Simultaneous occurrence of insulin allergy and immunologic insulin resistance has been reported in a few cases (1). A 62-year-old man with type 2 diabetes, who had been treated with insulin (premixed insulin of 30% aspart and 70% protaminated insulin aspart) for 3 months, noticed urticariform erythema and induration of the skin at the insulin-injection site. Erythema appeared immediately after the injection of insulin and disappeared after ∼20 min, while induration persisted for 3–4 days. HbA1c rose from 8.0 to 10.4% in the next 3 months. The plain chest X-ray film and chest computed tomography revealed a mass with a diameter of 3 cm in the right upper lobe, which was diagnosed as adenocarcinoma of the lung.

His serum insulin level was elevated (912 pmol/l while fasting) due to a high level of IgG anti-insulin antibodies (99.7% bound, reference range <10%). Human insulin–specific IgE, as determined by a radioallergosorbent test (RAST), was also elevated (12.20 UA/ml, RAST class 3, reference range <0.34 UA/ml). Despite injection of insulin aspart before each meal, the blood glucose level increased to 23.1 mmol/l postprandially and declined to 4.9 mmol/l during the night. This daily blood glucose pattern was not improved by the administration of mitiglinide and voglibose instead of insulin. Plasma interleukin (IL)-6 was elevated to 96.4 pg/ml (reference range <4.0 pg/ml). Chemotherapy was performed with carboplatin and docetaxel. As a result, the lung tumor was remarkably reduced in size. Three weeks later, the patient’s blood glucose level ranged from 5.1 to 11.9 mmol/l on therapy with mitiglinide and voglibose. Insulin IgG antibodies (percent bound), fasting serum insulin level, and human insulin-specific IgE antibodies declined to 82%, 305 pmol/l, and 4.67 UA/ml (RAST class 3), respectively. Plasma IL-6 level also fell to 8.0 pg/ml.

Increased serum levels of IL-6 have been reported in patients with lung cancer (2). IL-6 stimulates activated B-cells to induce the production of IgM, IgG, and IgA, as well as potentiates the IL-4–dependent response of IgE (3). IL-6 is also involved in the activation, growth, and differentiation of T-cells (3). In this case, multiple immune responses to insulin, including immediate allergy, delayed cutaneous hypersensitivity, and immunologic insulin resistance, were thought to have occurred as a paraneoplastic syndrome based on IL-6 secretion by lung cancer because chemotherapy resulted in a decrease of tumor size, a decline of plasma IL-6, and a reduction of insulin antibodies.

Ross JM, Murali MR, Delara TC, Cheron RG: Anaphylaxis and immunologic insulin resistance in a diabetic woman with ketoacidosis.
Diabetes Care
Yanagawa H, Sone S, Takahashi Y, Haku T, Shinohara T, Ogura T: Serum levels of interleukin 6 in patients with lung cancer.
Br J Cancer
Akira S, Taga T, Kishimoto T: Interleukin-6 in biology and medicine.
Adv Immunol