Two cases of insulin autoimmune syndrome induced by exogenous insulin in diabetic patients

Abstract Background The exact incidence, clinical features and uniform diagnostic criteria of exogenous insulin autoimmune syndrome (EIAS) are still unclear. The purpose of this study is to explore the clinical characteristics of EIAS and to provide a structural approach for clinical diagnosis, treatment and prevention. Methods The literature on EIAS in Chinese and English from 1970 to 2020 was collected for retrospective analysis. Results A total of 122 patients (33 males and 73 females) were included in the study with a median age of 67 years (range 14–86) and a median HbA1c of 7.7%. EIAS mainly occurred in type 2 diabetes mellitus patients using premixed insulin. Symptoms manifested were hypoglycemia in 86.54%, recurrent episodes of symptomatic hypoglycemia in 35.58%, nocturnal hypoglycemia along with daytime hyperglycemia in 21.15% and recurrent hypoglycemia after discontinued insulin in 64.43%. The onset of symptoms occurred at night, in the early morning or during fasting, ranging from a few days to 78 months after the administration of insulin. The mean blood glucose level during the hypoglycemic phase was 2.21 mmol/L (range 1–3.4), and the serum insulin levels were mainly ≥ 100 U/mL and were associated with low C-peptide levels (≤ 10 ng/ml). Insulin autoantibodies (IAAs) were positive in all EIAS patients. The 75-g extended oral glucose tolerance test (OGTT) mainly showed a diabetic curve. Pancreatic imaging was unremarkable. Withdrawal of insulin alone or combination of oral hypoglycemic agents or replacement of insulin formulations or with corticosteroid treatment eliminated hypoglycemia in a few days to 3 months. IAA turned negative in 6 months (median, range 1–12). No hypoglycemia episodes were observed at a median follow-up of 6 months (range 0.5–60). Conclusions EIAS is an autoimmune disease caused by insulin-binding antibodies in susceptible subjects. Insulin antibodies change glucose dynamics and could increase the incidence of hypoglycemic episodes. Detection of insulin antibodies is the diagnostic test. Changing therapeutic modalities reduced the incidence of hypoglycemic episodes.

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Insulin autoimmune syndrome: a rare cause of spontaneous hypoglycaemia in non-diabetic individuals

BMJ Case Reports ◽

10.1136/bcr-2020-234448 ◽

2020 ◽

Vol 13 (12) ◽

pp. e234448

Author(s):

Shruthi Ravindra ◽

Sahana Shetty

Keyword(s):

Endoscopic Ultrasound ◽

Insulin Autoantibodies ◽

Exogenous Insulin ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Pancreatic Tumour ◽

Biochemical Evaluation ◽

Antibody Levels ◽

Hyperinsulinemic Hypoglycaemia

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycaemia, characterised by recurrent hypoglycaemic episodes secondary to insulin autoantibodies in individuals who are not exposed to exogenous insulin. We are reporting a case of IAS in a 64-year-old gentleman, who presented with predominant postprandial hypoglycaemic episodes. On biochemical evaluation, he was found to have hyperinsulinemic hypoglycaemia. Localisation studies with MRI abdomen and endoscopic ultrasound (EUS) were negative for pancreatic tumour. Tests sent for insulin antibody levels were elevated. The patient was treated with frequent meals, acarbose and glucocorticoids. Patient condition improved and did not experience hypoglycaemia on follow-up.

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Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series

BMC Endocrine Disorders ◽

10.1186/s12902-019-0482-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Yimin Shen ◽

Xiaoxiao Song ◽

Yuezhong Ren

Keyword(s):

Diabetes Mellitus ◽

Case Series ◽

Insulin Injection ◽

Insulin Autoantibodies ◽

Hyperinsulinemic Hypoglycemia ◽

Exogenous Insulin ◽

Case Presentation ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Patients With Diabetes

Abstract Background Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies. Patients with IAS usually complain of hypoglycemia without any previous insulin received. Glucocorticoids and immunosuppressants are used to treat IAS. Case presentation We report four patients with diabetes who were diagnosed with non-classical IAS and describe the treatment of these patients. Moreover, the differential diagnosis with hyperinsulinism is discussed. Conclusion High levels of insulin autoantibodies, as well as hyperinsulinemic hypoglycemia, are found in patients with diabetes mellitus and prior exogenous insulin exposure. This situation that we classified as non-classical IAS should be attached importance to.

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“The Unusual Suspect” - Insulin Autoimmune Syndrome, an Extremely Rare Cause of Hypoglycemia

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.723 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A355-A355

Author(s):

Hassaan B Aftab ◽

Carl D Malchoff

Keyword(s):

Insulin Antibody ◽

Diabetic Patients ◽

High Dose ◽

Blood Draw ◽

Family History Of Diabetes ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Asian Descent ◽

History Of ◽

Antibody Titers

Abstract Background: Insulin autoimmune syndrome (IAS), also called Hirata syndrome, is a rare diagnosis which is characterized by hypoglycemia, normal or elevated fasting insulin level, and elevated anti-insulin antibody titers. Clinical Case: 45-year-old nondiabetic Caucasian female presented to the emergency department (ED) with chief complaint of near-syncope. She reported difficulty concentrating and feeling faint roughly 1 hour after consuming breakfast. Upon ED arrival, fingerstick glucose (FSG) was 47 mg/dL. Her symptoms resolved with ingestion of orange juice and repeat blood glucose (BG) 15 minutes later was 120 mg/dL. She reported similar symptoms in the last 5 years happening “every few months” without a predictable pattern; twice with witnessed loss of consciousness. Workup for syncope in the past included normal neurologic, cardiac, and tilt-table testing. She had no prior low FSG/BG recorded, no personal history of bariatric surgery or family history of diabetes mellitus and no access to antihyperglycemic medications. Past medical history included ulcerative colitis and medications included sulfasalazine and multivitamins. Pertinent review of systems was negative for weight loss, nausea, and diarrhea. Vital signs were within normal limits. Physical exam was unremarkable. Height was 165 cm, weight 67.8 kg and body mass index 24.9 kg/m2. Blood draw after overnight fast revealed BG of 78 mg/dL, C-peptide 0.7 ng/mL (ref range 0.8–3.5), insulin 10 µIU/mL (3–19), proinsulin <1.6 pmol/L (<8.0), insulin-like growth factor-2 (IGF-2) 339 ng/mL (180–580) and insulin antibody level 10.0 U/mL (0.0–0.4). She was managed conservatively with frequent small meals and patient has continued to do well without recurrence of symptoms. Conclusion: IAS is an exceedingly rare disease entity with about 460 cases described in literature, mostly in patients of Asian descent. Workup for hypoglycemia in non-diabetic patients should include insulin antibody titers to rule out IAS. There appears to be a genetic predisposition to developing IAS in patients with major histocompatibility complex (MHC) genes HLA-DQA1, HLA-DQB1 and HLA-DRB1. It is now being more frequently described in patients of non-Asian descent, particularly those with other autoimmune or plasma cell dyscrasias. It is also associated with drugs containing sulfhydryl groups and viral infections. Treatment should be tailored to severity of disease. Most drug induced IAS resolves after cessation of culprit drug. Conservative management is usually the first step with frequent, low carbohydrate meals with diazoxide or octreotide as adjunctive options. Immunosuppression (high-dose prednisolone or rituximab) and plasma exchanged are reserved severe or refractory cases.

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Clinical and Laboratory Aspects of Insulin Autoantibody-Mediated Glycaemic Dysregulation and Hyperinsulinaemic Hypoglycaemia: Insulin Autoimmune Syndrome and Exogenous Insulin Antibody Syndrome

10.33176/aacb-20-00008 ◽

2020 ◽

Vol 41 (3) ◽

pp. 93-102

Author(s):

Tony Huynh

Keyword(s):

Medical Literature ◽

Case Reports ◽

Insulin Antibody ◽

Complex Nature ◽

Exogenous Insulin ◽

Hyperinsulinaemic Hypoglycaemia ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Insulin Autoantibody ◽

Life Threatening

Autoimmune glycaemic dysregulation and hyperinsulinaemic hypoglycaemia mediated by insulin autoantibodies is an increasingly recognised but controversial phenomenon described in both exogenous insulin naïve (insulin autoimmune syndrome) and exposed (exogenous insulin antibody syndrome) individuals. There has been a significant proliferation of case reports, clinical studies and reviews in the medical literature in recent years which have collectively highlighted the discrepancy between experts in the field with regard to the nomenclature, definition, proposed pathophysiology, as well as the clinical and biochemical diagnostic criteria associated with the condition. The essential characteristics of the condition are glycaemic dysregulation manifesting as episodes of hyperglycaemia and unpredictable hyperinsulinaemic hypoglycaemia associated with high titres of endogenous antibodies to insulin. Although the hypoglycaemia is often life-threatening and initiation of targeted therapies critical, the diagnosis is often delayed and attributable to various factors including: the fact that existence of the condition is not universally accepted; the need to exclude surreptitious causes of hypoglycaemia; the diverse and often complex nature of the glycaemic dysregulation; and the challenge of diagnostic confirmation. Once confirmed, the available therapeutic options are expansive and the reported responses to these therapies have been variable. This review will focus on our evolving understanding, and the associated diagnostic challenges – both clinical and laboratory – of this complex condition.

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Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0079 ◽

2016 ◽

Vol 2016 ◽

Cited By ~ 6

Author(s):

Chih-Ting Su ◽

Yi-Chun Lin

Keyword(s):

High Serum ◽

Insulin Antibodies ◽

Insulin Analog ◽

Hyperinsulinemic Hypoglycemia ◽

Oral Glucose ◽

List Type ◽

Exogenous Insulin ◽

C Peptide ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome

Summary Insulin antibodies (IA) associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA) found in insulin autoimmune syndrome (IAS), which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%), high insulin concentration (111.9 IU/mL) and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly. Learning points: Insulin autoimmune syndrome (IAS) or IAS-like situation should be one of the differential diagnosis in patients with hyperinsulinemic hypoglycemia. Although less reported, insulin antibodies (IA) caused by exogenous insulin analog should be considered as the cause of hypoglycemia. Patients with suspected insulin autoimmune syndrome (IAS) should be screened for drugs related to autoimmunity to endogenous insulin.

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Insulin autoimmune syndrome: a rare cause of hypoglycemia. The case report of the syndrome in pediatric practice

Problems of Endocrinology ◽

10.14341/probl2017633189-194 ◽

2017 ◽

Vol 63 (3) ◽

pp. 189-194

Author(s):

Elena S. Kuznetsova ◽

Oxana V. Pilipenko ◽

Maria А. Melikyan

Keyword(s):

Case Report ◽

Genetic Predisposition ◽

Insulin Level ◽

Penicillin G ◽

Exogenous Insulin ◽

Pediatric Practice ◽

The Third ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Caucasian Girl

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia accompanied by an increased insulin level and presence of insulin autoantibodies while no exogenous insulin was used. This disorder is the third leading cause of hypoglycemia in Southeastern Asia. The disorder develops in individuals with a genetic predisposition, mostly after they had administered drugs containing a sulfhydryl moiety, such as methimazole, penicillin g, etc. The syndrome is typical of adults and extremely rare among children. We report the case of developing IAS in a 3.5-year-old Caucasian girl, possibly induced by pyritinol therapy.

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