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Physiol. Rev. 87: 507-520, 2007; doi:10.1152/physrev.00024.2006
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Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance

David B. Savage, Kitt Falk Petersen and Gerald I. Shulman

Departments of Internal Medicine and Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut

Although abnormal glucose metabolism defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid/lipid metabolism and insulin resistance. As "mouse models of insulin resistance" were comprehensively reviewed in Physiological Reviews by Nandi et al. in 2004, we will concentrate on human studies involving the use of isotopes and/or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide additional mechanistic insight.

1 The lipodystrophic syndromes encompass a rare group of conditions characterized by partial or complete absence of adipose tissue. The disorders may be genetic or acquired and are further classified according to the anatomic distribution of the lipodystrophy.

2 In contrast to our data, Summers et al. (110) recently argued that ceramides may be a key factor in the pathogenesis of insulin resistance. This is largely based on in vitro data.

3 Autoregulation refers to the tendency of hepatic glycogenolysis to compensate for increased gluconeogenesis, thereby preventing an increase in HGP.




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