MON-629 - When Insulin Stops Working: Autoimmune Type B Insulin Resistance in an Adolescent

Type B insulin resistance syndrome (TBIRS) is a rare autoimmune disorder caused by autoantibodies against the insulin receptor, resulting in impaired insulin signaling and severe dysglycemia. While profound insulin resistance and refractory hyperglycemia are typical, paradoxical hypoglycemia or mixed glycemic patterns may occur due to variable agonist and antagonist antibody activity or reduced insulin clearance. TBIRS most commonly affects middle-aged individuals and is strongly associated with systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE) and Sjögren’s syndrome. Characteristic features include marked hyperinsulinemia, acanthosis nigricans, and hyperandrogenism.

We present an 18-year-old female with a complex history of SLE, psoriasis, and hypertension who developed progressive hyperglycemia, profound insulin resistance, and hyperandrogenism. SLE was diagnosed in 2021 following pancytopenia, low complement levels, and positive ANA and anti-Smith antibodies. Treatment included prednisone, mycophenolate mofetil, and hydroxychloroquine. Her course was complicated by recurrent autoimmune flares and thrombotic microangiopathy following a ruptured ovarian cyst in 2022, requiring surgery, intensive care, and eculizumab. She subsequently required additional immunosuppression with belimumab and IL-17 inhibition.

In 2024, she developed severe and rapidly escalating insulin resistance, with her HbA1c rising above 14% despite good adherence and insulin up to 6.7 U/kg/day with elevated C-peptide (3.8 ng/mL). Diabetes autoantibodies were negative on two separate evaluations, her BMI was normal (24 kg/m²). During this period, she also developed severe facial hirsutism, marked acanthosis nigricans, and oligomenorrhea. Evaluation revealed marked hyperandrogenism, with a total testosterone of 462 ng/dL and free testosterone of 23 pg/mL . Pelvic ultrasound and CT showed bilaterally enlarged polycystic ovaries without evidence of a neoplasm, and adrenal imaging was normal. Serum 17-hydroxyprogesterone, DHEA-S, and cortisol levels were normal. She exhibited multiple features consistent with receptor-level insulin resistance seen in TBIRS, including low IGF-1, elevated growth hormone, and normal triglycerides, liver enzymes, sex hormone binding globulin, free fatty acids, and uric acid. Insulin receptor antibodies were subsequently detected, confirming the diagnosis of TBIRS.

TBIRS causes profound hyperinsulinemia, which stimulates ovarian androgen production and can clinically mimic an androgen-secreting tumor. Early recognition is essential, as metabolic improvement depends on immunosuppressive therapy that reduces antibody production. This case underscores the importance of considering TBIRS in young patients with disproportionate insulin resistance and underlying autoimmune disease.

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