Insulin Resistance and Cancer: In Search for a Causal Link

Abstract

Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.

Keywords: PPARγ; cancer; epigenetics; gut microbiota; hyperglycemia; insulin resistance; metformin.

Figure 1

Insulin receptor signaling and cancer: scheme. INSR, insulin receptor; IRS1, INSR substrate 1; PI3K, phosphoinositide 3-kinase; PDK1, phosphoinositide-dependent protein kinase-1; AKT, Ak strain transforming/protein kinase B; FoxO1/3a, forkhead box protein O1/3a; TSC, tuberous sclerosis complex; Rheb, Ras homolog enriched in brain; mTORC1/2, mammalian target of rapamycin complexes; black dotted arrows, activation; blue dotted arrows, biological effects of the downstream signaling.

Figure 2

Multidimensional model through which obesity, hyperinsulinemia, and related inflammation influence tumor development. IGF1/2, insulin-like growth factor 1/2; IGFBP1, IGF binding protein 1, INSR, insulin receptor; IGFR, IGF receptor; HR, hybrid receptor; IRS1, INSR substrate 1; PI3K, phosphoinositide 3-Kinase; PDK1, phosphoinositide-dependent protein kinase-1; AKT, Ak strain transforming/protein kinase B; Ras, rat sarcoma; Raf, rapidly accelerated fibrosarcoma; MEK mitogen-activated protein kinase; ERK, extracellular signal-regulated protein kinase; Jak, janus kinase; STAT, signal transducer and activator of transcription; SHBG, sex-hormone binding globulin; red lines, inhibition.

Figure 3

Actions of miRNAs in cancer and insulin resistance. INSR/IGFR, insulin receptor/insulin-like growth factor receptor; IRS1, INSR substrate 1; PI3K, phosphoinositide 3-Kinase; PDK1, phosphoinositide-dependent protein kinase-1; PTEN, phosphatase and TENsin homolog deleted on chromosome 10; AKT, Ak strain transforming/protein kinase B; FoxO1/3a, forkhead box protein O1/3a; mTORC1, mammalian target of rapamycin complex 1; black dotted arrows, activation; red lines, inhibition; blue dotted arrow, biological effects of the downstream signaling.

Figure 4

Anticancer action of metformin. INSR/IGFR, insulin receptor/insulin-like growth factor receptor; AMPK, 5′ adenosine monophosphate-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; HIF1, hypoxia-inducible factor 1; black dotted arrows, activation; red lines, inhibition.

Figure 5

Anticancer actions of TZDs. INSR/IGFR, insulin receptor/insulin-like growth factor receptor; TZD, thiazolidinediones; PPARγ, proliferator-activated receptor γ; black dotted arrows, activation; red lines, inhibition.