Table 1.

Summary of data linking IRS proteins to cardiac dysfunction

IRS involved	Mouse model	Organ affected	Main findings	Reference
IRS1, IRS2	Myocardium-specific Irs1 −/−; Irs2 −/− mice	Heart	In the absence of both Irs1 and Irs2, thinning walls, global dilatation, diastolic failure and decreased systolic activity were evident. Heart failure markers such as β-myosin heavy chain increased and interstitial fibrosis was associated with increased TGFβ1 and collagen 1 mRNA. Myocardium-specific Irs1 −/−; Irs2 −/− mice died at 6–8 weeks of age, yet heterozygous myocardium Irs1 +/−; Irs2 +/− mice survived to at least 6 months of age before fatal cardiac dysfunction developed	Qi et al (2013) [78]
	Mice with specific hepatic deletion of Irs1 and Irs2	Liver	Hepatic deletion of Irs1 and Irs2 caused a decrease in cardiac IRS1 and IRS2, and similar, albeit less severe, effects on the heart were observed. These mice showed p38MAPK activation, which mediated IRS protein degradation in response to chronic insulin stimulation. These data suggest a new link between hepatic insulin signalling and IRS protein levels in the heart	Qi et al (2013) [78]
IRS1	ob/ob mice (model of type 2 diabetes)	Heart	Myocardial IRS1–PI3K activity was significantly increased in ob/ob mice vs control. These data were similar to IRS1–PI3K activity in both individuals with type 2 diabetes and those with left ventricular dysfunction, whose myocardium was insulin resistant. IR-β, IRS1 and total and phospho-Akt were also increased in ob/ob mice; however, total IRS1 was unchanged in individuals with type 2 diabetes and left ventricular dysfunction. Insulin-induced Akt phosphorylation was greater in control mice than in ob/ob mice with no alterations in total Akt	Cook et al (2010) [17]a

^aMouse- and human-based research summarised