Prediabetes and Cancer Risk: The Overlooked Connection

Prediabetes and Cancer- Plausible Hyperinsulinemic Activation of Oncogenic Pathways: ​​

Insulin's anabolic and anti-apoptotic effects drive tumor progression in individuals with hyperinsulinemia by binding to the insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-IR), or hybrid IR-IGF-IR complexes. Both receptors are implicated in tumorigenesis; for instance, IR overexpression has been observed in breast and prostate cancers, where elevated levels correlate with poorer prognosis. Consequently, cancer cells become hypersensitive to insulin, particularly under conditions of obesity and diabetes that amplify its expression. Receptor activation by insulin recruits insulin receptor substrates (IRS-1 or IRS-2/4), triggering downstream pathways: the RAS/RAF/MEK/ERK cascade for mitogenic signaling and the PI3K/Akt/protein kinase B pathway for anti-apoptotic effects. Structural homology allows insulin and IGF-1 to cross-bind IR and IGF-IR, enabling insulin to exert metabolic functions primarily through IR while promoting cell growth and differentiation via IGF-IR. A hybrid IR-IGF-IR receptor emerges when both are co-expressed in the same tissue, preferentially binding IGF-1 over insulin and driving proliferative responses; such hybrids are overexpressed in malignant breast and thyroid tissues through heterodimerization. [3]

Chronic inflammatory mediators, including TNF-α and IL-6, amplify these pathways, with obesity-associated adipokine dysregulation creating a sustained pro-carcinogenic environment. [3]

Epidemiological data demonstrate significantly elevated risks for breast, colorectal, hepatocellular, pancreatic, endometrial, and prostate malignancies in IR populations, with meta-analyses confirming direct correlations to increased recurrence rates and reduced survival. [3]

Early identification of prediabetes-related metabolic dysfunction represents a critical clinical opportunity, as these pathophysiologic changes precede malignancy and constitute modifiable risk factors for cancer prevention and improved outcomes. [3]

Prediabetes and Risk of Cancer: Evidence Overview [4,5,6,7,8,9]

Early Intervention in Prediabetes: Need of the Hour

The disproportionately higher prevalence of prediabetes in India (15.3%; 15,496 of 107,119) compared with diabetes (11.4%; 10,151 of 107,119), together with rapid progression and barriers to lifestyle modification, requires the need for pharmacological strategies such as metformin. Early intervention is critical, particularly as 43.3% of Indians are metabolically obese with BMI <25 kg/m² (MONO) and face an elevated T2D risk (OR=6.90; 95% CI: 5.10–9.34; P<0.001). [11]

As per recent evidence, beyond the traditional microvascular and macrovascular complications of T2D, cancer has now been recognized as one of the emerging complications of T2D. [12]

Metformin in Prediabetes

Metformin is the oldest pharmacological agent indicated for the prevention or delay of T2D. [13]

• American Diabetes Association (ADA, 2025): Recommends considering metformin for prevention in high-risk adults (age 25–59 years, BMI >35 kg/m², FPG >110 mg/dL, HbA1c >6%, or history of GDM). (Level A recommendation) [14]
• RSSDI–ESI (India, 2020): Advises initiating metformin in younger individuals with risk factors—either one or more risk factors regardless of BMI, or overweight/obese with IFG + IGT, or IFG + HbA1c >5.7%. [15]

Globally, metformin has been approved for prediabetes in at least 66 countries, reflecting its established role in diabetes prevention. [16]

Key Takeaways

• Prediabetes affects 634.8 million adults globally, with India's 89.9 million cases projected to reach 156.7 million by 2050.
• Prediabetes increases cancer risk by 18-42% across multiple cancers through hyperinsulinemic activation of pathways that promote tumor growth.
• India's prediabetes prevalence (15.3%) exceeds diabetes rates (11.4%), highlighting an urgent window for preventive intervention.
• Early metformin intervention is suggested by global guidelines for high-risk individuals with prediabetes to prevent diabetes and potentially mitigate associated health risks.

Abbreviations: ADA - American Diabetes Association, aHR - adjusted Hazard Ratio, AKT - Protein Kinase B, BMI - Body Mass Index, CI - Confidence Interval, ESI - Endocrine Society of India, FPG - Fasting Plasma Glucose, GDM - Gestational Diabetes Mellitus, HbA1c - Hemoglobin A1c (glycated hemoglobin), HR - Hazard Ratio, IDF - International Diabetes Federation, IFG - Impaired Fasting Glucose, IGF-1 - Insulin-like Growth Factor-1, IGT - Impaired Glucose Tolerance, IL-6 - Interleukin-6, IR - Insulin Resistance, IRS - Insulin Receptor Substrate, MAPK - Mitogen-Activated Protein Kinase, MONO - Metabolically Obese Normal-weight Obesity, mTOR - mechanistic Target of Rapamycin, OR - Odds Ratio, PI3K - Phosphoinositide 3-kinase, RAS - Rat Sarcoma, RR - Relative Risk, RSSDI - Research Society for Study of Diabetes in India, SHC - Src Homology 2 Domain Containing, T2D - Type 2 Diabetes, TNF-α - Tumor Necrosis Factor-alpha