molecular studies of the insulin receptor and its effector systems, including three reports in this issue of Science, have provided furither insight into the molecular defects associated with insulin-resistant forms of diabetes. Insulin action in target cells requires the trans-membrane signaling activity of the insulin receptor (1), a plasma membrane glycoprotein consisting of two a subunits, which bind insulin, and two d subunits, which possess tyrosine-specific protein kinase activity. Insulin binding to the a subunits stimulates the tyrosine kinase activity of the subunits, which in turn results in receptor autophosphorylation, conformational changes in the 1i subunit, and activation of the receptor kinase toward other sub-strates. Receptor activation is followed by rapid phosphorylation and dephosphorylation of intermediary substrates on serine residues, elaboration of secondary mediators of insulin action, modula-tion of metabolic enzyme activity, and changes in gene expression. Two rare clinical syndromes ofextreme resistance to insulin (type A syndrome and leprechaunism) have provided insights into the role of receptor defects in diabetes (2). Cultured cells from individuals with these syndromes have revealed genetic defects in the insulin receptor (3, 4), including one which affects receptor mRNA expres-sion, a point mutation that alters processing of the receptor precursor, a point mutation that blocks the insertion of the mature receptor into the plasma membrane, and others that result in reduced insulin binding. Genetic defects in the receptor tyrosine kinase domain also occur. An individual with the type A syndrome had a point mutation in the subunit resulting in the substitution of a serine residue for tryptophan in the kinase domain (4), and two type A individuals described in this issue of Science show new mutations in the kinase domain. Odawara et al.(5) describe an individual heterozygous for a point mutation that alters the Gly-X-Gly-XX-Gly sequence of the receptor, which is essential for the binding of adenosine triphosphate. Taira et al.(6) describe an individual heterozygous for a rearrangement of the insulin receptor gene that deletes the entire kinase domain. These individuals are interesting not only because they provide insight into structure-function relations of the receptor that may not have been otherwise subject to analysis, but also because many of them are heterozygous for their receptor defects, and thus express mixed populations of normal and mutant receptors. The presence of mutant receptors appears to have negative effects on the activity of the normal receptor (6). Studies with kinase-deficient insulin receptors transfected into cultured cells show that such receptors function as dominant-negative mutations and suppress the function of the endogenous insulin receptors (7). One of the cellular effects of insulin is the stimulation of glucose transport. Although most tissues have glucose transport systems, insulin stimulation of glucose transport occurs primarily in muscle and adipose tissue. At least six presumed glucose transport proteins have been cloned (8) including a glucose transporter expressed in HepG2 hepatoma cells and rat …