Insulin injections were stopped for a week, but the hypoglycemic episodes still persisted. During one episode of hypoglycemia, her random blood glucose value measured by glucometer was 23 mg/100mL. At the same time, serum insulin was 94.4 µU/mL (2.6-24.9) and serum C-peptide was <0.3 ng/mL (1.1-4.4). Hypo-glycemia with raised insulin and suppressed C-peptide could be due to the surreptitious use of exogenous insulin [2] or autoimmune hypoglycemia [3]. She was strictly monitored and ensured that she was not taking additional insulin. Insulin antibody levels by ELISA was 13 U/mL (Normal<12 U/mL). Insulin antibody studies by radio ligand assay was 6.8 mg/L (Normal 0-5) (research assay Addenbrooke’s Hospital, Department of Immunology, Cambridge). In the presence of insulin binding antibodies the insulin assay would be highly unreliable, and hence polyethylene glycol precipitation studies were done which showed low insulin recovery further providing indirect evidence for the presence of insulin-binding antibody. Gel filtration chromatography studies done twice on patient’s sample after incubating with insulin regular (Actrapid) showed the presence of high serum immunoreactivity against insulin. (Web Fig. 1 and 2).

The diagnosis of autoimmune hypoglycemia was confirmed and she was started on prednisolone (1mg/kg/day). She did not respond to steroids, and hence four cycles of plasmapheresis were performed. From the second cycle, her hypoglycemic episodes stopped. She was kept in observation in our ward for one more week after the completion of the plasmapheresis to ensure that she does not develop any hypoglycemic episode. Her repeat insulin antibody titer by ELISA one month after admission was 6 U/mL. She was discharged on basal bolus insulin regimen and for the past 18 months she is under our follow-up taking her usual regimen of insulin with no episode of hypoglycemia.

Antibodies to exogenous insulin, though common, rarely ever cause disturbances in glycemic control. These antibodies are commonly of IgG type, though IgE antibodies too have been described. The exact incidence of symptomatic hypoglycemia caused by the presence of antibodies to exogenous insulin is not known, with the published literature being in form of single case reports till now. Antibodies to insulin receptor may lead to a syndrome of extreme insulin resistance. These antibodies usually act as antagonist at the insulin receptor thereby causing insulin resistance and hyperglycemia. Rarely, these antibodies can act as agonist at the insulin receptor and cause symptomatic hypoglycemia [3]. Certain drugs like methimazole and alpha lipoic acid can also lead to the formation of antibodies to endogenous insulin in patients without prior exposure to exogenous insulin. When these antibodies to endogenous insulin cause symptomatic hypoglycemia it is called Hirata’s disease or Insulin Autoimmune syndrome, occurring predominantly in Japan [3]. Symptomatic hypoglycemia in a 72-year-old male due to antibody to insulin precipitated by pantoprazole has been earlier reported from India [4]. Our patient was not on any drug other than insulin.

The mechanism by which these antibodies against exogenous insulin cause clinical symptoms depend on their binding characteristics. Antibodies with high binding capacity and low affinity, bind the insulin and release the insulin at odd times with no relation to food intake resulting in unpredictable episodes of hypoglycemia [5]. Treatment options include prednisolone, plasmapheresis, rituximab, mycophenolate mofetil and immunoglobulin infusion [6]. In conclusion, hypoglycemia in a diabetic patient on insulin needs a careful stepwise approach to diagnosis, and merely titrating the dose of insulin to avoid hypoglycemia might not be enough.

Acknowledgements: David Church and RK Semple, Addenbrooke’s Hospital, NHS, UK for help in processing the samples.

Contributors: All authors were involved in all aspects of the manuscript.

Funding: None; Competing interests: None stated.

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