Insulin Resistance Caused by Insulin Antibodies

Insulin antibodies are seen in two conditions: 1, in insulin-naïve type-1 diabetic patients, insulin antibodies are developed together with some other autoantibodies against pancreatic islet cells; 2, in patients being treated with insulin, antibodies can be developed against exogenous insulins, in both type-1 and type-2 diabetes. These antibodies against exogenous insulins are found in >95% of patients treated with porcine and bovine insulins (1). Although the prevalence has decreased after the introduction of human insulin and insulin analogues, it is still not uncommon to detect these antibodies in insulin treated patients (2). However, these antibodies are rarely of clinical significance and laboratory test for insulin antibodies in insulin-treated patients has limited clinical value, except in rare cases where these antibodies are found to have immunologic role, causing insulin resistance. In some of these cases, postprandial hyperglycemia and nighttime hypoglycemia are both described due to reversible binding of insulin from antibodies (3), and patients were reported to respond to immunosuppressive therapies, and plasmapheresis in severe cases. 

We recently worked up a case for possible immunologic insulin resistance caused by insulin antibodies. In this case, patient is a 45 years old female with uncontrolled type-1 diabetes. She was found to have all four antibodies positive, including zinc transporter 8, islet antigens glutamate decarboxylase 65 (GADA), IA-2A, and insulin antibodies. Patient has been on multiple dose insulin injection (MDI) therapy, including insulin determir, aspart and lispro. She was reported to be compliant with medications and low carb diet. However, patient has poor glycemic control and presents with recurrent diabetic ketoacidosis. She was given high doses of insulins, but still presented with recurrent DKA and occasional hypoglycemia. Her HbA1c was consistently at >10% with daily glucose measured up to 500 mg/dL.

Immunologic insulin antibody and insulin receptor antibody were considered after ruling out more common causes of her uncontrolled diabetes. These two tests were then performed at a reference laboratory and patient was found to have positive insulin antibodies to analog insulin (determir and lispro) and negative insulin receptor antibodies. Significant insulin resistance by insulin antibodies was not found and the antibodies level did not suggest immunosuppressive therapy. Still, given her poor controlled diabetes, patient’s insulin was switched to human insulin and she was also recommend for pancreas transplant.

  1. Greenfield JR, Tuthill A, Soos MA, Semple RK, Halsall DJ, Chaudhry A, O’Rahilly S. Severe insulin resistance due to anti-insulin antibodies: response to plasma exchange and immunosuppressive therapy. Diabet Med. 2009 Jan;26(1):79-82. doi: 10.1111/j.1464-5491.2008.02621.x.
  2. Hall TR, Thomas JW, Padoa CJ, Torn C, Landin-Olsson M, Ortqvist E, Hampe CS. Longitudinal epitope analysis of insulin-binding antibodies in type 1 diabetes. Clin Exp Immunol. 2006 Oct;146(1):9-14.
  3. Hao JB, Imam S, Dar P, Alfonso-Jaume M, Elnagar N, Jaume JC. Extreme Insulin Resistance From Insulin Antibodies (Not Insulin Receptor Antibodies) Successfully Treated With Combination Immunosuppressive Therapy. Diabetes Care. 2017 Feb;40(2):e19-e20. doi: 10.2337/dc16-1975. Epub 2016 Dec 1.
Xin-small

-Xin Yi, PhD, DABCC, FACB, is a board-certified clinical chemist, currently serving as the Co-director of Clinical Chemistry at Houston Methodist Hospital in Houston, TX and an Assistant Professor of Clinical Pathology and Laboratory Medicine at Weill Cornell Medical College.

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