Cloned in 1990, glycogen synthase kinase-3 (GSK-3) represents a key regulator of glycogen synthase, one of the principal modulators of glycogen metabolism and hence glucose levels. GSK-3 also plays a role in the expression of the gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolypyruvate carboxykinase expression, further implicating GSK-3 in energy balance. Under healthy conditions insulin is able to inhibit GSK-3 and so during insulin resistant states GSK-3 activity is increased. Increased GSK-3 activity has been reported in both adipose and skeletal muscle tissue taken from diabetic subjects and this is generally accepted to play a major role in the hyperglycemic effects of insulin resistance. Thus, the development of GSK-3 inhibitors has received attention in an attempt to control the serious and growing clinical problem of diabetes. The use of transgenic mice has however suggested a much wider range of targets for this class of drug. Over-expression of GSK-3B in the brain of adult mice was found to produce neurodegeneration sharing many of the characteristics of Alzheimer's disease including tau hyperphosphorylation. Indeed, GSK-3B over expression is a feature of Alzheimer's disease and has been suggested to contribute to neurodegeneration. In addition, inhibition of GSK-3 was show to attenuate apoptotic signals, implicating its importance in more acute conditions such as stroke. Consequently GSK-3 inhibitors are in development for Alzheimer's disease, and protection against cell death. Finally, the effects of two mood-stabilizing drugs in common use, lithium and valproic acid appear to be mediated, at least in part, through the inhibition of GSK-3 and hence specific inhibitors of this enzyme may represent improved treatments of this manic depression. The development of GSK-3 inhibitors thus holds considerable promise for numerous serious and unmet pathologies including diabetes, Alzheimer's disease, stroke and manic depression. The full potential of GSK-3 inhibitors is just starting to be realized and the number of therapeutic candidates in development is still limited. Focusing attention on this exciting target could thus reap considerable clinical and economic rewards.

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