INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |Volume XII Issue VIII August 2025
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Hirata – Is Not a Peaceful Rice Paddy
Dr Sr Romia Rodriguez, Dr Abraham P George, Dr Sumesh Chacko
Physician Consultant, Lourdes Hospital, Ernakulam, Cochin, India
DOI: https://doi.org/10.51244/IJRSI.2025.120800034
Received: 06 August 2025; Accepted: 10 August 2025; Published: 30 August 2025
ABSTRACT
Background:
Insulin autoantibodies are an uncommon cause of non-diabetic hypoglycaemia in people who have never been
exposed to insulin before. This condition is called Insulin Autoimmune Syndrome (IAS), or Hirata's Disease.
Because of increased clinical awareness, instances are increasingly being found in various populations, although
being more frequently reported in East Asian nations.
Case Presentation:
We describe two cases of middle-aged women, a 45-year-old homemaker and a 38-year-old nurse, who had low
random blood glucose levels (35–59 mg/dL), giddiness, sweating, weariness, and tremors as symptoms of
recurrent postprandial hypoglycaemia. Both received baseline blood tests and systemic checks that were normal.
The results of the investigations showed significantly higher levels of C-peptide (1772 and 9782 pmol/L), insulin
autoantibody titers (>100 and >200), and serum insulin (>1000 µU/mL). Both patients had a history of taking
multivitamins that contained the known trigger alpha-lipoic acid. Hypoglycaemic episodes continued even after
dietary changes and steroid treatment, although rituximab treatment produced long-lasting clinical improvement.
Discussion:
IAS is a rare but crucial differential diagnosis for hypoglycaemia that is not diabetic, particularly in individuals
who are not receiving insulin therapy. It has been determined that alpha-lipoic acid frequently acts as a
precipitating agent. Similar to findings in steroid-refractory cases reported by Batra et al., our patients showed
conventional biochemical characteristics of IAS and reacted positively to rituximab, in accordance with earlier
investigations. Prolonged morbidity and needless investigations can be avoided with early detection and
awareness of IAS.
Conclusion:
Patients with increased insulin levels and spontaneous hypoglycaemia should be evaluated for IAS, especially if
exogenous insulin is not being used. Effective care requires a high index of suspicion, triggering agent
identification, and customized treatment, including immunosuppressive medication like rituximab.
INTRODUCTION
Autoantibodies against endogenous insulin in people who have never been exposed to exogenous insulin before
are an uncommon cause of spontaneous hypoglycaemia known as Insulin Autoimmune Syndrome (IAS), or
Hirata's Disease. First described by Hirata in Japan in 1970, IAS is more commonly reported in East Asian
populations but remains extremely rare in India and other Western countries [1]. Usually seen in people without
a history of diabetes, the syndrome manifests as postprandial hypoglycaemia with occasional hyperglycaemia.
Although the precise cause is unknown, several medications, especially those with sulfhydryl groups like alpha-
lipoic acid, are known to cause the autoimmune reaction in people who are genetically predisposed [2].
Clinical presentation and laboratory results, such as high titres of insulin autoantibodies in the absence of
INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |Volume XII Issue VIII August 2025
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exogenous insulin usage and higher levels of C-peptide and insulin, are used to make the diagnosis. Depending
on the severity, treatment options vary, from immunosuppressive medicine in refractory instances to dietary
changes and stopping triggering chemicals [5]. In this case study, we describe two middle-aged women without
diabetes or other comorbidities who experienced symptomatic hypoglycaemia as a result of IAS. After
corticosteroids failed to alleviate their symptoms, they needed immunosuppressive treatment with rituximab.
Clinical case
Insulin Antibody Syndrome (IAS) / Hirata’s Disease is a rare cause of non-diabetic hypoglycaemia.
Two patients, Mrs. ABC, a 38-year-old nurse, and Mrs. XYZ, a 45-year-old homemaker, both without
any known comorbidities, presented with fatigue, recurrent episodes of sweating, hunger, tremor,
giddiness, and palpitations.
Their random blood sugar levels were between 35–59 mg/dL, with most episodes occurring
approximately two hours postprandially and occurring up to three times daily.
Both had normal general and systemic examinations, with routine blood tests within normal limits.
GRBS monitoring revealed consistent postprandial hypoglycaemia, with some early morning episodes.
Laboratory investigations showed significantly elevated insulin (>1000) and C-peptide levels (1772 and
9782), along with high insulin antibody titres (>100 and >200).
Despite small, frequent mixed meals, hypoglycaemic episodes persisted, although with reduced
frequency.
Mrs. ABC and Mrs. XYZ had no known precipitating factors; however, both had a history of multivitamin
use, including alpha-lipoic acid.
Upon discontinuation and monitoring in the ward, clinical improvement was noted. Steroid trials were
ineffective in both patients, but treatment with rituximab led to clinical improvement.
DISCUSSION
Hirata's illness, also known as Insulin Autoimmune Syndrome (IAS), is a rare but significant cause of hyper-
insulinemic hypoglycaemia in individuals not receiving exogenous insulin. It is characterised by high titres of
insulin autoantibodies that cause irregular insulin release and unpredictable glycaemic swings. While more
common in East Asian countries, particularly Japan, reports from India and the West are increasing due to better
awareness and diagnostic tools. [1,2] HLA-restricted autoimmune disease (DRB1*04 subtypes) with
environmental triggers; not a tumour or monogenic disorder. [3,4]
In this case, both patients were middle-aged women with recurrent postprandial hypoglycaemia, no diabetes,
and no insulin use. They had markedly elevated insulin autoantibody titres along with high C-peptide and insulin
levels, consistent with previous reports in Indian IAS patients [5]. IAS can present in adulthood, with episodes
often occurring in the post-absorptive state, though fasting and exercise may also trigger symptoms [6]. It is
sometimes associated with autoimmune disorders such as Graves’ disease, systemic lupus erythematosus,
rheumatoid arthritis, and ankylosing spondylitis, but our patients had no such history.
Alpha-lipoic acid, a health supplement containing sulfhydryl groups, is a recognised trigger for IAS [7]. These
groups may impair immune tolerance and increase insulin autoantibody synthesis in genetically susceptible
individuals [2]. Both patients had taken multivitamins containing alpha-lipoic acid prior to symptom onset.
Similar associations have been documented by Censi et al. (2018), where discontinuation of the suspected agent
improved symptoms [2]. In our cases, hypoglycaemia persisted despite stopping alpha-lipoic acid, though dietary
changes provided partial relief.
INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
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Corticosteroids are considered first-line immunosuppressive therapy for IAS, with rituximab showing promise
in steroid-refractory cases. In line with Batra et al. (2021) [9], our patients responded well to rituximab, achieving
long-term clinical improvement.
Although IAS can resolve spontaneously, persistent or severe cases require treatment tailored to the cause and
symptom severity. Diagnosis should be based on:
• Documented spontaneous or postprandial hypoglycaemia
• Very high insulin levels with insulin-to-C-peptide ratio >1
• Positive insulin autoantibodies (IAA)
• No prior insulin use
• Exclusion of insulinoma or islet-cell disease via imaging
• Negative sulfonylurea screen
Early recognition is crucial to prevent misdiagnosis, unnecessary testing, and prolonged morbidity. Management
should address underlying triggers, with steroids or immunosuppressants reserved for more severe disease.
Despite rituximab's positive results in steroid-refractory IAS, a number of factors limit its use. Due to the drug's
high cost, limited availability in public health systems, and requirement for hospital-based intravenous
administration, access is restricted in many low- and middle-income nations. Off-label autoimmune indications
like IAS may not be covered by insurance or government subsidies, even in situations where rituximab is
accessible [9].
Hepatitis B virus (HBV) reactivation or latent TB, late-onset neutropenia, infusion-related responses, and a
heightened vulnerability to opportunistic infections as a result of chronic B-cell depletion are among the risks
[10]. The majority of the evidence for rituximab's safety in IAS comes from case reports and limited series, and
there are no long-term safety data available.
Comparison with other causes of hypoglycaemia
Feature
IAS
(autoimmune)
Type B insulin-receptor
Ab syndrome
(autoimmune)
Insulinoma
(tumour)
Pathogenesis
IAA bind/release
insulin, causing
post-prandial or
fasting
hypoglycaemia
Anti-INSR antibodies;
usually severe insulin
resistance &
hyperglycaemia, but rare
hypoglycaemia phenotypes
occur
β-cell
neuroendocrine
tumour secreting
insulin
autonomously
Key genetics
**HLA-
DRB104:06 / 04:03
enrichment; drug
triggers (α-lipoic
acid, methimazole)
Autoimmunity; no fixed
germline variant; associated
autoimmune diseases
common
Somatic YY1
p.T372R (~15–
32%); MEN1
germline in familial
cases; other NET
pathways variably
involved
INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
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Autoantibodies
Insulin
autoantibodies
(IAA) positive
Insulin-receptor (INSR)
antibodies positive
Negative
Biochemistry
during event
High insulin & C-
peptide; insulin/C-
peptide ratio >1
possible due to IAA
kinetics
Variable; in classic TBIRS:
very high insulin with
hyperglycaemia; rare
hypoglycaemia variants
reported
High insulin and
high C-peptide;
proinsulin often
high
CONCLUSION
Patients who experience frequent episodes of hypoglycaemia should be evaluated for Insulin Autoimmune
Syndrome (IAS), a rare but important cause of non-diabetic hypoglycaemia, particularly when exogenous insulin
usage is not present. In order to avoid needless investigations and extended morbidity, early detection and proper
diagnostic evaluation—including insulin autoantibody testing—are crucial. Withdrawing triggering drugs like
alpha-lipoic acid may resolve IAS, however immunosuppressive medication may be necessary in certain
situations. Our examples show that in steroid-refractory IAS, rituximab may be a useful treatment option. In
suitable clinical circumstances, clinicians should keep a high index of suspicion for IAS in order to facilitate
prompt diagnosis and individualized treatment.
Clinical pearls
IAS is a rare, non-diabetic cause of hyperinsulinemic hypoglycaemia—should be suspected in
recurrent, unexplained postprandial or spontaneous episodes with elevated insulin and insulin
autoantibodies.
HLA-DRB1*04 subtypes are genetically associated with IAS, with environmental triggers such as
sulfhydryl-containing drugs (e.g., alpha-lipoic acid, methimazole).
Alpha-lipoic acid is a well-documented precipitant; stopping the agent can improve symptoms, though
not always completely.
Biochemical hallmark: very high insulin and C-peptide with positive IAA and absence of prior
exogenous insulin exposure.
Diagnosis requires exclusion of insulinoma, factitious hypoglycaemia, and other autoimmune causes
(e.g., Type B insulin receptor antibody syndrome).
First-line therapy: trigger withdrawal, dietary modification, and steroids; rituximab may be effective
in steroid-refractory cases.
Rituximab limitations: high cost, limited access in LMICs, intravenous administration needs, and
potential serious risks including HBV reactivation, TB reactivation, late-onset neutropenia, and increased
infection susceptibility.
Early recognition prevents unnecessary investigations and prolonged morbidity; maintain high
suspicion in patients with recurrent hypoglycaemia without insulin use.
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