Differential Hepatic Distribution of Insulin Receptor Substrates Causes Selective Insulin Resistance in Diabetes and Obesity

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Oct 7

PMID 27708333

Citations 50

Authors

Naoto Kubota

Tetsuya Kubota

Eiji Kajiwara

Tomokatsu Iwamura

Hiroki Kumagai

Taku Watanabe

Mariko Inoue

Iseki Takamoto

Takayoshi Sasako

Katsuyoshi Kumagai

Motoyuki Kohjima

Makoto Nakamuta

Masao Moroi

Kaoru Sugi

Tetsuo Noda

Yasuo Terauchi

Kohjiro Ueki

Takashi Kadowaki

Affiliations

Soon will be listed here.

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.

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