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Diabetes

Insulin resistance and obesity

Nature volume 402, pages 860–861 (1999)Cite this article

Type 2 diabetes mellitus is a serious health problem in the Western world. It arises when resistance to the glucose-lowering effects of insulin combines with impaired insulin secretion to raise the levels of glucose in the blood beyond the normal range. Studies into the molecular basis of insulin resistance have focused on the peroxisome proliferator-activated receptor gamma (PPARγ). This molecule, a member of the nuclear-hormone-receptor family, is the cellular target of thiazolidinedione drugs, which are used to treat diabetes by increasing sensitivity to insulin.

What are the endogenous ligands for PPARγ? How does it promote the insulin-stimulated uptake of glucose? And is this effect essential for the normal action of insulin? The answer to the last of these questions may be nearer thanks to a study by Barroso et al.1 on page 880 of this issue. They report the identification of two loss-of-function mutations of PPARγ that are associated with severe insulin resistance and type 2 diabetes mellitus in humans. Although such mutations are rare — detected in just three of 85 insulin-resistant people, and none of 314 controls — the implication that PPARγ is required for normal insulin sensitivity in humans is an important advance.

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Figure 1: Molecular complex formed by dimerization of PPARγ and the retinoid X receptor (RXR).

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Authors and Affiliations

  1. the Department of Medicine, University of Washington, Harborview Medical Center and VA Puget Sound Health Care System, Seattle, 98108, Washington, USA

    Michael W. Schwartz & Steven E. Kahn

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  1. Michael W. Schwartz
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  2. Steven E. Kahn
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Correspondence to Michael W. Schwartz.

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Schwartz, M., Kahn, S. Insulin resistance and obesity. Nature 402, 860–861 (1999). https://doi.org/10.1038/47209

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