A Novel Type of Extreme Insulin Resistance: Nonhypoglycemic Insulin Autoimmune Syndrome

Context Extreme insulin resistance is caused by genetic defects intersecting with the insulin action pathway or by the insulin receptor antibodies. Insulin autoimmune syndrome (IAS) is not considered one of the causes of extreme insulin resistance. Objective This work aimed to expand the current knowledge of extreme insulin resistance and to propose the diagnostic criteria and management strategy of a novel type of extreme insulin resistance. Methods A patient with IAS never experienced hypoglycemia but had persistent hyperglycemia and extreme insulin resistance with treatment with 200 U of intravenous insulin per day. Immunoreactive insulin (IRI), free insulin, and total insulin were measured. The ratio of free insulin to total insulin (insulin-free ratio, IFR) was calculated. Results Extreme insulin resistance has not been reported to be caused by IAS. At admission, IRI and free insulin were undetectable in our patient; total insulin was more than 20 160 pmol/L; and the IFR was lower than 0.03% (control, 90.9%). After adding 500 U porcine insulin to the precipitate containing insulin antibodies, the IRI was still undetectable. Since the patient started glucocorticoid therapy, the free insulin has gradually increased to 11.16 pmol/L, his total insulin has decreased to 5040 pmol/L, and the IFR has increased to 18.26%. Intravenous insulin was stopped, with good glycemic control. Conclusion High-affinity insulin autoantibodies with a large capacity can induce a novel type of extreme insulin resistance characterized by extremely high total insulin and very low free insulin levels. The IFR can be used to evaluate therapeutic effects.

SAT-LB116 Extreme Insulin Resistance: The Diagnostic Challenges When Cost Is a Limitation

Introduction: Insulin resistance occurs most commonly in association with obesity but may result from multiple causes, e.g. medications, lipodystrophy, or antibodies to insulin or insulin receptors. We review a case of an unusual presentation of insulin resistance. We highlight challenges of diagnostic testing and treatment when there are cost limitations. Clinical Case:A 41 year old Hispanic male with T2DM and a history of well-controlled BPD on quetiapine only presents for management of diabetes. His current treatment is metformin and a TDD of 170 U human insulin; A1C is 12.2%. He was diagnosed at age 32 via routine lab tests. At diagnosis BW was 96.4 kg, BMI 29, BP 100/70, CHOL 152, TG 247, HDL 35, LDL 68. Physical exam was unremarkable without acanthosis or lipodystrophy. Anti-GAD, anti-islet cell antibodies, insulin and C-peptide levels were ordered, but not obtained due to cost. He was managed with lifestyle modification for 2 years with maintenance of A1C <7%. At age 35 he developed symptomatic hyperglycemia with A1C 9.4% and was started on metformin and glyburide. At age 36 A1C was >11%, with no change in BW. Glargine 5 U was added, and glyburide was changed to glipizide. Glargine was increased to 40 U without changes in glycemia. At age 37 glipizide was stopped, and he could not afford glargine. He was switched to 70/30 human insulin. Insulin dosages were progressively increased to 220 U a day with no change in glycemia. Liraglutide was tried but not continued due to cost, and quetiapine was switched to trazodone without improvement in A1C. LFTs, CBC, HIV, Hepatitis C and B have been negative. The patient has had multiple visits for education with documented adequate disease understanding and performance of injections. Nonadherence was suspected; for its evaluation, the patient was observed in clinic self-injecting 30 U of regular insulin (brought from home); fasting was confirmed for 3hrs post-injection. BG was 327mg/dL pre-injection and 326mg/dL 3hrs post-injection. Insulin antibodies were requested but not obtained due to cost. Insulin receptor antibodies are not commercially available in the US. Potential empiric strategies, e.g. the NIH protocol for insulin type B resistance (rituximab + dexamethasone + cyclophosphamide) was considered but cost is a limitation. We discussed steroids or methotrexate for possible antibody mediated insulin resistance versus a trial of thiazolidinedione, which has been reported to decrease severe insulin resistance in patients with lipodystrophy. The patient opted to initially try a thiazolidinedione. Conclusion:Although poor adherence has not been excluded, the patient appears to have no response to high doses of injected human insulin, suggesting extreme insulin resistance. Cost limitations preclude optimal diagnostic evaluation. Empiric treatment with low cost options potentially may provide diagnostic information as well as efficacious treatment.

Diabetes Mellitus, Extreme Insulin Resistance, and Hypothalamic-Pituitary Langerhans Cells Histiocytosis

Background. Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm characterized by an infiltration of organs by Langerin + (CD207+) and CD1a+ histiocytes. Diabetes insipidus is a frequent manifestation of the disease, while diabetes mellitus is very rare. We report the first case of a 20-year-old man suffering from hypothalamopituitary histiocytosis and diabetes mellitus with serum anti-insulin receptor antibodies. Case Presentation. A 20-year-old patient was admitted for the evaluation of growth delay and hyperphagia. HbA1c level and fasting blood glucose were in the normal range. The diagnosis of hypothalamopituitary histiocytosis was based on histological features after biopsy of a large suprachiasmatic lesion identified on magnetic resonance imaging (MRI). Association of vinblastine and purinethol was started followed by a second-line therapy by cladribine. During the follow-up, the patient was admitted for recurrence of hyperglycemic states and extreme insulin resistance. The screening for serum anti-insulin receptor antibodies was positive. Each episode of hyperglycemia appeared to be correlated with tumoral activity and increase in serum anti-insulin receptor antibodies and appeared to be improved when the disease was controlled by chemotherapy. Conclusion. We report the first description of a hypothalamopituitary histiocytosis associated with serum anti-insulin receptor antibodies, extreme insulin resistance, and diabetes. Parallel evolution of glucose levels and serum anti-insulin receptor antibodies seemed to be the consequence of immune suppressive properties of cladribine.