Discordant associations of IGF-binding proteins 1 & 2 with diabetes and cardiovascular disease: insights from UK Biobank

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The insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) axis has been implicated in diabetes mellitus and the associated burden of cardiovascular complications. Higher circulating levels of IGFBP-1 and IGFBP-2 have been established as markers of protection from incident type 2 diabetes, yet their associations with cardiovascular disease remain unclear. Utilising the UK Biobank (UKB) resource to integrate disease outcomes, plasma proteomics and MRI data, we examined associations of IGFBP-1 and IGFBP-2 with incident diabetes and cardiovascular disease. Approximately 50,000 UKB participants with plasma proteomic measurements for IGFBP-1 and IGFBP-2 were included. Multivariate Cox regression models revealed that participants in the highest quartiles of IGFBP-1 and IGFBP-2 had a substantially lower risk of incident diabetes (hazard ratio (HR) = 0.31 and 0.32 respectively), but, paradoxically, had increased risks of incident macrovascular disease, all-cause and cardiovascular-related mortality (HR = 1.81 and 2.39). Both proteins were negatively associated with HbA1c levels, triglyceride/HDL ratio and abdominal adiposity, yet positively associated with NT-proBNP, troponin I, cardiac chamber size and aortic dimensions. In summary, negative associations of IGFBP-1 and IGFBP-2 with incident diabetes mellitus did not translate to a reduced cardiovascular risk, suggesting potentially complex actions of IGFBP-1 and IGFBP-2 in the pathophysiology of cardiometabolic disease.

Graphical Abstract

Graphical abstract illustrating the analysis pipeline and aims of this study to identify associations of IGFBP-1 and IGFBP-2 with cardiometabolic disease. Graphical abstract created with BioRender.com .

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Article highlights

a) The associations of IGFBP-1/-2 with macrovascular disease in cohorts with and without type 2 diabetes are conflicting.

b) Can UK Biobank help to clarify the associations of IGFBP-1 and IGFBP-2 with cardiometabolic disease?

c) Higher levels of both proteins are associated with a reduced risk of diabetes incidence, but an increased risk of cardiovascular disease. This is the first study to integrate survival analyses with large-scale imaging data, showing consistent associations with a favourable metabolic profile, but novel associations with cardiac measures.

d) These findings highlight the limitations of using IGFBP-1 and IGFBP-2 as biomarkers in cardiometabolic disease.