Being overweight or obese, characterized by abnormal or excessive fat accumulation with a very high body mass index (BMI, 25 to >30 overweight and >30 is obese), are chronic health problems. As per a recent WHO report, being overweight or obese accounts for 44% of the diabetes cases, 23% of the ischemic heart disease problems and between 7-41% of various cancer cases (endometrial, breast, and colon). Over time, data from various epidemiological and meta-analyses show a link between obesity and PC.8
Recently, three large pooled analyses and two meta-analyses looked for an association between obesity/high BMI, the effect of long standing diabetes, smoking, age, as well as waist and hip circumference on pancreatic cancer risk.8
This study revealed that both central and overall obesity are associated with a 1.4 to 2-fold increased risk of PC.9
A plethora of studies have been carried out to explore the road from obesity to pancreatic cancer. Although the compete pathway remains obscure, the major players in the journey from obesity to PC include the development of a perturbed energy balance, chronic inflammation, insulin resistance, hyperinsulinemia, oxidative stress, altered secretion of adipokines, glucose intolerance and the development of diabetes. Inflammation, in conjunction with the immune system, plays a central role in the development of insulin resistance, diabetes and PC.
White adipose tissue (both subcutaneous and visceral forms) with its richness of triglycerides is the central energy store of the body. Additionally, it has an endocrine role and is involved in the secretion of a variety of cytokines and chemokines, including leptin, adiponectin, resistin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, visfatin, retinol-binding protein-4 and serum amyloid A (SAA), that manages the homeostatic balance of the body.38
First and foremost, the cause for obesity is an energy imbalance caused by an intake of a higher number of calories than calories being consumed. An accumulation of excess calories in adipocytes leads to an increase in their number (hyperplastic) and size (hypertrophic) along with dysregulation of their endocrine functioning. Enlarged adipocytes secretes chemotactic adipokines and chemokines (CCL5, CXCL12 and CCL20), leading to the recruitment of pro-inflammatory cells into an adipose tissue.39
Infiltration of adipose tissues especially visceral adipose tissue by inflammatory cells including alternatively polarized macrophages, Treg cells, neutrophils, eosinophils, CD8+
T cells and IL-17- secreting γδT leads to the development of insulin resistance (IR). Further free fatty acid present in circulation are implicated in development of insulin resistance. Lumneg et al.
observed that adipose tissue macrophages are M2 polarized with IL-10 and arginase expression in lean insulin sensitive animals. These adipokines (especially IL-10) recruits alternatively polarized M1 macrophages with low IL-10 expression and increased inducible nitric oxide synthase (iNOS) and TNF-α production.40
These CCR2+ macrophages overpower the protective effects of M2 macrophages and produce an inflammatory environment governed by TNF-α and iNOS. Inflammatory cytokines, in conjunction with adipokines, induce the Jun N terminal kinase (JNK) and Ikappa-B kinase (IKK) signaling pathways and block and interfere with insulin signaling in adipose tissue and skeletal muscle. Additionally, the housekeeper of innate immunity i.e.
TLR and advanced glycation end products directly activates Jun N terminal kinase (JNK) and Ikappa-B kinase (IKK) signaling leading to the development of inflammatory milleu.41, 42
TLR mediated activation of the NF-κβ pathway could be mediated by circulating fatty acid thus directly linking the aggravated immune system and an increased amount of circulating fatty acids observed in obese individuals.43
Once developed, insulin resistance (IR) leads to β-cell stress, excessive activation of insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) and subsequently β-cell apoptosis. Further, insulin resistance causes obligatory hyperinsulemia and diabetes.
Diabetes is a life-long chronic disease characterized by polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger) with insulin resistance being associated with type II diabetes. Lately, various epidemiological studies have revealed the bilateral association between diabetes (especially type II) and PC. Diabetes is associated with 1.8 fold increased risk of PC. Furthermore, newly diagnosed diabetes cases (<4 years) have a 50% greater risk of PC development as compared to individuals with long-standing diabetes (≥5 years) odd ratio (OR), 2.1 [95% CI, 1.9–2.3] vs.
OR, 1.5 [95% confidence interval (CI), 1.3–1.8]; P=0.005).9, 44
Additionally, PC also acts as a causative agent for the development of diabetes.9, 45
Although the molecular mechanism from diabetes to PC is still unclear, the insulin resistance, inhibition of insulin secretion, increase in insulin and C-peptide levels to oral glucose challenge, hyperglycemia, altered metabolism in presence of genetic predisposition, unhealthy diet are considered as major player in further developments.46
Overall, these studies provide striking examples of the compounding effects of various risk factors. Coupled with inflammation, these risk factors contribute to the development of PC ().