Condition

Mechanism/Link to IR

Estimated Prevalence

< 5 Years IR Duration

5-10 Years IR Duration

10-20 Years IR Duration

> 20 Years IR Duration

US Affected (Million)

UK Affected (Million)

HYPERTENSION

Hyperinsulinemia → increased renal sodium reabsorption, sympathetic activation, endothelial dysfunction

45% of US adults; 150% increased risk with IR

REVERSIBLE – BP normalizes within 3-6 months with VLCD+IF

REVERSIBLE – May require 6-12 months; some vascular remodeling

PARTIALLY REVERSIBLE – Vascular remodeling established; may need continued intervention

LARGELY IRREVERSIBLE – Permanent vascular changes; arterial stiffening

117

24

TYPE 2 DIABETES

Progressive beta-cell failure from chronic hyperinsulinemia; hepatic glucose overproduction

11% diagnosed; ~38% prediabetes

REVERSIBLE – Complete remission possible with weight loss, VLCD; HbA1c normalizes 2-6 months

REVERSIBLE – Remission achievable but may require sustained intervention; some beta-cell damage

PARTIALLY REVERSIBLE – Significant beta-cell loss (~50%); glucose control possible but may require medication

LARGELY IRREVERSIBLE – Advanced beta-cell failure; insulin often required; complications established

29 diagnosed + 98 prediabetes

3.9 diagnosed + 7.5 prediabetes

NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD/NASH)

IR → hepatic de novo lipogenesis; triglyceride accumulation; inflammation

30-40% of adults; 70-80% of obese/T2DM

REVERSIBLE – Steatosis reverses with 7-10% weight loss in 3-6 months; liver enzymes normalize

REVERSIBLE – NASH reversible with sustained intervention; early fibrosis may regress

PARTIALLY REVERSIBLE – Advanced fibrosis (F3) difficult to reverse; cirrhosis risk increased

LARGELY IRREVERSIBLE – Cirrhosis established; transplant may be needed; HCC risk

78-104

16-21

POLYCYSTIC OVARY SYNDROME (PCOS)

Hyperinsulinemia → ovarian androgen production; disrupted ovulation

6-21% of reproductive-age women

REVERSIBLE – Ovulation restores with insulin sensitization; hirsutism improves; fertility restored

REVERSIBLE – Metabolic/reproductive features improve with weight loss, metformin, lifestyle

PARTIALLY REVERSIBLE – Long-term anovulation may cause permanent ovarian changes

PARTIALLY REVERSIBLE – Metabolic features persist; reproductive window may have closed

8-27 (reproductive age)

1.6-5.6 (reproductive age)

CARDIOVASCULAR DISEASE (Atherosclerosis, CAD)

IR → endothelial dysfunction, inflammation, dyslipidemia, hypertension; plaque formation

Leading cause of death; IR increases risk 2-3x

PARTIALLY REVERSIBLE – Early endothelial dysfunction reverses; plaque stabilization possible

PARTIALLY REVERSIBLE – Plaque progression slows; some regression possible with aggressive treatment

LARGELY IRREVERSIBLE – Established plaques; risk reduction but not reversal; events preventable

IRREVERSIBLE – Advanced disease; bypass/stents needed; high event risk despite treatment

126 (with CVD)

26 (with CVD)

DYSLIPIDEMIA (High TG, Low HDL, Small Dense LDL)

IR → hepatic VLDL overproduction; impaired LPL activity; altered lipoprotein metabolism

~53% have abnormal lipids; nearly universal with IR

REVERSIBLE – Triglycerides drop 40-60% within weeks of VLCD; HDL increases 3-6 months

REVERSIBLE – Full normalization possible with sustained dietary intervention and weight loss

REVERSIBLE – Lipids normalize with IR reversal regardless of duration

REVERSIBLE – Metabolic correction reverses dyslipidemia even after decades

138

28

CHRONIC KIDNEY DISEASE

Hyperinsulinemia → glomerular hyperfiltration, mesangial cell proliferation, glomerulosclerosis

15% of adults; accelerated by diabetes/HTN

REVERSIBLE – Hyperfiltration reverses; microalbuminuria improves with glycemic control

PARTIALLY REVERSIBLE – Early nephropathy may stabilize or improve; proteinuria reduces

LARGELY IRREVERSIBLE – GFR loss continues; structural damage permanent; progression slows with treatment

IRREVERSIBLE – End-stage renal disease; dialysis or transplant required

39

8

ALZHEIMER’S DISEASE / DEMENTIA (“Type 3 Diabetes”)

Brain insulin resistance; impaired glucose metabolism; inflammation; amyloid accumulation

6.7M in US; IR increases risk 2-3x

REVERSIBLE – Cognitive function improves with metabolic correction; brain glucose metabolism improves

PARTIALLY REVERSIBLE – Mild cognitive impairment may improve; disease progression slows

LARGELY IRREVERSIBLE – Neuronal loss and plaques established; slowing progression is goal

IRREVERSIBLE – Advanced neurodegeneration; symptomatic treatment only

6.7

0.9

CANCER (Breast, Colon, Pancreatic, Liver)

Hyperinsulinemia as growth factor; IGF-1 activation; chronic inflammation

IR increases risk 20-50% various cancers

PREVENTABLE – Risk reduction with metabolic correction; detected cancer requires standard treatment

PREVENTABLE – Metabolic intervention reduces incidence; existing cancer requires oncologic care

VARIABLE – Once cancer develops, IR correction is adjunctive therapy only

VARIABLE – Cancer treatment independent of IR; metabolic health impacts outcomes

Variable by type

Variable by type

PERIPHERAL NEUROPATHY

Hyperglycemia; advanced glycation end products; oxidative stress; microvascular damage

50% of diabetics; can occur in prediabetes

REVERSIBLE – Early neuropathy symptoms improve with strict glycemic control within 6-12 months

PARTIALLY REVERSIBLE – Pain may improve; nerve conduction may stabilize; structural damage limits recovery

LARGELY IRREVERSIBLE – Established nerve damage; symptom management; progression may slow

IRREVERSIBLE – Permanent sensory loss; autonomic dysfunction; amputation risk

14.5 (diabetic)

2.0 (diabetic)

RETINOPATHY

Hyperglycemia → retinal microaneurysms, hemorrhages, macular edema; VEGF overproduction

28% of diabetics over 40

REVERSIBLE – Early background retinopathy may regress with excellent glucose control

PARTIALLY REVERSIBLE – Nonproliferative changes may stabilize; laser treatment prevents progression

LARGELY IRREVERSIBLE – Proliferative retinopathy; vitreous hemorrhage; requires laser/anti-VEGF

IRREVERSIBLE – Advanced disease; retinal detachment; vision loss; blindness risk

8.1 (diabetic)

1.1 (diabetic)

ERECTILE DYSFUNCTION

Endothelial dysfunction; reduced NO production; atherosclerosis of penile arteries

52% of men; strongly linked to IR/MetS

REVERSIBLE – Endothelial function improves with weight loss, exercise; function restoration 3-6 months

REVERSIBLE – Metabolic intervention effective; may require PDE5 inhibitors temporarily

PARTIALLY REVERSIBLE – Vascular damage limits full recovery; medications often needed

LARGELY IRREVERSIBLE – Structural vascular changes; medications less effective

68 (men affected)

14 (men affected)

OBSTRUCTIVE SLEEP APNEA

Visceral obesity; pharyngeal fat deposition; inflammatory cytokines worsen IR bidirectionally

30M in US; 70% of obese adults

REVERSIBLE – Weight loss of 10-15% significantly improves or resolves OSA in 3-6 months

REVERSIBLE – Sustained weight loss reverses OSA; CPAP may be discontinued

REVERSIBLE – OSA improves with weight loss regardless of duration; anatomic factors may persist

PARTIALLY REVERSIBLE – Long-term obesity may cause permanent pharyngeal structural changes

30

6

GOUT / HYPERURICEMIA

Hyperinsulinemia → reduced renal uric acid excretion; fructose metabolism increases uric acid

4% of adults; increasing with obesity/MetS

REVERSIBLE – Uric acid levels drop with VLCD, IF within weeks; acute attacks resolve

REVERSIBLE – Dietary intervention normalizes uric acid; tophi may dissolve over months-years

PARTIALLY REVERSIBLE – Chronic tophaceous gout; joint damage may be permanent

PARTIALLY IRREVERSIBLE – Established joint erosions; tophi may persist despite treatment

10

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