Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms

Abstract

Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.

Figure 1

A multidimensional model of cancer development, which suggests insulin resistance and inflammation as driving forces behind cancer. TG: triglycerides; FFA: free fatty acids; TNF-α: tumor necrosis factor α; IL-6: interleukin-6; ROS: reactive oxygen species; SHBG: sex-hormone-binding globulin; IGF-I: insulin-like growth factor I; PAI-1: plasminogen activator inhibitor-1; IGFBPs IGF-I binding proteins; VEGF, vascular endothelial growth factor.

Figure 2

INSR gene expression in breast cancer. (a) AP2-α overexpression increases INSR expression in breast tumour [37]. Transactivation of the INSR gene by AP2-α occurs indirectly through physical and functional cooperation with HMGA1 and Sp1. (b) By binding to AP2-α and Sp1, PPARγ and agonists may attenuate the stimulatory effect of AP2-α on INSR gene transcription in breast cancer.

Figure 3

Schematic representation of the two major signaling cascades operating in cancer, following overactivation of the INSR/IGF-IR signaling pathways. Binding of insulin, IGF-I (and IGF-II) triggers the intrinsic tyrosine kinase receptor domain, leading to activation of the PI3K/Akt/mTOR signaling and the MAP/ERK-kinase pathway. HR: hybrid receptors; ERK: extracellular regulated kinase; IRS: INSR substrate; MEK: mitogen-activated protein kinase kinase; mTOR: mammalian target of rapamycin; PI3K: Phosphoinositide-3 kinase; PIP2: phosphatidylinositol [4,5]-bisphosphate; PIP3: phosphatidylinositol [3,4, 5]-trisphosphate; PDK1: phosphoinositide-dependent kinase 1; Raf: rapidly fibrosarcoma; Ras: rat sarcoma; Rheb: Ras homolog enriched in brain; TSC: tuberous sclerosis complex.