A 45-year-old Caucasian woman presented with weight loss of 20 kg over 9 months and acanthosis nigricans of her face and lumbar and groin areas (A). One year earlier, diabetes mellitus had been diagnosed. The initial treatment with metformin and sitagliptin was unsuccessful. Plasma glucose levels (500 mg/dl) and glycated hemoglobin (HbA1c, 11.3%) were high. Intensive conventional insulin therapy and administration of 600 IU/d via insulin pump failed to achieve acceptable blood glucose levels. At admission, her body mass index was only 18 kg/m2. We initiated continuous iv insulin. To achieve blood glucose levels of approximately 300 mg/dL, approximately 6 IU/h were required. After administering insulin iv for 72 hours, we started an intensive conventional insulin therapy plan (isophan insulin [NPH; Protaphane, Novo Nordisk Pharma GmbH] 50–50–50 IU, Insulin human rDNS [NovoRapid, Novo Nordisk Pharma GmbH] 26–34–34 IU, plus correction with a factor of 1:15, with a blood glucose target of 90–120 mg/dL). Extensive examination failed to reveal any (para)neoplastic cause for the weight loss and insulin resistance. We considered the possibility of type B insulin resistance syndrome because of acanthosis nigricans combined with weight loss and elevated serum markers of autoimmunity, especially anti-Sjögren's-syndrome-related antigen A and antiribosomal P protein (). However, an initial insulin receptor antibody assay was negative. Finally, an immunoprecipitation assay was strongly positive for anti-insulin-receptor antibodies (A), confirming the diagnosis of type B insulin resistance. Neither Ig iv (Intratect 20 g/d; Biotest Pharma GmbH) over 6 days nor plasmapheresis (five times in 14 d) improved her blood glucose or allowed reduction of the daily insulin dose. We therefore started the patient on a combination protocol of rituximab (750 mg/m2 in two doses 2 wk apart), cyclophosphamide (100 mg/d orally, continuously), and dexamethasone (40 mg/d for 4 days every month), in accordance with the NIH protocol (B) (), which was well tolerated. B cells were depleted already 2 weeks after the first rituximab application but returned to almost normal levels 4 months later without relapse (B). Cyclophosphamide was temporarily withdrawn due to low white blood cells. No other major side effects were reported. Over the next 2 months, her daily insulin doses could be reduced to 30 IU/d, already indicating a response to therapy. The patient's well-being greatly improved. Fasting glucose levels ranged from 80 to 110 mg/dL, and the HbA1c decreased from 11.8 to 9.9%. Four months after her initial rituximab dose, insulin treatment could be withdrawn completely, and blood glucose levels remained within the normal range from 66 to 107 mg/dL. HbA1c continued to decrease to 6.5% (B). The acanthosis nigricans improved (B). Congruent with the complete clinical remission, insulin receptor autoantibodies were now negative (A). We therefore discontinued cyclophosphamide and dexamethasone and started her on a maintenance regime with azathioprine 100 mg daily for 1 year. Azathioprine was chosen because of the experience with this immunosuppressive drug in systemic lupus erythematosus and because many type B insulin resistance patients are positive for lupus-associated antibodies, including our patient. She has been in remission since then (B).