SAT-560 - Dangerous Lows after Extreme Highs: Hypoglycemia Unawareness in Type B Insulin Resistance

Background:
Type B insulin resistance (TBIR) is a rare autoimmune disorder caused by insulin receptor autoantibodies, most often associated with systemic lupus erythematosus (SLE). Although classically characterized by extreme insulin resistance and severe hyperglycemia, TBIR may cause recurrent hypoglycemia due to partial agonist antibody activity This creates a high-risk clinical state that is misdiagnosed and may result in dangerous hypoglycemia.

Case Presentation:
A 21-year-old woman with SLE presented with marked hyperglycemia. She was initially diagnosed with type 1 diabetes; however, pancreatic autoantibodies were negative and C-peptide was preserved. Shortly after insulin initiation, she developed recurrent, severe hypoglycemia requiring IV dextrose despite insulin dose reductions. An extensive evaluation excluded adrenal insufficiency, insulinoma, medication induced hypoglycemia, and factitious causes. Given concern for autoimmune mediated insulin resistance, she was referred to the NIH for specialized evaluation and for targeted immunosuppression.

As autoimmune disease activity fluctuated her metabolic phenotype shifted to profound insulin resistance with persistent hyperglycemia. She required escalating insulin doses up to 500 units per day. Despite this, glycemic control remained unstable and was complicated by recurrent hypoglycemia, necessitating stepwise insulin de-escalation and eventual discontinuation.

Following discharge, she remained off insulin yet continued to have frequent hypoglycemia documented by continuous glucose monitoring (CGM), particularly overnight. Importantly, she demonstrated hypoglycemia unawareness, reporting minimal adrenergic and no neuroglycopenic symptoms despite repeated nocturnal hypoglycemia. Family members frequently had to awaken her in response to CGM alarms.

Management has focused on hypoglycemia prevention, including dietary strategies with mixed macronutrient meals, uncooked cornstarch supplementation, cautious carbohydrate correction to maintain glucose levels above 70 mg/dL, and escalation of immunosuppression with corticosteroid pulses followed by maintenance prednisone. Despite these interventions, her hypoglycemic burden remains significant.

Discussion
This case highlights hypoglycemia, particularly hypoglycemia unawareness, as a critical and underrecognized manifestation of TBIR. The striking transition from high insulin requirements to spontaneous hypoglycemia off insulin underscores the need for early recognition of TBIR to avoid inappropriate insulin escalation and to prioritize immunosuppression and aggressive hypoglycemia prevention strategies.

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