What is Type B Insulin Resistance Syndrome?
Type B insulin resistance syndrome is a rare autoimmune disorder caused by autoantibodies against the insulin receptor that block insulin binding to target tissues, resulting in severe insulin resistance, extreme hyperglycemia (often requiring hundreds to thousands of units of insulin daily), acanthosis nigricans, and paradoxically can also cause hypoglycemia when the antibodies act as insulin agonists. 1
Pathophysiology
- The syndrome results from anti-insulin receptor antibodies that bind to the insulin receptor, thereby blocking insulin from binding to its receptor in target tissues 1
- In some cases, these same antibodies can paradoxically act as insulin agonists after binding to the receptor, causing hypoglycemia rather than hyperglycemia 1, 2
- This represents an extreme state of insulin resistance distinct from genetic defects in the insulin receptor itself (Type A insulin resistance) 1
Clinical Features
Patients typically present with:
- Severe, refractory hyperglycemia requiring massive insulin doses (often 500-1000+ units daily) that fails to adequately control blood glucose 3, 4, 5
- Acanthosis nigricans (dark, velvety skin changes, particularly in body folds) is nearly universal 1, 3
- Hypercatabolic state with significant weight loss despite hyperglycemia 3, 6
- Hyperandrogenism in women, including virilization and enlarged, cystic ovaries 1
- Paradoxical hypoglycemia can occur when antibodies act as insulin agonists 1, 5, 2
Associated Conditions
- The syndrome is frequently found in patients with systemic lupus erythematosus and other autoimmune diseases 1
- Mixed connective tissue disease, vitiligo, and other autoimmune conditions commonly coexist 3, 6
- Can rarely occur in patients with pre-existing type 1 diabetes, manifesting as dramatically increased insulin requirements 5
Diagnosis
Diagnosis is confirmed by:
- Detection of anti-insulin receptor antibodies through immunoprecipitation assays or binding studies showing inhibition of insulin binding to erythrocytes or lymphocytes 4, 5, 2
- Clinical presentation of extreme insulin resistance (>2 units/kg/day) with acanthosis nigricans and associated autoimmune disease 3, 4
- Serological confirmation may not be necessary in all cases due to high mortality without timely treatment, so clinical suspicion should prompt empiric therapy 3
Treatment Approach
The most effective treatment protocol combines rituximab, cyclophosphamide, and pulse corticosteroids:
- A standardized intensive immunosuppression protocol using rituximab, cyclophosphamide, and pulse corticosteroids achieves remission in the majority of patients 4
- This combination achieved remission (defined as normalization of glycated hemoglobin, discontinuation of insulin, and resolution of hyperandrogenism) in all seven treated patients in the largest NIH cohort, with remission occurring on average within 8 months 4
Alternative regimens when rituximab is unavailable:
- Pulse methylprednisolone (1000 mg/day for 3 days) followed by cyclophosphamide can achieve remission without rituximab, as demonstrated in resource-limited settings 3, 6
- Response to treatment typically becomes evident after 3-4 weeks, with dramatic reduction in insulin requirements 3, 6
Critical Management Pitfalls
- As patients respond to immunosuppression, insulin doses must be rapidly reduced or discontinued to prevent severe hypoglycemia, as the antibody blockade resolves and endogenous insulin action is restored 3, 5
- Mild postprandial hyperglycemia should be acceptable during the transition period to avoid dangerous hypoglycemia 3
- Timely treatment is essential as the condition carries high mortality without appropriate immunosuppression 3, 4
- Plasmapheresis can provide temporary benefit during relapses but is not sufficient as monotherapy 5