University of Tasmania

File(s) under permanent embargo

Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice

journal contribution
posted on 2023-05-17, 13:48 authored by Simmgen, M, Knauf, C, Lopez, M, Choudhury, AI, Charalambous, M, Cantley, J, Bedford, DC, Claret, M, Miguel IglesiasMiguel Iglesias, Heffron, H, Cani, PD, Vidal-Puig, A, Burcelin, R, Withers, DJ
AIMS/HYPOTHESIS: Hepatic insulin resistance is thought to be a critical component in the pathogenesis of type 2 diabetes but the role of intrinsic insulin signalling pathways in the regulation of hepatic metabolism remains controversial. Global gene targeting in mice and in vitro studies have suggested that IRS2 mediates the physiological effects of insulin in the liver. Reduced hepatic production of IRS2 is found in many cases of insulin resistance. To investigate the role of IRS2 in regulating liver function in vivo, we generated mice that specifically lack Irs2 in the liver (LivIrs2KO). MATERIALS AND METHODS: Hepatic insulin signalling events were examined in LivIrs2KO mice by western blotting. Glucose homeostasis and insulin sensitivity were assessed by glucose tolerance tests and hyperinsulinaemic-euglycaemic clamp studies. The effects of high-fat feeding upon glucose homeostasis were also determined. Liver function tests were performed and expression of key metabolic genes in the liver was determined by RT-PCR. RESULTS: Proximal insulin signalling events and forkhead box O1 and A2 function were normal in the liver of LivIrs2KO mice, which displayed minimal abnormalities in glucose and lipid homeostasis, hepatic gene expression and liver function. In addition, hepatic lipid homeostasis and the metabolic response to a high-fat diet did not differ between LivIrs2KO and control mice. CONCLUSIONS/INTERPRETATION: Our findings suggest that liver IRS2 signalling, surprisingly, is not required for the long-term maintenance of glucose and lipid homeostasis, and that extra-hepatic IRS2-dependent mechanisms are involved in the regulation of these processes.


Publication title

Diabetologia: Clinical and Experimental Diabetes and Metabolism








School of Health Sciences



Place of publication

175 Fifth Ave, New York, USA, Ny, 10010

Rights statement

Copyright 2006 Springer-Verlag

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

Usage metrics

    University Of Tasmania


    Ref. manager