Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity.

Naoto Kubota,Mariko Inoue,Katsuyoshi Kumagai,Motoyuki Kohjima,Taku Watanabe,Masao Moroi,Yasuo Terauchi,Iseki Takamoto,Tetsuo Noda,Tomokatsu Iwamura,Kohjiro Ueki,Tetsuya Kubota,Makoto Nakamuta,Takashi Kadowaki,Hiroki Kumagai,Eiji Kajiwara,Takayoshi Sasako,Kaoru Sugi

doi:10.1038/ncomms12977

Abstract

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance'. Here, we show that ‘selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.

Highlights

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis
By investigating the differential insulin signalling in the hepatic periportal (PP) zone, the primary site of gluconeogenesis and hepatic perivenous (PV) zone, the primary site of lipogenesis, we found that insulin signalling was impaired in the PP zone, but rather enhanced in the PV zone, caused by the downregulation of Irs[2] in both the PP and PV zones, coupled with intact expression of Irs[1], which is predominantly expressed in the PV zone
In the livers of mice on a high-fat (HF) diet, while the Irs[1] messenger RNA (mRNA) expression levels remained unaffected, the mRNA expression levels of Irs[2] were markedly downregulated (Fig. 1b). These data suggest the possibility that Irs1-mediated signalling is enhanced, whereas Irs2-mediated signalling is impaired in the livers in the cases of type 2 diabetes and obesity

Summary

Introduction

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. By investigating the differential insulin signalling in the hepatic periportal (PP) zone, the primary site of gluconeogenesis and hepatic perivenous (PV) zone, the primary site of lipogenesis, we found that insulin signalling was impaired in the PP zone, but rather enhanced in the PV zone, caused by the downregulation of Irs[2] in both the PP and PV zones, coupled with intact expression of Irs[1], which is predominantly expressed in the PV zone These data suggest that the differential distribution and alterations of Irs[1] and Irs[2] cause ‘selective insulin resistance’

Methods

Results

Conclusion