A 56 year-old Hispanic male with hypertension and a 10-year history of diabetes was hospitalized for abrupt worsening of glycemic control and diabetic ketoacidosis (DKA). His diabetes was initially managed on metformin and sitagliptin, with insulin added six years after diagnosis. His glycemic control had been stable with home self-monitored blood glucoses (SMBG) averaging around 160 mg/dL, however there was an abrupt rise in SMBG to around 400 mg/dL starting six months prior to presentation. After hospitalization at another institution two months prior for DKA, he was discharged on detemir insulin 20 units every morning, detemir insulin 40 units every evening, and aspart insulin 15 units before each meal.
He presented to our emergency department with 18-kg weight loss, initial blood glucose 427 mg/dL, and a hemoglobin A1c 12.4% (112 mmol/mol) with bicarbonate 15 mmol/L (20-30 mmol/L), anion gap 18, moderate serum ketones, and 2+ urine ketones. On physical exam he weighed 57.9 kg, with a BMI of 24.93 kg/m2. He was normotensive with regular heart rate. No acanthosis nigricans, dorsoclavicular fat pad, abdominal striae, or skin lesions were present. He was started on intravenous regular insulin infusion. Despite prompt normalization of the metabolic acidosis, he continued to have markedly high insulin needs to keep serum glucose levels between 150-250 mg/dL. The peak insulin infusion rate was 2,526 units/24 hours (Figure 1). There was no meaningful reduction in daily insulin requirements that occurred with the addition of metformin 500 mg oral twice daily or concentrated U-500 regular insulin (up to 300 units before each meal). Adiponectin level was normal at 18 mcg/mL (4-20 mcg/mL) with intact C-peptide of 3.0 ng/mL (1.1-4.3 ng/mL) and concomitant serum glucose level of 226 mg/dL. He was diagnosed with antibody-mediated insulin resistance with evidence of elevated insulin antibody levels (12.4 U/mL, normal range 0.0-0.4 U/mL). No commercial assay was available to measure the insulin receptor antibody level. Despite being unable to confirm the presence of insulin receptor antibodies, the decision was made to initiate the NIH treatment protocol for Type B insulin resistance, which includes rituximab, dexamethasone, and cyclophosphamide. Evaluation for malignancy, rheumatologic disease, and infection was performed prior to initiating immunosuppression. Computed tomography (CT) of the chest, abdomen, and pelvis was negative for malignancy. Serum and urine protein electrophoresis was negative for monoclonal gammopathy, and flow cytometry was negative for lymphoproliferation. Prostate specific antigen was normal at 0.44 ng/mL (0-3.5 ng/mL). Autoimmune workup revealed mildly elevated antinuclear antibody titer (1 : 80, normal <1 : 40) and double stranded DNA antibody level (220 IU/mL, normal <=200 IU/mL) but was otherwise unremarkable (negative for glutamic acid decarboxylase-65, thyroid peroxidase, SSA, SSB, smith, smooth muscle, centromere B, cyclic citrulline, RNP, scleroderma, and Jo 1 antibodies). Infectious workup revealed positive Mycobacterium tuberculosis Quantiferon-GOLD TB-Nil > 10 IU/mL (positive >=0.35 IU/mL), but subsequent acid-fast culture and stain and respiratory Mycobacterium tuberculosis PCR were negative. CT of the chest did not show evidence of active tuberculosis. Remaining infectious disease studies were negative (Hepatitis B core Ig, Hepatitis B surface antigen, Hepatitis C antibody, Hepatitis A IgM, HIV-1/2 Ag/Ab, strongyloides IgG, coccidioides IgG/IgM, and urine histoplasma antigen). After initiation of treatment for latent tuberculosis with isoniazid and pyridoxine, he underwent cycle 1 of the NIH immunomodulatory protocol with marked reduction in daily insulin requirements (Figure 1). Pioglitazone 45 mg daily was then initiated. One month following two treatment cycles, insulin therapy was discontinued and blood glucose levels were controlled on metformin and pioglitazone alone (Figure 1).