Insulin Autoimmune Syndrome

Insulin autoimmune syndrome is spontaneous hypoglycaemia, typically after meals, caused by high titre autoantibodies to endogenous insulin in people who have not received exogenous insulin. Total insulin concentrations are very high.

It is reported mainly in East Asian populations (strong HLA-DRB1 allele 04:06 association), rare in other populations.

Triggers are drugs with a sulphydryl group (carbimazole, methimazole, alpha lipoic acid, captopril, penicillamine, glutathione), autoimmune disease (Graves disease, rheumatoid arthritis, systemic lupus erythematosus), monoclonal gammopathy and viral infection.

It is usually self-limited, remitting within weeks to months of removing the trigger. Relapse can occur.

Pathophysiology.

Antibodies bind insulin secreted after a meal, buffering glucose in the early phase. Later, insulin dissociates from the antibody in an unregulated way and causes hypoglycaemia.

Sulphydryl groups probably alter insulin structure and increase immunogenicity.

• Neuroglycopenic and adrenergic symptoms, mainly 2 to 4 hours after meals, sometimes fasting.
• Documented low glucose, relief with glucose, and features of coexisting autoimmune or thyroid disease.

• Confirm hypoglycaemia: glucose under 3.0 mmol/L (54 mg/dL), symptoms and relief with glucose.
• Critical sample during spontaneous hypoglycaemia: glucose, insulin, C-peptide, proinsulin, beta hydroxybutyrate and a sulphonylurea and meglitinide screen.
• Insulin very high (often over 1000 pmol/L), with C-peptide high or inappropriately normal, and a markedly raised insulin to C-peptide molar ratio (over 1). Insulin autoantibody titre high. Confirm with polyethylene glycol precipitation, showing reduced insulin recovery.
• Postprandial hypoglycaemia is the pattern, so a 72-hour fast may be normal; a mixed meal test can help.
• Imaging (CT, MRI or endoscopic ultrasound) only if insulinoma is still possible.

Differential diagnosis.

• Insulinoma (no antibodies, imaging positive).
• Factitious insulin use (C-peptide suppressed) and sulphonylurea use (positive drug screen).
• Insulin receptor antibody syndrome, non-islet cell tumour hypoglycaemia (insulin suppressed) and post-bariatric hypoglycaemia.
• Adrenal insufficiency, hypopituitarism and severe liver disease.

• Stop sulphydryl containing drugs. Frequent small low-glycaemic-index meals every 2 to 3 hours, avoiding refined sugars.
• Acute hypoglycaemia: 15 to 20 g oral glucose, or intravenous 10% glucose 150 to 200 mL over 15 minutes (or 20% glucose 75 to 100 mL), then slow release carbohydrate; glucagon 1 mg intramuscularly if no access.
• Acarbose 50 to 100 mg with each main meal to slow carbohydrate absorption. Diazoxide and octreotide have variable effect.
• Refractory or severe disease: prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg), tapered over weeks to months. Rituximab, azathioprine or plasmapheresis in very refractory cases.
• Treat associated disease. For Graves disease, consider radioiodine or surgery in place of a sulphydryl antithyroid drug.

Monitoring. Glucose (continuous monitoring if possible) and insulin antibody titre every 1 to 3 months until remission.

Referral and escalation. Endocrinology for all cases. Haematology if a monoclonal gammopathy is found.