Insulin Resistance Syndrome

Insulin resistance syndrome (metabolic syndrome) is a cluster of central obesity, raised blood pressure, dyslipidaemia and impaired glucose regulation, driven by reduced tissue response to insulin. It increases the risk of type 2 diabetes, cardiovascular disease and fatty liver disease.

It affects roughly 20 to 35% of adults, with higher rates in older age, South Asian, Hispanic and Pacific populations, and increasing rates in urban Africa. It is commonly linked with polycystic ovary syndrome, obstructive sleep apnoea and non-alcoholic fatty liver disease.

A working definition requires central obesity plus at least two other features.

Central obesity is a waist circumference of 94 cm or more in men and 80 cm or more in women (90 cm and 80 cm in South Asian people).

The other features are: triglyceride 1.7 mmol/L (150 mg/dL) or more, HDL cholesterol under 1.0 mmol/L in men or under 1.3 mmol/L in women, blood pressure 130/85 mmHg or more (or treated), and fasting glucose 5.6 mmol/L (100 mg/dL) or more (or diabetes).

Pathophysiology.

Excess visceral and ectopic fat, free fatty acids and inflammatory cytokines impair insulin signalling in muscle, liver and fat. The pancreas compensates with hyperinsulinaemia until beta cell failure leads to diabetes.

Hyperinsulinaemia raises hepatic triglyceride production and lowers HDL, increases sodium retention and sympathetic activity, and raises androgens in women.

• Central obesity, acanthosis nigricans, skin tags, hypertension, fatigue and sleep apnoea symptoms (snoring, daytime sleepiness).
• Women: hirsutism, oligomenorrhoea and infertility (polycystic ovary syndrome).
• Complications: type 2 diabetes, fatty liver, cardiovascular disease, gout and some cancers.

Red flags.

• Severe insulin resistance with lipodystrophy features, extreme acanthosis or virilisation in a lean patient.
• Rapid weight gain with Cushingoid features.

• Waist circumference, blood pressure and BMI.
• Fasting glucose with HbA1c, or a 75 g oral glucose tolerance test (impaired fasting glucose 5.6 to 6.9 mmol/L; impaired glucose tolerance 7.8 to 11.0 mmol/L at 2 hours).
• Fasting lipids, liver tests and (if steatosis is suspected) fibrosis scoring or elastography, urate, kidney function and urine albumin to creatinine ratio.
• In women with menstrual disturbance: androgens, thyroid function and prolactin.
• Fasting insulin and insulin sensitivity indices are not needed for routine care.

Differential diagnosis.

• Cushing syndrome, hypothyroidism, polycystic ovary syndrome and growth hormone deficiency.
• Lipodystrophy and severe monogenic insulin resistance syndromes (insulin receptor variants, type B syndrome with receptor antibodies).
• Drug induced weight gain and hyperglycaemia (glucocorticoids, antipsychotics).

• Lifestyle: weight loss of 5 to 10% of body weight, at least 150 minutes of moderate activity each week, resistance exercise, a diet rich in fibre, vegetables and unsaturated fat with fewer refined carbohydrates, and stopping smoking.
• Impaired glucose regulation: metformin starting 500 mg daily with food and increasing to 1000 mg twice daily (maximum 1000 mg daily at eGFR 30 to 44 mL/min; stop under 30 mL/min).
• Obesity: semaglutide 2.4 mg weekly (start 0.25 mg weekly, increase every 4 weeks) or tirzepatide up to 15 mg weekly (start 2.5 mg weekly, increase by 2.5 mg every 4 weeks), with attention to gastrointestinal effects and gallstones.
• Treat each component: blood pressure with an ACE inhibitor or angiotensin receptor blocker as first choice; statin for cardiovascular risk; fenofibrate 145 mg daily for triglyceride over 10 mmol/L (880 mg/dL).
• Bariatric surgery for BMI 35 kg/m2 or more (30 kg/m2 or more with diabetes, with lower cut offs in Asian populations).
• Treat sleep apnoea and fatty liver disease.

Special groups. South Asian, African and Hispanic populations: apply lower waist and BMI cut offs. Women with polycystic ovary syndrome: lifestyle and metformin. Children: family based lifestyle treatment.

Monitoring. Weight, waist, blood pressure and HbA1c every 3 to 6 months, lipids and liver tests yearly, and urine albumin to creatinine ratio yearly.

Referral and escalation. Endocrinology for severe insulin resistance, young onset or diagnostic doubt; bariatric service for eligible patients; hepatology for advanced fibrosis.