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CC BY 4.0 · Journal of Diabetes and Endocrine Practice
DOI: 10.1055/s-0045-1812873
Case Report

Alpha-Lipoic Acid (ALA)-Related Insulin Autoimmune Syndrome

Authors

  • Hala Shahrour

    1   Department of Internal Medicine, Tawam & STMC Hospitals, Pure Health, Al Ain, United Arab Emirates

  • Mohamed Alqedra

    1   Department of Internal Medicine, Tawam & STMC Hospitals, Pure Health, Al Ain, United Arab Emirates

  • Raya Almazrouei 

    2   Division of Endocrinology, Department of Internal Medicine, Tawam & STMC Hospitals, Pure Health, Al Ain, United Arab Emirates
    3   Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain. United Arab Emirates

Funding and Sponsorship This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Abstract

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by autoantibodies against endogenous insulin, often triggered by sulfhydryl-containing compounds such as alpha-lipoic acid (ALA). We report the case of a 43-year-old previously healthy woman who presented with recurrent fasting and postprandial hypoglycemia. Biochemical evaluation revealed inappropriately elevated insulin and C-peptide levels with negative sulfonylurea screen and no pancreatic lesion on imaging. Further history uncovered recent use of ALA, and markedly elevated insulin autoantibodies confirmed the diagnosis of ALA-induced IAS. Discontinuation of the supplement and dietary modification led to complete resolution of symptoms. This case highlights the importance of considering IAS in the differential diagnosis of unexplained hypoglycemia and underscores the need for detailed medication and supplement history.


Keywords

insulin autoimmune syndrome - hypoglycemia - alpha-lipoic acid - insulin autoantibodies - drug-induced autoimmunity

Introduction

Insulin autoimmune syndrome (IAS), also known as Hirata's disease, is a rare autoimmune disorder first described by Hirata in 1970. It is characterized by the spontaneous development of insulin autoantibodies (IAAs) leading to episodes of hypoglycemia, markedly elevated insulin concentrations, and the absence of pancreatic islet cell pathology or prior exposure to exogenous insulin.[1]

Clinically, patients typically present with Whipple's triad: first, symptoms and signs of hypoglycemia, including autonomic manifestations (tremor, palpitations, anxiety, sweating, hunger, and sensory disturbances, largely attributable to sympathetic activation) and neuroglycopenic manifestations (cognitive impairment, behavioral changes, psychomotor dysfunction, seizures, or even coma when blood glucose concentrations fall significantly); second, documented blood glucose < 2.8 mmol/L during the symptomatic episode; and third, prompt resolution of symptoms following glucose administration or other glucose-raising therapies.[2]

IAS is frequently associated with other autoimmune disorders, with approximately 80% of cases occurring in patients with concurrent autoimmune diseases, most commonly Graves' disease, but also systemic lupus erythematosus, rheumatoid arthritis, and chronic hepatitis.[2] Among the proposed etiological factors, certain medications—particularly those containing sulfhydryl groups—have been strongly implicated in the pathogenesis of IAS. Notably, methimazole and alpha-lipoic acid (ALA) have been reported as common pharmacological triggers. ALA, widely prescribed for the treatment of diabetic peripheral neuropathy, was first recognized as a potential cause of IAS in Japan in 2003.[1]

Here, we report the case of a previously healthy woman who developed IAS shortly after initiating over-the-counter ALA supplementation for neuropathic symptoms. Discontinuation of the supplement resulted in resolution of hypoglycemia. This case underscores the importance of considering drug-induced autoimmune syndromes in the differential diagnosis of unexplained hypoglycemia.


Case Presentation

A 43-year-old Filipino woman with no significant past medical history presented to the emergency department with a 1-week history of recurrent hypoglycemia. She described episodes of dizziness, unsteadiness during ambulation, and diaphoresis, but denied syncope or falls. Hypoglycemic events occurred in both fasting and postprandial states, and multiple capillary glucose readings obtained at her workplace consistently ranged from 1.7 to 2.8 mmol/L. She initially sought care at another hospital, where she was treated with intravenous glucose and discharged; however, as her symptoms persisted, she presented to our institution for further evaluation. Five weeks before presentation, she had undergone accessory navicular bone excision with tibialis posterior tendon advancement on her right foot. She denied the use of insulin, oral hypoglycemic agents, or other prescribed medications.

On admission, her vital signs were stable and her body mass index was 29.6 kg/m2. Abdominal examination revealed no organomegaly and normal bowel sounds, and the remainder of the systemic examination was unremarkable. A supervised 72-hour fasting test was initiated ([Table 1]). At a plasma glucose level of 2.7 mmol/L, both insulin and C-peptide concentrations (The Roche Elecsys platform) were found to be inappropriately elevated, while a urine sulfonylurea screen was negative, thereby excluding exogenous insulin or sulfonylurea use. Cross-sectional imaging with contrast-enhanced abdominal computed tomography demonstrated no pancreatic mass or intra-abdominal abnormality. IAA testing revealed markedly elevated titers, strongly supporting the diagnosis of IAS.

Table 1

Results of supervised 72-hour fasting test

Test

Result

Normal range

Plasma glucose

2.7

3.9–6.1 mmol/L

C-peptide level

0.77

≥ 0.26 nmol/L

Insulin level

258.2

2–25 mIU/L

Proinsulin level

7.3

3.6–22 pmol/L

Beta-hydroxybutyrate

1.3

< 0.4 mmol/L

Cortisol

533

63–536 nmol/L

Insulin antibodies

99.16 COI (reactive)

< 0.9 COI (nonreactive)

Abbreviation: COI, cutoff index.


Further discussion with the patient regarding recent medication exposures uncovered that, following her recent orthopaedic surgery, she had been prescribed ALA 600 mg twice daily for 1 month (she presented 5 weeks postsurgery). Given the well-described association between sulfhydryl-containing compounds and IAS, a diagnosis of ALA-induced IAS was established. The supplement was discontinued, and she was advised on dietary modifications including frequent small meals, avoidance of simple sugars, and a preference for complex carbohydrates. At subsequent follow-up, she remained asymptomatic and home glucose monitoring confirmed normoglycemia with no recurrence of hypoglycemia. Unfortunately, insulin antibody titter was not repeated due to financial issue.


Discussion

Several case reports and series have described presentations similar to our patient's, where ALA was identified as the precipitating factor for IAS. In a review by Uchigata et al, drug-induced IAS accounted for up to 70% of reported cases, with ALA emerging as a predominant trigger, particularly in nondiabetic individuals.[2] Chang et al subsequently reported a case of ALA-induced IAS in a Korean patient, underscoring that this condition extends beyond the Japanese population where it was first described.[3] More recently, more documented cases from India confirmed ALA-induced IAS, further expanding the spectrum of affected ethnicities.[4] [5] [Table 2] depicts the causes of hypoglycemia in general, along with the specific triggers for IAS.

Table 2

Differential diagnosis of hypoglycemia with common triggers of insulin autoimmune syndrome (IAS)

Category

Main causes/Examples

Key clues/Common triggers (for IAS)

Endogenous hyperinsulinism

Insulinoma; Non-insulinoma pancreatogenous hypoglycemia (NIPHS); Congenital hyperinsulinism

High insulin + C-peptide during hypoglycemia; pancreatic lesion or genetic defect

Autoimmune

Insulin autoimmune syndrome (IAS); Exogenous insulin antibody syndrome (EIAS); Type B insulin-resistance syndrome

Very high insulin (> 100 µIU/mL), insulin:C-peptide ratio > 1, positive insulin or insulin-receptor antibodies

Drug-induced

Sulfonylureas, meglitinides, surreptitious insulin

High insulin with high (secretagogues) or low (insulin) C-peptide; positive drug screen

Hormonal deficiency (adrenal and pituitary)

Primary adrenal insufficiency (Addison); Secondary adrenal insufficiency (pituitary disease, steroid withdrawal); Severe hypothyroidism

Low cortisol ± abnormal ACTH; other pituitary hormone deficits

Critical illness/organ failure

Severe liver failure, end-stage renal disease

Low insulin and C-peptide; abnormal liver/renal function

Nonislet cell tumors

IGF-2–secreting tumors (e.g., hepatic, mesenchymal)

Suppressed insulin and C-peptide, high IGF-2

Postsurgical/alimentary

Post-bariatric surgery (dumping)

Postmeal hypoglycemia after gastric bypass

Other

Alcohol excess, inborn errors of metabolism

History of alcohol use or metabolic defect

Common IAS triggers

Drugs: Antithyroid (methimazole, carbimazole, propylthiouracil); Supplements (α-lipoic acid, glutathione, methionine, pyrithione); Cardiovascular (clopidogrel, captopril, hydralazine, procainamide, diltiazem); Proton-pump inhibitors (pantoprazole, omeprazole); Others (loxoprofen, corticosteroids, imipenem, isoniazid, glimepiride, tofacitinib, albumin preparations, penicillamine, α-interferon). Viral infections: mumps, Rubella, Coxsackie B, hepatitis C, varicella-zoster, measles, COVID-19

Abbreviations: ACTH, adrenocorticotropic hormone; COVID-19, coronavirus disease 2019; IGF-2, insulin-like growth factor 2.


In IAS, blood glucose fluctuations stem from the formation of insulin–autoantibody complexes. During fasting, when circulating insulin is low, most IAAs remain unbound. After a meal, rising glucose stimulates pancreatic β-cells to secrete insulin, which binds to IAAs, forming complexes that impair insulin clearance and action, causing postprandial hyperglycemia. As glucose levels fall and insulin secretion decreases, the low-affinity antibodies gradually release their bound insulin, triggering delayed hypoglycemia. This dynamic explains the characteristic alternation of hyperglycemia and recurrent hypoglycemia, sometimes with impaired glucose tolerance or diabetes. The severity and timing of hypoglycemia depend on the antibodies' dissociation rate, titer, and intrinsic affinity. Notably, insulin binding to IAAs occurs independently of blood glucose, underpinning the unpredictable glycemic swings seen in IAS.[6]

Additionally, IAS has a strong association with specific human leukocyte antigen (HLA) subtypes, particularly HLA-DRB104:06, DQB103:02, DQA103:01, DRB104:15, and DRB1*13:01, which may confer susceptibility to the syndrome.[7]

Patients with IAS typically present with markedly elevated serum insulin concentrations—often exceeding 100 μIU/mL—accompanied by increased C-peptide and proinsulin levels. A characteristic feature is the discordance between insulin and C-peptide or proinsulin, with an inverted molar insulin–to–C-peptide or insulin–to–proinsulin ratio greater than 1. Under normal physiological conditions, insulin and C-peptide are generated in equimolar amounts from proinsulin and secreted simultaneously by pancreatic β-cells. Because insulin undergoes rapid hepatic metabolism (half-life about 5–10 minutes) whereas C-peptide is cleared more slowly by the kidneys (half-life about 30–35 minutes), the plasma insulin:C-peptide molar ratio in healthy individuals remains below 1. In IAS, IAAs bind circulating insulin, markedly prolonging its half-life from minutes to several hours while leaving the half-life of C-peptide essentially unchanged. This disproportionate extension of insulin persistence leads to disproportionately high serum insulin levels and the observed reversal of molar ratios. Although IAAs predominantly target insulin, rare cases have shown antibody binding to proinsulin or C-peptide, which can occasionally yield a molar ratio below 1 despite the typical biochemical profile.[8]

It is worth noting that, in our patient, β-hydroxybutyrate was not suppressed despite markedly elevated insulin levels. This can be explained by the presence of IAAs: laboratory assays detect both free and antibody-bound insulin, yet only the free fraction is biologically active. Consequently, insufficient bioavailable insulin failed to suppress ketogenesis, resulting in detectable ketone levels.

Management of IAS typically involves withdrawal of the offending agent and implementation of dietary measures, such as frequent small meals and reduction of simple carbohydrates, to mitigate glucose fluctuations. Findings from pooled cases of ALA-associated IAS demonstrated that discontinuation of ALA alone resulted in spontaneous resolution of hypoglycemia in most patients.[9] Most cases resolve within a few months, with a gradual decline in autoantibody levels, highlighting the importance of timely recognition and withdrawal of the offending agent to avoid unnecessary investigations or interventions.[9]

For patients with more severe or refractory disease, immunosuppressive therapies have been reported to suppress antibody production.[1] [10] Glucocorticoids can be the first medication of choice, where necessary. Around 60% of patients required steroid in the literature.[5] The steroid helped in reducing the titer of antibodies, but also directly increased gluconeogenesis and glycogenolysis, thereby increasing plasma glucose and preventing hypoglycemia. Among the other second-line therapeutic options, immunosuppressants (azathioprine and 6-mercaptopurine), monoclonal antibodies (rituximab), plasmapheresis, and strategies to reduce insulin release (somatostatin analogs, diazoxide, and pancreatectomy), all demonstrated varying efficacy in the management of IAS.[11]

Additional therapeutic options include agents that suppress pancreatic insulin secretion, such as somatostatin analogs, and plasmapheresis to reduce circulating autoantibodies.

In our case, conservative management with discontinuation of ALA and dietary counseling was sufficient to achieve resolution of symptoms within 2 weeks. This outcome aligns with prior reports of drug-induced IAS detected early in its course.

This case highlights the importance of including IAS in the differential diagnosis of spontaneous hypoglycemia, especially in patients without a history of diabetes or insulin therapy. Careful review of medication and supplement use is essential, as ALA and other sulfhydryl-containing compounds are widely available over the counter and may represent an underrecognized cause of autoimmune hypoglycemia.


Conclusion

This case illustrates a rare but important cause of hypoglycemia due to ALA-induced IAS. Recognition of the condition requires a high index of suspicion, particularly in patients with no prior exposure to insulin or hypoglycemic agents. Prompt identification and withdrawal of the offending supplement, along with supportive dietary measures, can result in complete resolution of symptoms and may prevent unnecessary diagnostic procedures or invasive interventions.


Declarations



Conflict of Interest

The authors have nothing to disclose. ChatGPT (OpenAI, USA) was used exclusively for grammar and language correction. It did not contribute to data analysis, interpretation, or the generation of scientific content.

Acknowledgments

The authors express their gratitude to colleagues who participated in the care of the reported patient.

Patient Consent Statement

Informed consent was obtained from the patient for publication of this case report.


Authors' Contributions

All authors were involved in data collection, manuscript drafting, and finalizing. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.


Compliance with Ethical Principles

No ethical approval is required for single case report.


Availability of Data and Material

For confidentiality reasons, the original data cannot be shared. However, all results are presented in this manuscript.



Address for correspondence

Raya Almazrouei, MD
P.O. Box 15258. Tawam Hospital. Al Ain
United Arab Emirates   

Publication History

Article published online:
31 October 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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