Why Insulin Resistance Undermines Cancer Treatment — and What to Do About It

Insulin resistance is one of the most overlooked factors influencing cancer outcomes.

While oncology focuses on tumour genetics, drug targets, and immune checkpoints, a growing body of evidence suggests that the metabolic environment surrounding the tumour can quietly determine whether treatments work—or fail.

This is not about replacing standard cancer therapy. It’s about understanding why the same drug can produce dramatically different outcomes in different patients, even with identical tumour markers.

What Is Insulin Resistance (and Why It Matters in Cancer)?

Insulin resistance occurs when cells no longer respond effectively to insulin, forcing the body to produce higher levels of insulin to maintain normal blood glucose.

This leads to:

• Chronic hyperinsulinaemia

• Elevated IGF-1 signalling

• Increased inflammation

• Altered immune cell function

All of these are biologically relevant to cancer.

Cancer does not grow in isolation. It grows inside a metabolic system.

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How Insulin Resistance Actively Undermines Cancer Treatment

1. Insulin and IGF-1 Directly Promote Tumour Growth

High insulin and IGF-1 levels activate:

• PI3K–AKT–mTOR

• MAPK

• Wnt/β-catenin pathways

These are the same survival pathways many cancer drugs attempt to inhibit.

Clinical implication:
A metabolically insulin-resistant patient may be pharmacologically “pressing the brake” while metabolically “stepping on the accelerator.”

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2. Insulin Resistance Reduces Immunotherapy Effectiveness

Immune checkpoint inhibitors rely on metabolically fit T-cells.

Insulin resistance:

• Impairs T-cell glucose flexibility

• Promotes T-cell exhaustion

• Increases suppressive immune populations (Tregs, MDSCs)

Several observational studies show:

• Obesity and insulin resistance correlate with lower response rates to immunotherapy in multiple cancers

• Poor metabolic health predicts shorter progression-free survival

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3. Chemotherapy Resistance Is Metabolically Reinforced

Insulin resistance contributes to:

• Increased drug efflux pump expression

• Altered tumour blood flow

• Hypoxic tumour microenvironments

• Reduced apoptosis signalling

This can blunt the effectiveness of:

• Platinum agents

• Taxanes

• Antimetabolites

Not because the drugs are ineffective—but because the terrain is hostile.

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4. Insulin Resistance Fuels Cancer Recurrence

Even after “successful” treatment:

• High insulin levels promote residual tumour cell survival

• Dormant cancer stem cells are metabolically protected

• Recurrence risk increases independent of tumour stage

This may help explain why:

Two patients with identical staging and therapy can have completely different long-term outcomes.

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Cancers Most Strongly Linked to Insulin Resistance

Evidence is strongest for:

• Breast cancer (especially post-menopausal)

• Colorectal cancer

• Pancreatic cancer

• Endometrial cancer

• Prostate cancer

• Hepatocellular carcinoma

Importantly, normal BMI does not exclude insulin resistance.
Up to 40% of metabolically unhealthy individuals are not obese.

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Why Insulin Resistance Is Rarely Addressed in Oncology

There are structural reasons:

• Oncology guidelines focus on tumour-centric variables

• Metabolic correction takes time and multidisciplinary care

• Lifestyle interventions lack pharmaceutical sponsorship

• Trials rarely stratify patients by insulin sensitivity

As a result, insulin resistance is treated as a background condition rather than a modifiable risk factor.

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What Can Be Done: Evidence-Based Strategies

This is about adjunctive metabolic optimisation, not alternative therapy.

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1. Measure What Matters

Commonly missed markers:

• Fasting insulin (not just glucose)

• HOMA-IR

• Triglyceride-to-HDL ratio

• HbA1c trends

• Waist-to-height ratio

You can’t manage what you don’t measure.

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2. Nutrition: Reduce Insulin Load Without Malnutrition

Evidence supports:

• Lower refined carbohydrate intake

• Adequate protein to prevent sarcopenia

• Stable caloric intake during treatment

• Avoidance of extreme fasting during chemotherapy without supervision

This is metabolic support, not dietary dogma.

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3. Physical Activity as Metabolic Therapy

Resistance and aerobic exercise:

• Improves insulin sensitivity

• Enhances immune surveillance

• Reduces treatment-related fatigue

• Preserves lean mass

Even modest activity can produce measurable metabolic shifts.

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4. Pharmacologic Adjuncts (Where Appropriate)

Some agents with supportive evidence:

• Metformin (context-dependent)

• Statins (select populations)

• GLP-1 pathway modulation (emerging, nuanced)

These should be clinician-guided and cancer-specific.

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5. Address Sleep, Stress, and Circadian Disruption

Chronic cortisol elevation worsens insulin resistance and immune suppression.

Poor sleep:

• Impairs glucose regulation

• Reduces treatment tolerance

• Increases inflammatory signalling

These factors are not “soft variables”—they are biological inputs.

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What This Does Not Mean

• ❌ It does not mean cancer is “caused by sugar”

• ❌ It does not replace chemotherapy, immunotherapy, or surgery

• ❌ It does not imply blame or personal failure

It means metabolic context matters.

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The Bigger Picture: Cancer as a Systems Disease

Modern oncology is extraordinarily powerful—but incomplete when isolated from physiology.

The future of cancer care is not:

• Tumour or metabolism
  but

• Tumour within metabolism

Insulin resistance is one of the most actionable, measurable, and neglected variables in cancer treatment today.

Why have clinical trials for insulin-targeting cancer therapies been disappointing?

Clinical trials for insulin-targeting therapies, such as Type I IGF receptor (IGF-IR) inhibitors and insulin-sensitising drugs like metformin, have been largely disappointing due to complex biological feedback mechanisms, redundant signaling pathways, and issues with trial design.

The primary reasons for these failures include:

Self-Defeating Feedback Loops

A significant hurdle in clinical trials, particularly for PI3K inhibitors, is that these drugs disrupt glucose metabolism, leading to transient hyperglycemia. In response, the pancreas releases a spike of insulin to normalize blood sugar levels. This treatment-induced hyperinsulinemia can reactivate the PI3K-mTOR signaling axis within the tumor, effectively overriding the drug’s inhibitory effects and allowing the cancer to continue growing.

Compensatory Signaling and Redundancy

The insulin-signaling system is highly redundant, making single-target therapies less effective:

• Insulin Receptor (InsR) Compensation: The IGF-IR is highly homologous to the insulin receptor. When trials block IGF-IR, the tumor may switch to using the InsR (particularly the InsR-A isoform) to bind IGFs and insulin, thereby sustaining tumor growth and survival.
• Receptor Tyrosine Kinase (RTK) Cross-talk: Inhibiting one receptor often triggers system rewiring, where other RTKs such as EGFR, ErbB2, ErbB3, or MET compensate for the loss of IGF-IR signaling.
• Kinase-Independent Functions: Many targeted agents only inhibit the kinase activity of the receptor. However, receptors like IGF-IR have non-canonical functions, such as translocating to the cell nucleus to directly regulate gene expression, which may not be hindered by standard inhibitors.

Metformin-Specific Limitations

Despite promising observational data, prospective trials adding metformin to anticancer therapy have failed to show survival benefits in advanced or metastatic settings. Possible reasons include:

• Insufficient Dosing: The conventional doses used to treat diabetes may not reach sufficient concentrations within tumor tissue to exert a direct antineoplastic effect.
• Tumor Burden and Sensitivity: The anticancer effects of metabolic interventions may be limited in patients with large tumor burdens or in cancer types that are not inherently responsive to insulin levels.

Issues with Clinical Trial Design

• Lack of Patient Stratification: Most clinical trials for these agents were conducted in unselected cancer patients. Researchers note that efficacy might be limited to specific molecular subtypes, but validated predictive biomarkers to identify these "responders" have not yet been successfully implemented in trials.
• Tumor Heterogeneity: The high degree of genetic and molecular diversity within and between tumors presents a major challenge for therapies that target a single metabolic or growth factor pathway.

Recent studies suggest that for these therapies to succeed, they may need to be paired with dietary interventions (like the ketogenic diet) or SGLT2 inhibitors to suppress insulin feedback, or developed as multikinase inhibitors that block both IGF-IR and InsR simultaneously. (Nature 2021, Nature 2018)

Key Takeaway

Cancer drugs act on tumours. Metabolic health shapes whether those drugs can succeed. Addressing insulin resistance may not cure cancer—but ignoring it may quietly undermine everything else.