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Novel pharmacological approaches to the prevention and treatment of non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is most commonly the final stage of a sequence of deleterious events: obesity and genetic factors lead to decreased insulin sensitivity of muscle, liver and adipose tissue, which can initially be compensated for by increased insulin secretion and which may only be apparent as a decrease in glucose tolerance. Over the years, however, pancreatic b-cell function starts to fail progressively in some patients, resulting in fasting hyperglycemia. This, and the associated glucotoxicity and possibly lipotoxicity further decrease b-cell function, eventually resulting in overt NIDDM. Although the pathogenesis of NIDDM is clearly a multifactorial process with several genetic and environmental factors determining the predisposition to insulin resistance and b-cell dysfunction, the onset of reduced sensitivity of target tissues to insulin is thought to be the pivotal initiating factor. However, virtually all current treatments for NIDDM are targeted at increasing the availability of circulating insulin, with the notable exception of weight loss which is highly effective in reversing insulin resistance. Since the success rate of the latter intervention is notoriously disappointing, pharmacological strategies have been sought to increase the effectiveness of insulin signaling. While various high-throughput and combinatorial screening strategies were and still are being employed to identify proteins and small molecules enhancing insulin action at or beyond its receptor, the first clinically promising insulin sensitizers are derived from an apparently unrelated area of research dealing with nuclear hormone receptors and retinoids. The first indication that nuclear receptors can improve insulin action came from studies demonstrating that the insulin-sensitizing thiazolidinediones (TZDs) are ligands for the peroxisome proliferator-activated receptor (PPAR) g. This ligand-activated transcription factor is expressed in human adipose tissue and, to a lesser degree, also in muscle (1), where it binds as a heterodimer with the 9-cis retinoic acid receptor RXR to the regulatory DNA sequences of specific target genes. Intriguingly, this PPAR:RXR complex has now been shown by several groups to be susceptible to activation not only by TZDs, but also by natural and pharmacological RXR ligands, such as LG100268 (‘rexinoid’) (2, 3). In the presence of both ligands, a strong synergistic effect is observed in