The double life of Irs

Abstract

The liver plays a central role in lipid and glucose metabolism. Two studies in this issue (Kubota et al., 2008; Dong et al., 2008) on the insulin-signaling adaptors Irs1 and Irs2 prompt a critical reappraisal of the physiology of fasting and of the integrated control of hepatic insulin action.

Figure 1. The Changing Face of Hepatic Insulin Resistance

(A) The prevailing model had been that liver insulin signaling occurred by way of branched pathways. One pathway, associated with Irs2 and Foxo1, was thought to preside over the inhibition of glucose production (indicated by a red “tee” symbol). The other pathway, mediated by Irs1 and Foxa2, was thought to mediate lipid synthesis and lipoprotein assembly/secretion (indicated by a thick green arrow). (B) The work of Kubota et al. and Dong et al. supports a model in which Irs1 and Irs2 act in different conditions (fasting or feeding), but in essentially linear pathways, both effected through Foxo1. The decrease in TG levels and secretion in double Irs knockouts (denoted by the thin green line, as opposed to the thick green line in A) is consistent with a role of excessive insulin signaling, rather than insulin resistance, in the pathogenesis of the lipid abnormalities of type 2 diabetes.