Insulin Resistance

At a cellular level, insulin resistance involves impaired insulin receptor substrate (IRS) signalling, reduced GLUT4 translocation in muscle, and dysregulated PI3K/AKT pathway activity. Ectopic lipid accumulation in liver (causing hepatic insulin resistance) and skeletal muscle (impairing glucose disposal) is central to its development.

Adipose tissue dysfunction — particularly in visceral fat — drives insulin resistance via release of pro-inflammatory cytokines (TNF-α, IL-6), free fatty acids, and suppressed adiponectin. Visceral adiposity is therefore a key mediating factor between lifestyle and metabolic disease.

The compensatory hyperinsulinaemia itself may have downstream hormonal effects: insulin stimulates ovarian androgen production in women (relevant in PCOS) and suppresses SHBG production in the liver (increasing free testosterone in women, but relevant in men too — low SHBG is a strong clinical signal for insulin resistance).

Gold-standard measurement is the hyperinsulinaemic-euglycaemic clamp — infeasible in routine clinical practice. The homeostatic model assessment of insulin resistance (HOMA-IR), calculated as: HOMA-IR = (fasting insulin [μIU/mL] × fasting glucose [mmol/L]) / 22.5, is the most widely used clinical surrogate.

HOMA-IR interpretation: <1.0 is considered insulin sensitive; 1.0-2.0 is borderline; >2.5 suggests significant insulin resistance; >5.0 is consistent with overt type 2 diabetes or severe metabolic syndrome. These thresholds vary by population and some guidelines use slightly different cut-offs.

Additional clinical surrogates: fasting insulin (>15 μIU/mL is suspicious; >25 μIU/mL with normal glucose strongly suggests resistance), triglyceride:HDL ratio (>2.0 in US units / >0.9 in SI units is a useful surrogate), waist circumference, and HbA1c trajectory.

Insulin resistance and testosterone levels are inversely correlated in large epidemiological studies. Multiple mechanisms are proposed: elevated insulin suppresses LH pulsatility, impairs Leydig cell function, and reduces SHBG (thereby increasing clearance of free testosterone). Additionally, visceral obesity increases aromatase activity, converting testosterone to oestradiol.

Low SHBG — itself a downstream consequence of hepatic insulin resistance — is now recognised as an independent predictor of type 2 diabetes risk. Men with low SHBG should be assessed for insulin resistance even in the absence of elevated fasting glucose.

The relationship is bidirectional: testosterone deficiency also promotes insulin resistance and visceral fat accumulation, creating a cycle that can be difficult to interrupt without addressing both metabolic and hormonal components simultaneously.

Insulin resistance is the unifying pathophysiology behind metabolic syndrome (abdominal obesity, dyslipidaemia, hypertension, impaired fasting glucose). It precedes overt type 2 diabetes by years to decades and is largely reversible at this stage.

Non-alcoholic fatty liver disease (NAFLD), now termed MASLD, is both a consequence and amplifier of insulin resistance. Elevated ALT or GGT in the context of a metabolic risk profile should prompt insulin resistance assessment.

Lifestyle interventions — sustained caloric deficit, aerobic and resistance exercise, sleep optimisation — are the most effective interventions for improving insulin sensitivity. Pharmacological options include metformin, GLP-1 receptor agonists (semaglutide, tirzepatide), and pioglitazone.