Insulin Resistance

The reduced ability of organs to respond to 'physiological' insulin levels, thought to primarily occur through reduced insulin sensing and/or signalling

Aetiology

• Insulin resistance is most commonly associated with obesity, however near complete absence of adipose also results in insulin resistance

• Normal adipose functionality should be considered a key mediator of insulin sensitivity (rather than fat being considered an antagonist of insulin action)

• There are also some genetic forms of insulin resistance

Pathophysiology

Development of insulin resistance

• Different tissues will have different mechanisms of insulin resistance

• In skeletal muscle, insulin resistance is caused by impairment of insulin signalling
• FFAs decreases insulin receptor tyrosine kinase which decreases the activation of downstream proteins
• End result is that GLUT4 does not get translocated to the skeletal muscle cell membrane, so it is unable to take up glucose into the cell

• In adipose tissue, insulin resistance is caused by obesity-induced inflammation as adipose tissue secretes pro-inflammatory cytokines e.g. TNF-⍺
• Cytokines can move into other tissues e.g. liver, skeletal muscle to cause systemic resistance

• Liver: pathway-selective hepatic insulin resistance
• Hepatic lipogenesis remains elevated in insulin-resistant subjects - insulin signaling to glucose metabolism is impaired so glucose uptake is reduced, but insulin signaling to lipid metabolism is intact
• The increased lipogenesis is caused by the increase of FFAs seen in obesity which allows VLDL secretion to increase

Insulin resistance and disease

• 90% of people with T2DM have insulin resistance

• Insulin resistance is also associated with hypertension, hyperlipidaemia, hyperglycaemia (even in the absence of diabetes), chronic kidney disease, Alzheimer's disease and others

• Metabolic syndrome is associated with increased risk of CHD, MI, stroke and CV death

Genetic insulin resistance

• Monogenetic severe insulin resistance can occur due to mutation in key signalling pathways but this is very rare

• Rare autosomal genetic trait involving mutations in the insulin receptor

• Severe insulin resistance and developmental abnormalities e.g. growth retardation, abscence of SC fat, caused by defects in insulin binding or insulin receptor signalling

• Rare autosomal recessive trait which presents with severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia

• Other clinical features include developmental abnormalities and acanthosis nigricans

• Patients have fasting hypoglycaemia (due to hyperinsulinaemia)

• Patients are very prone to diabetic ketoacidosis

• Severe cases linked to mutations in the insulin receptor that reduce sensitivity

Clinical presentation

• No symptoms

Investigations

• Risk factors can be reviewed by heath providers

• If at risk, blood glucose levels should be checked for pre-diabetes/diabetes

• The hyperinsulinemic-euglycemic clamp is the gold standard for the measurement of insulin sensitivity

Risk factors