Abstract
Exogenous insulin can induce insulin antibodies that have a low affinity/high binding capacity. Similar to what is observed in insulin autoimmune syndrome, these insulin antibodies can cause fasting hypoglycemia and postprandial hyperglycemia, a phenomenon known as “exogenous insulin antibody syndrome” (EIAS). Cases of EIAS in patients with type 1 and type 2 diabetes have been sporadically reported, mainly in Asia. However, there has been no report on EIAS in patients with diabetes secondary to total pancreatectomy treated with insulin analogs. A 74-year-old man with diabetes after total pancreatectomy had been treated with continuous subcutaneous insulin infusion using an insulin analog, lispro, and developed recurrent early morning hypoglycemia even after discontinuation of nocturnal basal insulin. His fasting serum lispro level was high even approximately 9 h after the last lispro dose. He had a high titer (72.7%) of insulin antibodies, and a Scatchard analysis revealed low affinity/high binding capacity. These findings suggested that the patient’s recurrent early morning hypoglycemia was associated with insulin antibodies against lispro, and we, therefore, switched from lispro to another insulin analog, glulisine. His hypoglycemia improved, accompanied by a dramatic decrease in his insulin antibodies and serum glulisine levels. Early morning hypoglycemia in patients with diabetes secondary to total pancreatectomy may often be explained by high glycemic variability, malnutrition, and/or glucagon deficiency. However, in cases of recurrent early morning hypoglycemia, EIAS should be considered as a potential differential diagnosis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
References
Hirata Y, Ishizu H. Elevated insulin-binding capacity of serum proteins in a case with spontaneous hypoglycemia and mild diabetes not treated with insulin. Tohoku J Exp Med. 1972;107:277–86.
Censi S, Mian C, Betterle C. Insulin autoimmune syndrome: from diagnosis to clinical management. Ann Transl Med. 2018;6:335.
Hu X, Chen F. Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients. Endocr Connect. 2018;7:R47-55.
Huynh T. Clinical and laboratory aspects of insulin autoantibody-mediated glycaemic dysregulation and hyperinsulinaemic hypoglycaemia: insulin autoimmune syndrome and exogenous insulin antibody syndrome. Clin Biochem Rev. 2020;41:93–102.
Matsuyoshi A, Shimoda S, Tsuruzoe K, Taketa K, Chirioka T, Sakamoto F, et al. A case of slowly progressive type 1 diabetes with unstable glycemic control caused by unusual insulin antibody and successfully treated with steroid therapy. Diabetes Res Clin Pract. 2006;72:238–43.
Honda M, Kawashima Y, Kawamura H, Fujikawa H, Kikuchi K, Ohashi H, et al. Acute liver dysfunction complicated with uncontrollable glycemia due to insulin antibody: successful treatment with glucocorticoid and lispro insulin. Intern Med. 2006;45:1225–9.
Ishizuka T, Ogawa S, Mori T, Nako K, Nakamichi T, Oka Y, et al. Characteristics of the antibodies of two patients who developed daytime hyperglycemia and morning hypoglycemia because of insulin antibodies. Diabetes Res Clin Pract. 2009;84:e21–3.
Kawamura R, Miyao S, Onuma H, Uchigata Y, Kawasaki E, Ohashi J, et al. Recurrent hypoglycemia due to a high titer of insulin antibody in response to exogenous insulin administration in two cases of type 1 diabetes. Intern Med. 2022;61:687–95.
Hu X, Ma X, Wang X, Zhao X, Xu X, Gong H, et al. Insulin antibodies in patients with type 2 diabetic receiving recombinant human insulin injection: a report of 12 cases. Ann Endocrinol (Paris). 2015;76:694–7.
Hayashi A, Takano K, Kawai S, Shichiri M. SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies. Endocr J. 2016;63:187–91.
Tamura Y, Kimbara Y, Funatsuki S, Mabuchi S, Kodera R, Yoshimoto A, et al. A case of insulin antibody-induced glucose instability in an elderly woman with type 2 diabetes on hemodialysis, successfully ameliorated with liraglutide. Diabetol Int. 2013;4:71–5.
Kaneko K, Satake C, Izumi T, Tanaka M, Yamamoto J, Asai Y, et al. Enhancement of postprandial endogenous insulin secretion rather than exogenous insulin injection ameliorated insulin antibody-induced unstable diabetes: a case report. BMC Endocr Disord. 2019;19:5.
Asai M, Kodera T, Ishizeki K, Uebori S, Kashiwaya T, Itoh H, et al. Insulin lispro reduces insulin antibodies in a patient with type 2 diabetes with immunological insulin resistance. Diabetes Res Clin Pract. 2003;61:89–92.
Itoh A, Saisho Y, Mitsuishi M, Oikawa Y, Kawai T, Tanaka M, et al. Insulin glulisine may ameliorate nocturnal hypoglycemia related to insulin antibody–a case report. Diabetes Res Clin Pract. 2011;94:e53-4 (discussion e5).
Niwano F, Hiromine Y, Noso S, Babaya N, Ito H, Yasutake S, et al. Insulin deficiency with and without glucagon: a comparative study between total pancreatectomy and type 1 diabetes. J Diabetes Investig. 2018;9:1084–90.
Heurtault B, Reix N, Meyer N, Gasser F, Wendling MJ, Ratomponirina C, et al. Extensive study of human insulin immunoassays: promises and pitfalls for insulin analogue detection and quantification. Clin Chem Lab Med. 2014;52:355–62.
Eguchi Y, Uchigata Y, Yao K, Yokoyama H, Hirata Y, Omori Y. Longitudinal changes of serum insulin concentration and insulin antibody features in persistent insulin autoimmune syndrome (Hirata’s disease). Autoimmunity. 1994;19:279–84.
Heise T, Linnebjerg H, Coutant D, LaBell E, Zijlstra E, Kapitza C, et al. Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: a phase 1 randomized, crossover study. Diabetes Obes Metab. 2020;22:1789–98.
Eguchi Y. Scatchard analysis of insulin autoantibodies in the insulin autoimmune syndrome (in Japanese). J Tokyo Women Med Coll. 1989;59:1296–305.
Yoshida R, Ohkubo K, Akehi Y, Harada S, Shinohara K, Kawashima H, et al. Clinical application of the different cross-reactivities of anti-insulin antibodies to insulin lispro to evaluate endogenous insulin secretion. Clin Chim Acta. 2013;415:250–4.
Fineberg SE, Huang J, Brunelle R, Gulliya KS, Anderson JH Jr. Effect of long-term exposure to insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes. Diabetes Care. 2003;26:89–96.
Yanai H, Adachi H, Hamasaki H. Diabetic ketosis caused by the insulin analog aspart-induced anti-insulin antibody: successful treatment with the newest insulin analog glulisine. Diabetes Care. 2011;34: e108.
Ozaki N, Oiso Y. Immunologic tolerance to the insulin analogue glulisine. Diabetes Care. 2010;33: e39.
Becker RH, Frick AD. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet. 2008;47:7–20.
Uchigata Y, Kuwata S, Tokunaga K, Eguchi Y, Takayama-Hasumi S, Miyamoto M, et al. Strong association of insulin autoimmune syndrome with HLA-DR4. Lancet. 1992;339:393–4.
Li Z, Yi D, Zheng L, Li S, Fang W, Wang C. Analysis of the clinical characteristics of insulin autoimmune syndrome induced by exogenous insulin in diabetic patients. Diabetol Metab Syndr. 2021;13:38.
Acknowledgements
The authors wish to thank Tosoh, Co., Japan, for their assistance in measuring the serum IRI levels using the ST AIA-PACK IRI.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Compliance with ethical standards
This article does not contain any studies with human or animal subjects performed by any of the authors. The patient provided written informed consent for the publication of this case report.
Conflict of interest
TY received lecture fees from Eli Lilly Japan K.K. The other authors declare that they have no competing interests associated with this case report.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Obata, Y., Takayama, K., Nishikubo, H. et al. Exogenous insulin antibody syndrome in a patient with diabetes secondary to total pancreatectomy. Diabetol Int 14, 211–216 (2023). https://doi.org/10.1007/s13340-022-00611-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13340-022-00611-z