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New drug targets for type 2 diabetes and the metabolic syndrome

Nature volume 414, pages 821–827 (2001)Cite this article

Abstract

An insidious increase in features of the 'metabolic syndrome' — obesity, insulin resistance and dyslipidaemia — has conspired to produce a worldwide epidemic of type 2 insulin-resistant diabetes mellitus. Most current therapies for this disease were developed in the absence of defined molecular targets or an understanding of disease pathogenesis. Emerging knowledge of key pathogenic mechanisms, such as the impairment of glucose-stimulated insulin secretion and the role of 'lipotoxicity' as a probable cause of hepatic and muscle resistance to insulin's effects on glucose metabolism, has led to a host of new molecular drug targets. Several have been validated through genetic engineering in mice or the preliminary use of lead compounds and therapeutic agents in animals and humans.

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Figure 1: A better understanding of defects involving several key organ systems has led to new drug targets for type 2 diabetes.
Figure 2: Important pathways regulating glucose metabolism in the liver.
Figure 3: Biosynthesis and regulation of glucagon-like peptide 1 (GLP-1).
Figure 4: Potential mechanisms of insulin sensitization by PPARγ ligands.

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Acknowledgements

I thank many colleagues at Merck Research Laboratories who have contributed to ideas discussed in this review. In particular, I also thank N. Thornberry, L. Rossetti and B. Zhang for helpful reviews of the manuscript. I apologize to numerous colleagues whose original papers were not cited owing to space limitations.

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  1. Departments of Molecular Endocrinology and Metabolic Disorders, Merck Research Laboratories, Rahway, 07065, New Jersey, USA

    David E. Moller

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Moller, D. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 414, 821–827 (2001). https://doi.org/10.1038/414821a

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