Insulin Resistance

Insulin resistance is a reduced response of muscle, liver and fat tissue to the action of insulin, so that more insulin is needed to maintain normal glucose. It is the central abnormality in prediabetes, type 2 diabetes, metabolic syndrome, polycystic ovary syndrome and fatty liver disease, and it often exists for 10 to 15 years before glucose rises above normal.

• Causes and contributors: excess visceral fat, physical inactivity, sleep deprivation and sleep apnoea, high refined carbohydrate intake, ageing, genetic factors (ethnic differences: South Asian, African, Hispanic, Middle Eastern), pregnancy (physiological), puberty, polycystic ovary syndrome, Cushing syndrome, acromegaly, hypothyroidism and hyperthyroidism, drugs (glucocorticoids, antipsychotics, protease inhibitors, thiazides, beta blockers, niacin, tacrolimus), chronic inflammation, and fatty liver.
• Rare severe forms: lipodystrophy, mutations in the insulin receptor (leprechaunism, Rabson-Mendenhall syndrome, type A insulin resistance), and type B insulin resistance from anti-insulin receptor antibodies.
• Consequences: compensatory hyperinsulinaemia, then progression to type 2 diabetes when beta cell function falls, together with hypertension, dyslipidaemia (raised triglycerides, low HDL), fatty liver, hyperandrogenism, and cardiovascular risk.
• It is a physiological measurement as much as a diagnosis, with no single accepted cut off.

• Frequently none. Central obesity, tiredness after meals, hunger and sugar cravings, difficulty losing weight, brain fog.
• Skin: acanthosis nigricans (dark velvety plaques on neck, axillae, groin), skin tags, acne, hirsutism and scalp hair loss in women.
• Women: irregular periods, subfertility (polycystic ovary syndrome).
• Associated findings: hypertension, fatty liver, sleep apnoea, gout.
• Children: acanthosis, early puberty, obesity.
• Red flags for severe forms: extreme acanthosis with very high insulin requirements, lipodystrophy (loss of fat in limbs with fat in neck and face), hirsutism with virilisation, unexplained severe hyperglycaemia in a lean person.

• Clinical diagnosis supported by risk factors and metabolic markers; no routine insulin measurement is needed.
• Measure waist, blood pressure, fasting glucose and HbA1c, fasting lipid profile (triglycerides 1.7 mmol/L or more with low HDL, a triglyceride to HDL ratio above 2.0 in mmol/L, or 3.0 in mg/dL, suggests insulin resistance), liver tests (ALT), uric acid.
• 75 g oral glucose tolerance test when fasting glucose or HbA1c is borderline, with a 2 hour glucose of 7.8 to 11.0 mmol/L (impaired glucose tolerance) or 11.1 mmol/L or more (diabetes).
• Fasting insulin and the homeostasis model assessment (HOMA-IR = fasting glucose in mmol/L multiplied by fasting insulin in microunits per mL, divided by 22.5; values above 2.5 suggest insulin resistance, although thresholds vary by assay and population); fasting insulin and C-peptide are used in research and severe forms.
• Women with irregular cycles or hirsutism: total testosterone, sex hormone binding globulin, pelvic ultrasound, thyroid stimulating hormone, prolactin, 17-hydroxyprogesterone.
• Fibrosis score (FIB-4) for fatty liver; sleep apnoea screening.
• Overnight dexamethasone suppression when Cushing features, growth hormone and IGF-1 when acromegaly features.
• Differentials: Cushing syndrome, acromegaly, lipodystrophy, drug effect, type 1 diabetes with obesity, monogenic diabetes.

Lifestyle (the most effective treatment)

• Weight loss of 5 to 10 percent, mainly of visceral fat, improves insulin sensitivity within weeks.
• Diet: Mediterranean or low glycaemic load pattern, high in fibre (30 g daily), vegetables, legumes, whole grains, nuts and olive oil; reduce refined carbohydrate, sugar sweetened drinks and ultra processed food; adequate protein (1.0 to 1.2 g/kg); time restricted eating (8 to 10 hour window) can help; avoid late heavy meals.
• Exercise: resistance training 2 to 3 times weekly (muscle is the main site of glucose uptake) and 150 to 300 minutes of aerobic activity weekly; a 10 to 15 minute walk after meals lowers glucose peaks.
• Sleep 7 to 8 hours; treat sleep apnoea with continuous positive airway pressure; stop smoking; limit alcohol; manage stress.

Medicines (when lifestyle is not sufficient, or in prediabetes with high risk)

• Metformin 500 mg orally once daily with the evening meal, increased weekly by 500 mg to 1 to 2 g daily in divided doses (modified release is better tolerated); check eGFR (avoid below 30; reduce at 30 to 45) and vitamin B12 yearly. It is used in prediabetes with BMI above 30 or prior gestational diabetes, and in polycystic ovary syndrome.
• GLP-1 based therapy for obesity: semaglutide 2.4 mg weekly (titrated from 0.25 mg every 4 weeks) or tirzepatide 2.5 mg weekly rising by 2.5 mg every 4 weeks to 5 to 15 mg, which sharply improve insulin sensitivity.
• Pioglitazone 15 to 30 mg once daily is specialist initiated, especially in fatty liver or lipodystrophy (weight gain, fluid retention, fractures; avoid in heart failure and bladder cancer history).
• Inositol (myo inositol 2 to 4 g daily) has limited evidence in polycystic ovary syndrome.
• Statins and antihypertensives are given on cardiovascular risk (atorvastatin 20 mg, ramipril or candesartan first for blood pressure).

Women with polycystic ovary syndrome

• Combined oral contraceptive (30 to 35 micrograms ethinylestradiol with a low androgenic progestogen) for cycle control and acne, metformin, spironolactone 50 to 100 mg daily for hirsutism (with reliable contraception), and cyclical progestogen to protect the endometrium if periods are infrequent.

Special groups

• Children and adolescents: family based lifestyle programme; metformin 500 mg twice daily in specialist care for prediabetes and polycystic ovary syndrome.
• Pregnancy: screen for gestational diabetes at 24 to 28 weeks (earlier if risk); advise physical activity and healthy weight gain.
• Severe insulin resistance syndromes: refer to specialist; options include metreleptin in lipodystrophy and high dose insulin.

Follow up

• Reassess weight, waist, blood pressure, lipids and HbA1c every 6 to 12 months; repeat oral glucose tolerance test every 1 to 3 years in high risk; refer when diabetes develops or if features suggest a secondary or severe form.