INTRODUCTION Type 2 diabetes mellitus (T2DM) has traditionally been viewed through the lens of hyperglycaemia, insulin resistance (IR) and vascular complications. However, a broader narrative has begun to emerge – one that implicates metabolic disorders not only in cardiovascular morbidity but also in oncogenesis. Insulin, beyond its role in regulating glucose homeostasis, exhibits powerful mitogenic and anti-apoptotic properties under certain physiological conditions.1 This dual nature has garnered attention in recent years as researchers probe the connections between chronic hyperinsulinaemia, IR and malignancy. As the global prevalence of T2DM continues to rise, so too does the burden of cancer, suggesting a possible epidemiological and mechanistic overlap.2 What makes this link even more compelling is the realisation that IR, rather than merely elevated blood glucose, may be a key orchestrator in the transformation of normal cells into cancerous ones. The insulin–cancer connection reflects a broader systemic disruption, involving hormonal imbalances, chronic inflammation, oxidative stress and dysregulated signalling cascades.3 Recognising this intricate web is essential for reframing cancer prevention strategies, particularly in metabolically vulnerable populations. EPIDEMIOLOGICAL EVIDENCE A wealth of population-level data supports a strong association between T2DM and increased cancer risk. For instance, an analysis of more than 400,000 individuals in the Shanghai Standardised Diabetes Management System between 2011 and 2018 demonstrated that individuals with diabetes mellitus had a 10% higher rate of malignancy compared to their counterparts without diabetes mellitus.4 The data revealed significantly elevated risks for cancers of the pancreas, liver, colon, breast, kidney, thyroid, bladder and colorectum. Intriguingly, the increase in cancer risk was most pronounced amongst younger individuals with diabetes, underscoring the cumulative impact of chronic metabolic dysfunction over time. Corroborating this evidence, the United Kingdom Biobank has been instrumental in elucidating the relationship between IR and site-specific cancers. Studies utilising IR indices, such as the triglyceride (TG)–glucose–body mass index product and the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, have shown a compelling correlation with the risk of oesophageal adenocarcinoma.5 Conversely, oesophageal squamous cell carcinoma exhibited an inverse relationship with these markers, suggesting that IR influences tumorigenesis in a tissue-specific and histological subtype-dependent manner.5 These findings are summarised in (Table 1),4-6 highlighting key studies that establish the epidemiological link between diabetes, IR and malignancy.Table 1: Selected epidemiological studies linking T2DM and cancer riskINSULIN RESISTANCE At the cellular level, insulin functions as more than a regulator of metabolism; it acts as a potent growth factor capable of influencing cell survival, proliferation and angiogenesis.7 In individuals with insulin resistance individuals, pancreatic β-cells compensate by increasing insulin secretion, resulting in chronic hyperinsulinaemia. Elevated insulin levels, in turn, activate the insulin receptor and insulin-like growth factor 1 receptor pathways, leading to enhanced cellular proliferation and reduced apoptosis. These mechanisms are integral to the initiation and progression of various cancers.8 Moreover, adipokines such as leptin and adiponectin, which are closely linked to insulin sensitivity, further modulate the tumour microenvironment. Leptin levels tend to be elevated in obesity and T2DM and are known to promote angiogenesis and proliferation, while adiponectin, typically reduced in these conditions, has anti-inflammatory and anti-tumorigenic properties.9 The endocrine, paracrine and autocrine influences of insulin and related molecules converge on neoplastic pathways, creating a biochemical milieu conducive to cancer development. This mechanistic interplay is increasingly seen as a plausible explanation for the higher cancer risk observed in insulin-resistant states. CANCER-SPECIFIC ASSOCIATIONS While IR is a shared feature amongst patients with T2DM, its effect on cancer risk is not uniform across all tumour types. Pancreatic cancer, for instance, exhibits one of the most strong associations with diabetes mellitus. Hyperinsulinaemia is believed to stimulate acinar cells in the pancreas, provoking increased enzyme secretion and inflammatory responses that may facilitate metaplasia and ultimately, neoplasia.7 Similarly, in breast cancer – especially in post-menopausal women – insulin and oestrogen work synergistically to promote tumour growth via increased cell proliferation and suppression of apoptosis.8 Colorectal cancer is another malignancy closely tied to metabolic dysfunction. Prospective cohort data from the United Kingdom Biobank demonstrate that a high TG/HDL-C ratio is associated with increased colorectal cancer risk, whereas lower ratios may offer a protective effect.6 Interestingly, lung cancer presents a more ambiguous picture. Some studies using the TG index found no correlation, while others suggest a possible link (Table 2) between IR as measured by homeostatic model assessment of IR and lung cancer risk.5Table 2: Site-specific cancer risk in relation to insulin resistance and diabetesTHERAPEUTIC IMPLICATIONS: TURNING THE METABOLIC TIDE Given the compelling evidence linking IR with carcinogenesis, therapeutic interventions targeting metabolic health may serve as effective cancer prevention strategies. Amongs pharmacologic agents, metformin has garnered the most attention for its potential anti-cancer effects. By activating adenosine monophosphate-activated protein kinase and inhibiting the mechanistic target of rapamycin pathway, metformin reduces insulin levels and exerts direct anti-proliferative effects.10 Published evidence suggests that metformin use may be associated with reduced risks of breast, colorectal and pancreatic cancers.11 Other agents, such as thiazolidinediones (e.g., pioglitazone), activate peroxisome proliferator-activated receptor gamma and improve insulin sensitivity, although concerns regarding bladder cancer have tempered enthusiasm for their widespread use.12 More recently, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have emerged as promising agents with favourable metabolic effects, although their long-term impact on cancer risk remains under investigation.12 These pharmacological strategies are outlined in (Table 3).Table 3: Pharmacologic agents targeting insulin resistance and their effects on cancer riskLIFESTYLE INTERVENTIONS: THE FOUNDATION OF METABOLIC REDEMPTION While pharmacotherapy offers valuable tools, lifestyle modifications remain the cornerstone of improving insulin sensitivity and reducing cancer risk. Physical activity, even in modest amounts, has been consistently associated with lower incidence rates of several cancers. A study involving over 346,000 individuals found that regular physical activity significantly reduced the overall risk of malignancies.4 Furthermore, accelerometer-based assessments from the United Kingdom Biobank revealed that increasing daily step count was linearly associated with decreased cancer incidence, emphasising the dose-response benefits of movement.4 Diet also plays a pivotal role. Plant-based, low-glycaemic index diets that are rich in fibre and antioxidants improve insulin sensitivity and modulate systemic inflammation.2 Weight management is another crucial aspect; even a modest 5%–10% reduction in body weight can result in significant improvements in IR and metabolic health.3 These evidence-based recommendations are vital for designing public health interventions and are summarised in (Table 4).Table 4: Life-style interventions that improve insulin sensitivity and impact cancer riskTHE WAY FORWARD The narrative surrounding insulin and cancer is evolving, moving beyond simplistic associations towards a deeper understanding of the shared pathophysiological pathways. IR, far from being a mere precursor to hyperglycaemia, may be a silent yet potent oncogenic force, subtly altering cellular behaviour long before glucose levels deviate from normal.6,7 The implications are profound. As the global rates of T2DM and cancer continue to rise, it is imperative that public health efforts emphasise strategies that restore metabolic integrity. Focusing on improving insulin sensitivity through lifestyle changes, targeted pharmacotherapy and molecular interventions holds promise not only for diabetes management but also for cancer prevention. A paradigm shift that recognises the metabolic roots of malignancy could redefine our approach to two of the 21st century’s most pressing health challenges. The war on cancer, it seems, might begin with the humble hormone insulin. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Muhammed Jasim Abdul Jalal (Wed,) studied this question.