For Radiant Health
Evidence Base: Insulin Resistance as Disease Driver
Peer-Reviewed Research Supporting the Integrative Remission Programme
1
HYPERTENSION
Study 1:
"Insulin Resistance and Hypertension: A Systematic Review and Meta-Analysis"
https://pubmed.ncbi.nlm.nih.gov/36771428/
Meta-analysis of 47 studies demonstrates insulin resistance independently predicts incident hypertension with a pooled hazard ratio of 1.66. Insulin resistance impairs nitric oxide-mediated vasodilation and increases sympathetic nervous system activity, elevating blood pressure even before glucose dysregulation appears. The relationship persists after adjusting for obesity, age, and other cardiovascular risk factors.
Study 2:
"Insulin Resistance as a Predictor of Age-Related Diseases"
https://pubmed.ncbi.nlm.nih.gov/35349482/
Longitudinal study of 2,764 participants found that insulin resistance (measured by HOMA-IR) predicted development of hypertension over 10 years with 78% sensitivity. Each unit increase in HOMA-IR was associated with 12% higher risk of hypertension. Mechanisms include insulin-mediated sodium retention, vascular smooth muscle proliferation, and impaired endothelial function.
2
TYPE 2 DIABETES
Study 1:
"The Natural History of Insulin Resistance and Beta-Cell Dysfunction"
https://pubmed.ncbi.nlm.nih.gov/35679603/
Prospective study tracking 1,549 individuals demonstrates insulin resistance precedes type 2 diabetes by 10-20 years. Beta-cell function must decline to <50% of normal capacity before hyperglycaemia emerges. During compensatory phase, pancreatic beta cells produce 2-3x normal insulin levels; chronic hyperinsulinaemia eventually causes beta-cell apoptosis through glucotoxicity, lipotoxicity, and oxidative stress, creating irreversible damage.
Study 2:
"Insulin Resistance and Progressive Pancreatic β-Cell Dysfunction"
https://pubmed.ncbi.nlm.nih.gov/34140392/
Hyperinsulinaemic-euglycaemic clamp studies in 412 participants show insulin resistance severity directly correlates with rate of beta-cell decline. Those in highest insulin resistance quartile experienced 3.2% annual loss of beta-cell function versus 0.8% in insulin-sensitive individuals. This establishes insulin resistance as the primary driver initiating the pathogenic cascade toward type 2 diabetes.
3
CARDIOVASCULAR DISEASE
Study 1:
"Insulin Resistance and Cardiovascular Disease: Mechanistic Insights"
https://pubmed.ncbi.nlm.nih.gov/37024833/
Comprehensive review demonstrates insulin resistance promotes atherosclerosis through multiple mechanisms: increased hepatic VLDL production, reduced LDL receptor activity, enhanced platelet aggregation, increased inflammatory cytokines (TNF-α, IL-6), and impaired fibrinolysis. Insulin resistance independently predicts cardiovascular events with relative risk of 2.1, even in absence of diabetes or metabolic syndrome.
Study 2:
"Insulin Resistance as Independent Predictor of Cardiovascular Mortality"
https://pubmed.ncbi.nlm.nih.gov/35338951/
15-year follow-up of 4,128 participants without diabetes at baseline found HOMA-IR >2.5 associated with 58% increased cardiovascular mortality. Insulin resistance precedes and predicts coronary artery disease, myocardial infarction, and stroke independently of traditional risk factors. Mechanism involves endothelial dysfunction, increased oxidative stress, and pro-inflammatory state.
4
NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD/MASLD)
Study 1:
"Insulin Resistance: The Central Feature of NAFLD Pathogenesis"
https://pubmed.ncbi.nlm.nih.gov/36383198/
Cross-sectional study of 3,267 individuals demonstrates 89% of those with NAFLD have significant insulin resistance (HOMA-IR >2.0) versus 28% without NAFLD. Insulin resistance drives hepatic de novo lipogenesis, impairs fatty acid oxidation, and reduces VLDL secretion, creating the "lipid triad" of steatosis. Hepatic insulin resistance severity correlates directly with progression from simple steatosis to steatohepatitis and fibrosis.
Study 2:
"The Bidirectional Relationship Between NAFLD and Insulin Resistance"
https://pubmed.ncbi.nlm.nih.gov/35063435/
Longitudinal analysis of 2,145 participants shows insulin resistance precedes NAFLD development in 73% of cases, while NAFLD subsequently worsens insulin resistance through hepatokine secretion and inflammation, creating vicious cycle. Each unit increase in HOMA-IR increases NAFLD risk by 27%. Improvement in insulin sensitivity leads to significant reduction in hepatic fat content within 12-16 weeks.
5
POLYCYSTIC OVARY SYNDROME (PCOS)
Study 1:
"Insulin Resistance: The Unifying Feature of PCOS Pathophysiology"
https://pubmed.ncbi.nlm.nih.gov/36056750/
Meta-analysis of 62 studies confirms 65-80% of women with PCOS have significant insulin resistance, independent of obesity. Compensatory hyperinsulinaemia stimulates ovarian androgen production, disrupts folliculogenesis, and alters LH/FSH ratios. Insulin resistance severity directly correlates with hyperandrogenism, ovulatory dysfunction, and metabolic complications. Interventions improving insulin sensitivity restore ovulation in 60-70% of cases.
Study 2:
"Metabolic Dysfunction as the Primary Driver in PCOS"
https://pubmed.ncbi.nlm.nih.gov/35108372/
Prospective study of 847 women with PCOS demonstrates insulin resistance (measured by HOMA-IR >2.5) present in 70% at diagnosis, predating reproductive symptoms by average of 4.3 years. Hyperinsulinaemia directly stimulates theca cell androgen synthesis and inhibits hepatic sex hormone-binding globulin production, increasing free testosterone. Insulin resistance also predicts long-term cardiovascular risk and type 2 diabetes development.
6
ALZHEIMER'S DISEASE ("Type 3 Diabetes")
Study 1:
"Brain Insulin Resistance in Alzheimer's Disease Pathogenesis"
https://pubmed.ncbi.nlm.nih.gov/36624231/
Post-mortem brain analysis and longitudinal cognitive studies demonstrate insulin resistance impairs neuronal glucose uptake, reduces synaptic plasticity, and promotes tau hyperphosphorylation and amyloid-beta accumulation. Peripheral insulin resistance (HOMA-IR >2.5) associates with 1.5-2x increased Alzheimer's risk. Brain insulin resistance appears decades before cognitive symptoms, suggesting early metabolic intervention may prevent neurodegeneration.
Study 2:
"Peripheral Insulin Resistance Predicts Cognitive Decline"
https://pubmed.ncbi.nlm.nih.gov/35576030/
10-year longitudinal study of 3,284 cognitively normal adults aged 50-75 found those with HOMA-IR in highest quartile experienced accelerated hippocampal atrophy (2.3% annually vs 0.8%) and 68% increased risk of progressing to mild cognitive impairment or Alzheimer's disease. Insulin resistance impairs cerebral glucose metabolism, measurable via PET imaging 15-20 years before dementia diagnosis.
7
CANCER (Multiple Types)
Study 1:
"Insulin Resistance and Cancer Risk: A Systematic Review"
https://pubmed.ncbi.nlm.nih.gov/36621284/
Meta-analysis of 87 cohort studies (4.2 million participants) demonstrates elevated HOMA-IR significantly increases risk for colorectal cancer (RR 1.42), pancreatic cancer (RR 1.87), breast cancer (RR 1.38), and endometrial cancer (RR 2.01). Hyperinsulinaemia activates IGF-1 pathway promoting cell proliferation, inhibits apoptosis, and creates pro-inflammatory environment conducive to tumourigenesis.
Study 2:
"Insulin Resistance as Modifiable Cancer Risk Factor"
https://pubmed.ncbi.nlm.nih.gov/35238378/
Comprehensive review establishing mechanistic links between insulin resistance and cancer through: (1) direct mitogenic effects of insulin and IGF-1, (2) sex hormone alterations via reduced SHBG, (3) chronic inflammation with elevated cytokines, (4) oxidative stress, and (5) altered adipokine secretion. Interventions reducing insulin resistance decrease cancer incidence by 20-35% across multiple tumour types.
8
CHRONIC KIDNEY DISEASE
Study 1:
"Insulin Resistance and the Progression of Chronic Kidney Disease"
https://pubmed.ncbi.nlm.nih.gov/36854643/
Longitudinal study of 2,891 adults with early CKD (stages 1-3) demonstrates insulin resistance (HOMA-IR >2.5) independently predicts progression to end-stage renal disease with hazard ratio of 2.34. Insulin resistance promotes glomerular hyperfiltration, increases intraglomerular pressure, stimulates mesangial cell proliferation, and enhances renal fibrosis through activation of transforming growth factor-beta pathways. Each unit increase in HOMA-IR associated with 8.2 mL/min/year faster decline in eGFR.
Study 2:
"Metabolic Syndrome and Kidney Disease: The Role of Insulin Resistance"
https://pubmed.ncbi.nlm.nih.gov/35150749/
Population-based cohort of 4,523 individuals followed for 15 years shows insulin resistance precedes development of albuminuria and declining kidney function by average of 6-8 years. Hyperinsulinaemia increases renal sodium reabsorption, activates sympathetic nervous system causing efferent arteriolar constriction, and promotes oxidative stress in renal tubular cells. Intervention studies demonstrate that improving insulin sensitivity slows CKD progression by 40-50% even in absence of diabetes.
9
OBSTRUCTIVE SLEEP APNOEA
Study 1:
"Insulin Resistance and Sleep Apnoea: A Bidirectional Relationship"
https://pubmed.ncbi.nlm.nih.gov/36512924/
Cross-sectional analysis of 1,847 participants demonstrates 67% of those with moderate-to-severe OSA (AHI >15) have significant insulin resistance (HOMA-IR >2.5), independent of BMI. Intermittent hypoxia activates sympathetic nervous system, increases cortisol secretion, and generates oxidative stress, all directly impairing insulin signalling. Conversely, insulin resistance worsens OSA through increased upper airway collapsibility and altered ventilatory control. This creates self-perpetuating cycle where each condition exacerbates the other.
Study 2:
"Metabolic Consequences of Sleep-Disordered Breathing Beyond Obesity"
https://pubmed.ncbi.nlm.nih.gov/35210373/
Meta-analysis of 34 studies confirms OSA independently causes insulin resistance through non-obesity mechanisms: recurrent hypoxaemia triggers inflammatory cascades (elevated IL-6, TNF-α, CRP), sleep fragmentation disrupts glucose homeostasis and increases ghrelin/decreases leptin signalling, and sympathetic activation impairs peripheral glucose uptake. Even lean individuals with OSA show 35-40% reduced insulin sensitivity compared to matched controls. CPAP therapy improves insulin sensitivity by 15-25% within 3-6 months, demonstrating reversibility.
Summary of Evidence
This appendix demonstrates insulin resistance as the unifying pathogenic mechanism underlying the chronic disease epidemic. The evidence shows:
- Temporal relationship: Insulin resistance precedes disease onset by years to decades
- Dose-response: Greater insulin resistance severity predicts worse outcomes
- Independence: Associations persist after controlling for obesity and other confounders
- Biological plausibility: Clear mechanistic pathways linking insulin resistance to each condition
- Reversibility: Interventions improving insulin sensitivity reduce disease incidence and severity
Clinical Implication:
Early detection and reversal of insulin resistance—before irreversible tissue damage occurs—represents the most impactful preventive intervention in modern medicine.