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Review
. 2021 May 20;11(3):23-45.
doi: 10.5662/wjm.v11.i3.23.

Epidemiological link between obesity, type 2 diabetes mellitus and cancer

Cornelius J Fernandez  1 , Annu Susan George  2 , Nikhila A Subrahmanyan  3 , Joseph M Pappachan  4
Affiliations
Review

Epidemiological link between obesity, type 2 diabetes mellitus and cancer

Cornelius J Fernandez et al. World J Methodol. .

Abstract

There exists a complex interaction between obesity, type 2 diabetes mellitus (T2DM) and cancer, and an increase in the incidence of cancer is expected with the growing obesity-diabetes pandemic. The association of cancer with diabetes mellitus and obesity appears to be site-specific, the highest risk being for post-menopausal breast cancer, endometrial cancer, and colorectal cancer. Moreover, there is worsening of hyperglycaemia with the onset of cancer, evidencing a bi-directional link between cancer and diabetes mellitus and the need for monitoring for diabetes in cancer survivors. In this review, we look at the epidemiological evidence from observational studies and Mendelian randomization studies linking obesity, diabetes, and cancer, as well as the complex pathophysiological mechanisms involved, including insulin resistance with associated hyperinsulinaemia, the effect of chronic low-grade inflammation, and the effect of various adipokines that are associated with obesity and T2DM. Additionally, we describe the novel therapeutic strategies, based on their role on the discrete pathophysiological mechanisms involved in the tumourigenesis.

Keywords: Cancer; Epidemiological link; Hyperinsulinaemia; Obesity; Type 2 diabetes mellitus.

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Conflict of interest statement

Conflict-of-interest statement: Dr. Pappachan and co-authors have nothing to declare.

Figures

Figure 1
Figure 1
The overall pathophysiological mechanisms linking obesity and diabetes to cancer with associated intracellular signalling. IL-1β: Interleukin-1β; IL-6: Interleukin-6; TNF-α: Tumour necrosis factor-α; IR: Insulin receptor; IGF-1: Insulin-like growth factor-1; IGF-1R: Insulin-like growth factor-1 receptor; IGFBP: Insulin-like growth factor binding protein; FFA: Free fatty acid; FFF-R: Free fatty acid receptor; ER-α: Oestrogen receptor-α; Ob-R: Leptin-receptor; Adipo-R: Adiponectin-receptor; SHBG: Sex hormone binding globulin; TG: Triglyceride; HDL: High density lipoprotein; PI3K: Phosphatidyl-inositol-3-kinase; AKT: Protein kinase B; mTORC1: Mechanistic target of rapamycin complex 1 (Mammalian target of rapamycin complex 1); RAS: Rat sarcoma; RAF: Rapidly accelerated fibrosarcoma; MAPK: Mitogen activated protein kinase; ERK: Extracellular-regulated kinase; JAK2: Janus kinase-2; STAT3: Signal transducer and activator of transcription-3; VEGF: Vascular endothelial growth factor; HIF-1α: Hypoxia inducible factor-1α; LKB1: Liver kinase B1; AMPK: Adenosine monophosphate-activated protein kinase; T2DM: Type 2 diabetes mellitus.
Figure 2
Figure 2
The pathophysiological mechanisms linking the hyperinsulinaemia in the tumour microenvironment to cancer with the associated intracellular signalling. IL-1β: Interleukin-1β; IL-6: Interleukin-6; TNF-α: Tumour necrosis factor-α; IR-A: Insulin receptor-A; IR-B: Insulin receptor-B; IGF-1: Insulin-like growth factor-1; IGF-2: Insulin-like growth factor-2; IGF-1R: Insulin-like growth factor-1 receptor; IR-A IGF1-R: Hybrid receptor of IR-A and IGF-1R; IR-B IGF1-R: Hybrid receptor of IR-B and IGF-1R; IGFBP: Insulin-like growth factor binding protein; ER-α: Oestrogen receptor-α; mER: membrane oestrogen receptor; Ob-R: Leptin-receptor; PI3K: Phosphatidyl-inositol-3-kinase; AKT: Protein kinase B; mTORC1: Mechanistic target of rapamycin complex 1 (Mammalian target of rapamycin complex 1); RAS: Rat sarcoma; RAF: Rapidly accelerated fibrosarcoma; MAPK: Mitogen activated protein kinase; ERK: Extracellular-regulated kinase; JAK2: Janus kinase-2; STAT3: Signal transducer and activator of transcription-3; VEGF: Vascular endothelial growth factor.
Figure 3
Figure 3
The potential pathophysiological mechanisms linking obesity to cancer with special emphasis to the white adipose tissue remodelling. WAT: White adipose tissue; IR: Insulin receptor; IGF-1R: Insulin-like growth factor-1 receptor; ER-α: Oestrogen receptor-α; Ob-R: Leptin-receptor; Adipo-R: Adiponectin-receptor; FFA: Free fatty acid; LD: Lipid droplets; ECM: Extracellular matrix; XIAP: X-linked inhibitor of apoptosis protein; VEGF: Vascular endothelial growth factor; HIF-1α: Hypoxia inducible factor-1α; GLUT4: Glucose transporter 4.
Figure 4
Figure 4
The potential pathophysiological mechanisms linking diabetes to cancer with special emphasis to the Wnt/β-catenin signalling pathway. IGF-1: Insulin-like growth factor-1; IGF-1R: Insulin-like growth factor-1 receptor; IL-1β: Interleukin-1β; IL-6: Interleukin-6; TNF-α: Tumour necrosis factor-α; IR-A: Insulin receptor-A; ROS: Reactive oxygen species; GLP-1RA: Glucagon like peptide-1 receptor agonist; MAPK: Mitogen activated protein kinase; PI3K: Phosphatidyl-inositol-3-kinase; AGEs: Advanced glycation end products; TME: Tumour microenvironment; LRP: Lipoprotein receptor-related protein; GSK3β: Glycogen synthase kinase-3β; SIRT1: Sirtuin 1 deacetylase; P300: P300 acetyl transferase; LEF: Lymphoid enhancer factor; TCF: T-cell factor.
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