RARE DISEASE
Insulin autoimmune syndrome
Insulin autoimmune syndrome
Insulin autoimmune syndrome
Synonyms: Hirata disease
Synonyms: Hirata disease
Synonyms: Hirata disease
Drug discovery
1
drug
With orphan designation
Overview
Insulin Autoimmune Syndrome (IAS) is a rare endocrine disorder characterized by spontaneous hypoglycemia due to endogenous insulin autoantibodies (IAAs), which bind insulin and unpredictably release it, causing postprandial or fasting hypoglycemia. Diagnosis requires elevated serum insulin, detectable IAAs without prior insulin exposure, and exclusion of insulinoma. Most cases are self-limiting, resolving within 3–6 months, but severe episodes may necessitate immunosuppression or plasmapheresis [1][6][12].
Population
Predominantly reported in Asian populations (especially Japanese), with genetic links to HLA-DR4 alleles [2][8].
Associated with sulfhydryl-containing medications (e.g., methimazole, alpha-lipoic acid) and autoimmune conditions (e.g., Graves' disease, rheumatoid arthritis) [1][6][17].
Increasingly observed in Caucasians, often linked to drug exposure [2][8].
Burden
High morbidity from neuroglycopenic symptoms (e.g., coma, seizures) and frequent hospitalizations [1][6].
Risk of misdiagnosis as insulinoma, leading to unnecessary surgeries [6][17].
Self-limiting in 70–80% of cases, but prolonged symptoms in patients with monoclonal antibodies or comorbidities [8][12][17].
Therapies
First-line: Dietary modifications (small, frequent low-carbohydrate meals), acarbose to delay glucose absorption [3][6][13].
Pharmacological: Diazoxide or somatostatin analogs to suppress insulin secretion; glucocorticoids, rituximab, or azathioprine for refractory cases [3][8][18].
Severe cases: Plasmapheresis or immunosuppressants to reduce antibody titers [1][3][8].
Categories: rare endocrine diseases
Research Papers
167 drug discovery papers about Insulin autoimmune syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
167 drug discovery papers about Insulin autoimmune syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-13 | Type B insulin resistance syndrome coexisting with aplastic anemia responsive to early immunosuppressive therapy.
Type B insulin resistance syndrome (IRS) is a rare autoimmune disorder characterized by severe insulin resistance caused by autoantibodies against the insulin receptor. Clinically, it presents with fluctuating hyperglycemia and hypoglycemia and is frequently associated with other autoimmune diseases. We report a case with the rarely reported combination of type B IRS and aplastic anemia. A 77-year-old woman with obesity presented with abrupt deterioration of glycemic control and bilateral lower extremity edema. Despite the administration of up to 300 units/day of insulin after hospitalization, hyperglycemia remained refractory. Markedly elevated insulin receptor autoantibody titers (85.9%) confirmed the diagnosis of type B IRS. Further evaluation for concomitant pancytopenia revealed aplastic anemia on bone marrow examination. Immunosuppressive therapy with cyclosporine and eltrombopag for aplastic anemia improved the hyperglycemia; however, early morning hypoglycemia, renal dysfunction associated with intravascular volume depletion, and persistent lower extremity edema remained unresolved. The addition of glucocorticoid therapy resulted in rapid clinical improvement and marked reduction in the insulin receptor autoantibody titers (8.6%). This case highlights the importance of early and appropriate immunomodulatory therapy to achieve remission in type B IRS, particularly in patients with multiple concomitant autoimmune diseases.
2026-07-13 | Insulin autoimmune hypoglycemia unmasking monoclonal gammopathy in type 2 diabetes.
Insulin autoimmune syndrome (IAS), also known as Hirata disease, is a rare cause of spontaneous hypoglycemia due to circulating insulin autoantibodies, most commonly described in East Asian individuals and those exposed to sulfhydryl-containing drugs. We describe a 58-year-old South Asian man with type 2 diabetes mellitus who presented with recurrent fasting and postprandial hypoglycemia despite cessation of all glucose-lowering medications. A spontaneous episode confirmed Whipple triad: plasma glucose 38 mg/dL (SI: 2.1 mmol/L; reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]), markedly elevated serum insulin at 156 µIU/mL (SI: 1083 pmol/L; reference range, 2.6-24.9 µIU/mL [SI: 18-173 pmol/L]), and C-peptide of 5.8 ng/mL (SI: 1.9 nmol/L; reference range, 0.5-2.0 ng/mL [SI: 0.17-0.66 nmol/L]), with a negative sulfonylurea screen and markedly elevated insulin autoantibody titers. Polyethylene glycol precipitation confirmed antibody-bound insulin sequestration. Workup identified IgG-kappa monoclonal gammopathy of undetermined significance as the probable precipitant. Dietary modification, oral glucocorticoids, and acarbose achieved near-complete resolution of hypoglycemia with declining autoantibody titers over 4 weeks. This case highlights the importance of considering IAS in unexplained hyperinsulinemic hypoglycemia and the need to screen for plasma cell dyscrasias in atypical presentations.
2026-02-27 | A Case of Antibody-Mediated Recurrent Hypoglycemia in a Patient With Mixed Connective Tissue Disease.
Insulin Autoimmune Syndrome (IAS) is a rare autoimmune condition in which the body produces antibodies to insulin, leading to recurrent episodes of severe hypoglycemia accompanied by elevated serum insulin and insulin antibody levels. Hypoglycemia can mimic neurological conditions such as stroke. Also known as Hirata's disease, IAS occurs in patients with autoimmune conditions or a genetic predisposition. IAS is typically treated with immunosuppressive agents, including steroids and rituximab, and patients often undergo thorough evaluations to rule out more common causes of hypoglycemia. Here, we present a case of a patient with pulmonary arterial hypertension (type 1) and mixed connective tissue disease who experienced persistent and recurrent symptomatic hypoglycemia, with glucose levels as low as 35 mg/dL (1.94 mmol/L). C-peptide, a marker of endogenous insulin production, was within normal limits at 2.9 ng/mL (0.96 nmol/L) while the patient was hypoglycemic (glucose <60 mg/dL (3.3 mmol/L)), indicating inappropriate insulin secretion. Total insulin levels were markedly elevated at 7,000 µU/mL (48,615.00 pmol/L), and free insulin levels were elevated at 24 µU/mL (166.68 pmol/L), which initially raised concern for an insulinoma. However, insulin antibodies were evaluated and found to be significantly elevated at >625 µU/mL (>4,340.63 pmol/L), confirming the diagnosis of Hirata's disease. The patient improved following dietary modifications, initiation of prednisone, and discontinuation of home hydroxychloroquine.
2026-02-16 | Insulin Autoimmune Syndrome Associated With Hashimoto Thyroiditis and Nodular Thyroid Disease: Clinical Management With Flash Glucose Monitoring and Prednisolone Therapy.
BACKGROUND Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hyperinsulinemic hypoglycemia, characterized by high titers of insulin autoantibodies in the absence of prior insulin exposure. It is most frequently reported in Asian populations and is often associated with other autoimmune conditions. Reports in White patients remain uncommon. CASE REPORT We describe a 63-year-old White woman presenting with recurrent symptomatic hypoglycemia, with plasma glucose as low as 27 mg/dL. Episodes were accompanied by sweating and transient loss of consciousness. Several weeks before the first episode of hypoglycemia, she experienced a single episode of a pruritic rash, which resolved spontaneously. The patient had no prior exposure to insulin therapy or sulfhydryl-containing drugs. Laboratory evaluation revealed markedly elevated insulin concentrations (reaching 19 300 μU/mL), increased C-peptide levels, and insulin autoantibody titer of 99.9%. Abdominal MRI excluded insulinoma. Continuous flash glucose monitoring demonstrated frequent nocturnal and postprandial hypoglycemic episodes. Additional testing confirmed Hashimoto's thyroiditis and a benign thyroid nodule. Management included dietary modification with frequent small meals and carbohydrate restriction. Because these measures were insufficient, prednisolone was initiated, resulting in rapid improvement in glycemic stability. Corticosteroid dose was tapered over 4 months, and the patient remained euglycemic. CONCLUSIONS IAS should be considered in patients with unexplained hyperinsulinemic hypoglycemia to avoid unnecessary invasive evaluation for insulinoma. When dietary measures alone are inadequate, prednisolone therapy is effective. Given the frequent coexistence of IAS with other autoimmune disorders, systematic screening is advisable, and incidental thyroid findings in the setting of autoimmune thyroiditis warrant careful assessment to exclude malignancy.
2026-01-27 | Unmasking Hirata: a mysterious case of Hypoglycemia triggered by immunologic storm.
We report a rare case of Insulin Autoimmune Syndrome in a 35-year-old woman with prior autoimmune features who developed hypoglycemia after an allergic reaction. Diagnosis was confirmed by insulin autoantibodies. Immunosuppressive therapy yielded significant improvement. This case suggests a broader autoimmune process may underlie seemingly isolated IAS presentations.
cell therapies
2022-07-12 | Islet Biology During COVID-19: Progress and Perspectives.
The coronavirus-2019 (COVID-19) pandemic has had significant impact on research directions and productivity in the past 2 years. Despite these challenges, since 2020, more than 2,500 peer-reviewed articles have been published on pancreatic islet biology. These include updates on the roles of isocitrate dehydrogenase, pyruvate kinase and incretin hormones in insulin secretion, as well as the discovery of inceptor and signalling by circulating RNAs. The year 2020 also brought advancements in in vivo and in vitro models, including a new transgenic mouse for assessing beta-cell proliferation, a "pancreas-on-a-chip" to study glucose-stimulated insulin secretion and successful genetic editing of primary human islet cells. Islet biologists evaluated the functionality of stem-cell-derived islet-like cells coated with semipermeable biomaterials to prevent autoimmune attack, revealing the importance of cell maturation after transplantation. Prompted by observations that COVID-19 symptoms can worsen for people with obesity or diabetes, researchers examined how islets are directly affected by severe acute respiratory syndrome coronavirus 2. Herein, we highlight novel functional insights, technologies and therapeutic approaches that emerged between March 2020 and July 2021, written for both scientific and lay audiences. We also include a response to these advancements from patient stakeholders, to help lend a broader perspective to developments and challenges in islet research. La pandémie de la maladie à coronavirus 2019 (COVID-19) a eu des répercussions importantes sur les orientations et la productivité de la recherche au cours de la dernière année. En dépit de ces enjeux, depuis 2020, plus de 2500 articles revus par les pairs sur la biologie des îlots pancréatiques ont été publiés, y compris des articles qui portent sur les rôles de l’isocitrate-déshydrogénase, de la pyruvate kinase et des incrétines dans la sécrétion de l’insuline, ainsi que sur la découverte de l’« inceptor » et de la signalisation par les ARN circulants. L’année 2020 a aussi donné lieu à des avancées des modèles in vivo et in vitro, notamment la nouvelle souris transgénique pour permettre l’évaluation de la prolifération de cellules bêta, le « pancréas sur puce » pour étudier la sécrétion d’insuline stimulée par le glucose et la réussite de l’édition génomique des principales cellules humaines d’îlots pancréatiques. Les biologistes spécialisés dans le domaine des îlots pancréatiques ont évalué la fonctionnalité des cellules de type îlots pancréatiques issues de cellules souches recouvertes de biomatériaux semi-perméables pour prévenir les attaques auto-immunes, révélatrices de l’importance de la maturation cellulaire après la transplantation. Du fait que l’aggravation des symptômes de la COVID-19 est observée chez les personnes obèses ou diabétiques, les chercheurs ont examiné la façon avec laquelle les îlots sont directement affectés par le coronavirus 2 du syndrome respiratoire aigu. Dans le présent article, nous présentons les nouvelles perspectives fonctionnelles, les technologies et les approches thérapeutiques qui sont apparues entre mars 2020 et juillet 2021, et destinées aux scientifiques et aux non-scientifiques. Nous proposons aussi une réponse à ces avancées issues des groupes de patients pour permettre de donner une perspective plus large aux développements et aux enjeux de la recherche sur les îlots pancréatiques.
2021-10-26 | [Insulin autoimmune syndrome : A rare, but important differential diagnosis of hypoglycemia].
A 69-year-old female patient was referred to the Medical University of Hanover for further diagnostic evaluation of recurrent severe hypoglycemia. The patient had previously been started on clopidogrel after arterial stenting for peripheral arterial obstructive disease (PAOD). The presence of an insulinoma and paraneoplastic syndrome was excluded. Increased serum insulin and insulin autoantibodies levels were confirmed, despite normal to low blood sugar levels. An insulin autoimmune syndrome was diagnosed, most likely induced by the prior intake of clopidogrel. Treatment with immunoadsorption was initiated, achieving a significant reduction in hypoglycemic events and a lasting response to treatment over 3 months.Eine 69-jährige Patientin mit rezidivierenden schweren Hypoglykämien wurde zur weiteren Diagnostik der Medizinischen Hochschule Hannover zugewiesen. Zuvor hatte die Patientin nach einem Stenting, das aufgrund einer peripheren arteriellen Verschlusskrankheit (pAVK) erforderlich war, mit einer Clopidogreleinnahme begonnen. Das Vorliegen eines Insulinoms und eines paraneoplastischen Syndroms wurde ausgeschlossen. Trotz niedrig normaler Blutzuckerkonzentrationen fanden sich erhöhte Insulin- und Insulinautoantikörperkonzentrationen. Diagnostiziert wurde ein Insulinautoimmunsyndrom, a.e. (am ehesten) ausgelöst durch vorausgegangene Clopidogreleinnahme. Eine Behandlung mithilfe der Immunadsorption wurde initiiert; diese erzielte eine signifikante Reduktion der hypoglykämischen Ereignisse und ein anhaltendes Therapieansprechen über 3 Monate.
2021-01-04 | Insulin Autoimmune Syndrome: A Case of Clopidogrel-induced Autoimmune Hypoglycemia.
Insulin autoimmune syndrome (IAS) is characterized by hyperinsulinemic hypoglycemia with elevated anti-insulin antibodies. Most commonly observed in the Japanese population, elsewhere it is rare and associated with autoimmune diseases, plasma cell dyscrasias, or sulfhydryl group medications. The active metabolite of clopidogrel has a sulfhydryl group and here we report a case of clopidogrel-induced IAS. A 67-year-old man was admitted with severe hyperinsulinemic hypoglycemia requiring continuous intravenous infusion of 10% dextrose to sustain euglycemia. His symptoms of hypoglycemia had started after commencing dual antiplatelet therapy (including clopidogrel) for ischemic heart disease 9 months earlier. The hypoglycemia was associated with elevated insulin, proinsulin, c-peptide, and anti-insulin antibody titers as well as the HLA-DRB1*04 haplotype. Multiple localizing studies were negative for an insulinoma. A diagnosis of IAS was thus made. Clopidogrel cessation, oral dexamethasone, and diazoxide therapy were not sufficient to safely wean the dextrose infusion. Plasma exchange was ultimately effective. This case highlights a case of severe IAS. Given the ubiquity of clopidogrel, IAS should be remembered as a rare adverse effect.
2020-12-09 | A combination of plasma exchange and steroids in the treatment of a-lipoic acid-induced insulin autoimmune syndrome
Not required for Clinical Vignette.
2020-02-22 | Insulin Autoimmune Syndrome Treated with Plasmapharesis
A 66-year male with a history of Central Serous Retinopathy presented with recurrent episodes of hypoglycemia. On evaluation, he was found to have insulin-mediated hypoglycemia with serum insulin of 300uIU/ml, C peptide 27.51ng/ml, when the blood glucose was 46mg/dl. High insulin levels above 100uIU/ml, led to suspicion of Autoimmune hypoglycemia and were confirmed by a high anti-insulin antibody titer of 300U/ml. Imaging was negative for Insulinoma. The patient was started on low dose oral prednisolone under ophthalmological monitoring, but as there was no symptomatic improvement, the dose was increased following which there was a flare-up of CSR. The patient was initiated on plasmapheresis following which his hypoglycemia improved with drop in anti-insulin antibody titers to 29U/ml. The patient was maintained on low dose steroids, which were tapered and stopped over the next six months with complete resolution of hypoglycemia and normalization of anti-insulin antibody titers.
antibodies
2026-05-29 | Refractory severe type B insulin resistance treated with daratumumab.
Type B insulin resistance syndrome (TBIRS) is a rare autoimmune condition characterized by insulin receptor autoantibodies, often in association with systemic lupus erythematosus (SLE). It can cause extreme insulin resistance, with fewer than 200 cases described worldwide. A 24-year-old man with no prior autoimmune history presented with diabetic ketoacidosis and severe insulin resistance, requiring up to 215 000 units of insulin daily. Laboratory studies revealed high-titer antinuclear antibodies, hypocomplementemia, lupus-specific autoantibodies, and mesangial proliferative lupus nephritis, confirming new-onset SLE. His management was complicated by latent tuberculosis, neutropenia, and cyclophosphamide-induced hearing loss. Despite intensive therapy with corticosteroids, rituximab, cyclophosphamide, obinutuzumab, plasmapheresis, and intravenous immunoglobulin, he remained profoundly insulin resistant, requiring very high daily insulin doses, with persistently elevated insulin receptor antibody titers. Initiation of daratumumab, a CD38 monoclonal antibody, resulted in marked clinical improvement, with progressive decline in insulin requirements and eventual discontinuation of insulin 17 months after presentation. He achieved durable remission with normalization of hemoglobin A1c. This unusually severe case of TBIRS highlights the limitations of conventional B-cell-directed therapies, where long-lived plasma cells sustain pathogenic autoantibodies. Plasma cell-targeted strategies such as daratumumab may represent an effective therapeutic option in refractory cases.
2026-03-13 | Clinical Characteristics and Risk Factors of Exogenous Insulin Antibody Syndrome in Patients with Diabetes: A Retrospective Cross-Sectional Study.
Insulin autoimmune syndrome (IAS) is a rare hypoglycemic disorder often confused with insulinoma or insulin overdose. Patients with diabetes on insulin therapy increasingly show insulin autoantibodies (IAAs), presenting symptoms similar to classic IAS, termed exogenous insulin antibody syndrome (EIAS). This study examines EIAS clinical features and risk factors. Patients with diabetes with IAA test results, admitted to our hospital between June 2023 and March 2024 were retrospectively enrolled. Participants were stratified into control and EIAS groups on the basis of IAA status. Clinical characteristics were compared between groups, independent risk factors for EIAS were identified by multivariate logistic regression, and the diagnostic utility of fasting insulin for predicting EIAS was assessed with receiver-operating-characteristic (ROC) curve analysis. Of 120 patients with diabetes and available IAAs results, 37 met criteria for EIAS. Compared with controls, EIAS patients were older, had longer diabetes duration, were more often treated with insulin aspart or premixed human insulin, and received higher daily insulin doses. Paradoxically, EIAS patients had markedly lower levels of fasting blood glucose and HbA1c, while higher fasting and 2-h post-prandial insulin concentrations, as well as HOMA-IR. Multivariate logistic regression analysis showed that elevated fasting insulin levels were independently associated with increased risk of EIAS. For every 1 uU/mL increase in fasting insulin, the risk of EIAS increased by 3% (OR = 1.03, 95% CI: 1.00-1.05). The fasting insulin level demonstrated high overall diagnostic and predictive efficacy for EIAS, with an area under the curve (AUC) of 0.782 (95% CI: 0.691-0.872). The optimal diagnostic cutoff value was 6.975 uU/mL, with a sensitivity of 73.0% and a specificity of 81.9%. EIAS patients were identified with advanced age, prolonged diabetes duration, high insulin dosage, hypoglycemia, and hyperinsulinemia. Fasting insulin level is independently associated with EIAS risk and demonstrates good diagnostic performance.
2026-02-05 | Three Interesting Cases of Hypoglycemia: A Case Series.
Hypoglycemia can be due to exogenous hyperinsulinemic hypoglycemia or endogenous hyperinsulinemic hypoglycemia (ENHH). ENHH is a rare entity characterized by inappropriately elevated plasma insulin in the background of low plasma glucose levels. ENHH, being an uncommon disease, is caused by many rare entities, with drug-induced being the most common cause of hypoglycemia. Other causes include insulinoma, insulin autoimmune syndrome, and nesidioblastosis. Here, we report three rare cases of non-diabetic hypoglycemia referred to the endocrinology clinic who had signs and symptoms of hypoglycemia fulfilling Whipple's triad with evidence of hyperinsulinemia despite low plasma glucose. All the appropriate biochemical investigations along with imaging studies were conducted to find out the etiology of hypoglycemia. After taking detailed medical history and clinical examination with biochemical and radiological investigations, patients were diagnosed with insulin autoimmune syndrome, insulinoma, and drug-induced hypoglycemia. Appropriate management was started, and patients were relieved of hypoglycemia. Diseases causing hypoglycemia have similar manifestation, but the diagnosis and management are always a challenging task. Hence, an accurate and early diagnosis is always a deciding factor for further prognosis.
2026-01-01 | Case Report on Hypoglycemia – Beyond Diet, Drugs and Diabetes
Hypoglycemia is a common presentation for various conditions presenting to the emergency department. After ruling out drugs as a cause, especially in nondiabetic individuals, classification to hyperinsulinemic or non-hyper insulinemic hypoglycemia is the next step. Since insulinoma is one of the most common causes of hyperinsulinemia, several imaging modalities are typically used in the search for it. However, in the presence of autoimmune autoantibody syndrome should be thought of. Here we report a case of an elderly non diabetic female with recurrent hypoglycemia. She was noticed to have late postprandial hypoglycemia. Investigation revealed raised insulin levels, raised C peptide levels, and high titers of insulin auto-antibodies. The patient was diagnosed with Insulin antibody syndrome (IAS). IAS may not be a rare syndrome; physicians need to be more vigilant to diagnose and manage such patients.
2025-07-23 | Successful treatment with rituximab of a type 2 diabetes patient with antibody-mediated insulin resistance syndrome: A case report.
Insulin antibody-mediated insulin resistance is a rare autoimmune mechanism that can cause severe hyperglycemia. A 52-year-old male patient was admitted to our hospital with complaints of polydipsia, polyuria, and weight loss (8 kg in 6 months). He was diagnosed with type 2 diabetes mellitus at age 33. Type 2 diabetes mellitus with antibody-mediated insulin resistance syndrome. Rituximab infusion in a 500 mg dose was given 2 times in a 2-week interval. A significant response was achieved 1 month later with fasting plasma glucose: 120 mg/dL (6.7 mmol/L), glycosylated hemoglobin A1c: 7.6% (59.6 mmol/mol), and anti-insulin antibodies: 0.001 U/mL. Clinically improved response persisted for about 6 months. Clinicians should be aware of the antibody-mediated insulin resistance, recognize suggestive signs and symptoms, pursue appropriate diagnostic evaluation, and treatment approach.
small molecules
2026-07-13 | Type B insulin resistance syndrome coexisting with aplastic anemia responsive to early immunosuppressive therapy.
Type B insulin resistance syndrome (IRS) is a rare autoimmune disorder characterized by severe insulin resistance caused by autoantibodies against the insulin receptor. Clinically, it presents with fluctuating hyperglycemia and hypoglycemia and is frequently associated with other autoimmune diseases. We report a case with the rarely reported combination of type B IRS and aplastic anemia. A 77-year-old woman with obesity presented with abrupt deterioration of glycemic control and bilateral lower extremity edema. Despite the administration of up to 300 units/day of insulin after hospitalization, hyperglycemia remained refractory. Markedly elevated insulin receptor autoantibody titers (85.9%) confirmed the diagnosis of type B IRS. Further evaluation for concomitant pancytopenia revealed aplastic anemia on bone marrow examination. Immunosuppressive therapy with cyclosporine and eltrombopag for aplastic anemia improved the hyperglycemia; however, early morning hypoglycemia, renal dysfunction associated with intravascular volume depletion, and persistent lower extremity edema remained unresolved. The addition of glucocorticoid therapy resulted in rapid clinical improvement and marked reduction in the insulin receptor autoantibody titers (8.6%). This case highlights the importance of early and appropriate immunomodulatory therapy to achieve remission in type B IRS, particularly in patients with multiple concomitant autoimmune diseases.
2026-07-13 | Insulin autoimmune hypoglycemia unmasking monoclonal gammopathy in type 2 diabetes.
Insulin autoimmune syndrome (IAS), also known as Hirata disease, is a rare cause of spontaneous hypoglycemia due to circulating insulin autoantibodies, most commonly described in East Asian individuals and those exposed to sulfhydryl-containing drugs. We describe a 58-year-old South Asian man with type 2 diabetes mellitus who presented with recurrent fasting and postprandial hypoglycemia despite cessation of all glucose-lowering medications. A spontaneous episode confirmed Whipple triad: plasma glucose 38 mg/dL (SI: 2.1 mmol/L; reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]), markedly elevated serum insulin at 156 µIU/mL (SI: 1083 pmol/L; reference range, 2.6-24.9 µIU/mL [SI: 18-173 pmol/L]), and C-peptide of 5.8 ng/mL (SI: 1.9 nmol/L; reference range, 0.5-2.0 ng/mL [SI: 0.17-0.66 nmol/L]), with a negative sulfonylurea screen and markedly elevated insulin autoantibody titers. Polyethylene glycol precipitation confirmed antibody-bound insulin sequestration. Workup identified IgG-kappa monoclonal gammopathy of undetermined significance as the probable precipitant. Dietary modification, oral glucocorticoids, and acarbose achieved near-complete resolution of hypoglycemia with declining autoantibody titers over 4 weeks. This case highlights the importance of considering IAS in unexplained hyperinsulinemic hypoglycemia and the need to screen for plasma cell dyscrasias in atypical presentations.
2026-02-27 | A Case of Antibody-Mediated Recurrent Hypoglycemia in a Patient With Mixed Connective Tissue Disease.
Insulin Autoimmune Syndrome (IAS) is a rare autoimmune condition in which the body produces antibodies to insulin, leading to recurrent episodes of severe hypoglycemia accompanied by elevated serum insulin and insulin antibody levels. Hypoglycemia can mimic neurological conditions such as stroke. Also known as Hirata's disease, IAS occurs in patients with autoimmune conditions or a genetic predisposition. IAS is typically treated with immunosuppressive agents, including steroids and rituximab, and patients often undergo thorough evaluations to rule out more common causes of hypoglycemia. Here, we present a case of a patient with pulmonary arterial hypertension (type 1) and mixed connective tissue disease who experienced persistent and recurrent symptomatic hypoglycemia, with glucose levels as low as 35 mg/dL (1.94 mmol/L). C-peptide, a marker of endogenous insulin production, was within normal limits at 2.9 ng/mL (0.96 nmol/L) while the patient was hypoglycemic (glucose <60 mg/dL (3.3 mmol/L)), indicating inappropriate insulin secretion. Total insulin levels were markedly elevated at 7,000 µU/mL (48,615.00 pmol/L), and free insulin levels were elevated at 24 µU/mL (166.68 pmol/L), which initially raised concern for an insulinoma. However, insulin antibodies were evaluated and found to be significantly elevated at >625 µU/mL (>4,340.63 pmol/L), confirming the diagnosis of Hirata's disease. The patient improved following dietary modifications, initiation of prednisone, and discontinuation of home hydroxychloroquine.
2026-02-16 | Insulin Autoimmune Syndrome Associated With Hashimoto Thyroiditis and Nodular Thyroid Disease: Clinical Management With Flash Glucose Monitoring and Prednisolone Therapy.
BACKGROUND Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hyperinsulinemic hypoglycemia, characterized by high titers of insulin autoantibodies in the absence of prior insulin exposure. It is most frequently reported in Asian populations and is often associated with other autoimmune conditions. Reports in White patients remain uncommon. CASE REPORT We describe a 63-year-old White woman presenting with recurrent symptomatic hypoglycemia, with plasma glucose as low as 27 mg/dL. Episodes were accompanied by sweating and transient loss of consciousness. Several weeks before the first episode of hypoglycemia, she experienced a single episode of a pruritic rash, which resolved spontaneously. The patient had no prior exposure to insulin therapy or sulfhydryl-containing drugs. Laboratory evaluation revealed markedly elevated insulin concentrations (reaching 19 300 μU/mL), increased C-peptide levels, and insulin autoantibody titer of 99.9%. Abdominal MRI excluded insulinoma. Continuous flash glucose monitoring demonstrated frequent nocturnal and postprandial hypoglycemic episodes. Additional testing confirmed Hashimoto's thyroiditis and a benign thyroid nodule. Management included dietary modification with frequent small meals and carbohydrate restriction. Because these measures were insufficient, prednisolone was initiated, resulting in rapid improvement in glycemic stability. Corticosteroid dose was tapered over 4 months, and the patient remained euglycemic. CONCLUSIONS IAS should be considered in patients with unexplained hyperinsulinemic hypoglycemia to avoid unnecessary invasive evaluation for insulinoma. When dietary measures alone are inadequate, prednisolone therapy is effective. Given the frequent coexistence of IAS with other autoimmune disorders, systematic screening is advisable, and incidental thyroid findings in the setting of autoimmune thyroiditis warrant careful assessment to exclude malignancy.
2026-01-27 | Unmasking Hirata: a mysterious case of Hypoglycemia triggered by immunologic storm.
We report a rare case of Insulin Autoimmune Syndrome in a 35-year-old woman with prior autoimmune features who developed hypoglycemia after an allergic reaction. Diagnosis was confirmed by insulin autoantibodies. Immunosuppressive therapy yielded significant improvement. This case suggests a broader autoimmune process may underlie seemingly isolated IAS presentations.
cell therapies
2022-07-12 | Islet Biology During COVID-19: Progress and Perspectives.
The coronavirus-2019 (COVID-19) pandemic has had significant impact on research directions and productivity in the past 2 years. Despite these challenges, since 2020, more than 2,500 peer-reviewed articles have been published on pancreatic islet biology. These include updates on the roles of isocitrate dehydrogenase, pyruvate kinase and incretin hormones in insulin secretion, as well as the discovery of inceptor and signalling by circulating RNAs. The year 2020 also brought advancements in in vivo and in vitro models, including a new transgenic mouse for assessing beta-cell proliferation, a "pancreas-on-a-chip" to study glucose-stimulated insulin secretion and successful genetic editing of primary human islet cells. Islet biologists evaluated the functionality of stem-cell-derived islet-like cells coated with semipermeable biomaterials to prevent autoimmune attack, revealing the importance of cell maturation after transplantation. Prompted by observations that COVID-19 symptoms can worsen for people with obesity or diabetes, researchers examined how islets are directly affected by severe acute respiratory syndrome coronavirus 2. Herein, we highlight novel functional insights, technologies and therapeutic approaches that emerged between March 2020 and July 2021, written for both scientific and lay audiences. We also include a response to these advancements from patient stakeholders, to help lend a broader perspective to developments and challenges in islet research. La pandémie de la maladie à coronavirus 2019 (COVID-19) a eu des répercussions importantes sur les orientations et la productivité de la recherche au cours de la dernière année. En dépit de ces enjeux, depuis 2020, plus de 2500 articles revus par les pairs sur la biologie des îlots pancréatiques ont été publiés, y compris des articles qui portent sur les rôles de l’isocitrate-déshydrogénase, de la pyruvate kinase et des incrétines dans la sécrétion de l’insuline, ainsi que sur la découverte de l’« inceptor » et de la signalisation par les ARN circulants. L’année 2020 a aussi donné lieu à des avancées des modèles in vivo et in vitro, notamment la nouvelle souris transgénique pour permettre l’évaluation de la prolifération de cellules bêta, le « pancréas sur puce » pour étudier la sécrétion d’insuline stimulée par le glucose et la réussite de l’édition génomique des principales cellules humaines d’îlots pancréatiques. Les biologistes spécialisés dans le domaine des îlots pancréatiques ont évalué la fonctionnalité des cellules de type îlots pancréatiques issues de cellules souches recouvertes de biomatériaux semi-perméables pour prévenir les attaques auto-immunes, révélatrices de l’importance de la maturation cellulaire après la transplantation. Du fait que l’aggravation des symptômes de la COVID-19 est observée chez les personnes obèses ou diabétiques, les chercheurs ont examiné la façon avec laquelle les îlots sont directement affectés par le coronavirus 2 du syndrome respiratoire aigu. Dans le présent article, nous présentons les nouvelles perspectives fonctionnelles, les technologies et les approches thérapeutiques qui sont apparues entre mars 2020 et juillet 2021, et destinées aux scientifiques et aux non-scientifiques. Nous proposons aussi une réponse à ces avancées issues des groupes de patients pour permettre de donner une perspective plus large aux développements et aux enjeux de la recherche sur les îlots pancréatiques.
2021-10-26 | [Insulin autoimmune syndrome : A rare, but important differential diagnosis of hypoglycemia].
A 69-year-old female patient was referred to the Medical University of Hanover for further diagnostic evaluation of recurrent severe hypoglycemia. The patient had previously been started on clopidogrel after arterial stenting for peripheral arterial obstructive disease (PAOD). The presence of an insulinoma and paraneoplastic syndrome was excluded. Increased serum insulin and insulin autoantibodies levels were confirmed, despite normal to low blood sugar levels. An insulin autoimmune syndrome was diagnosed, most likely induced by the prior intake of clopidogrel. Treatment with immunoadsorption was initiated, achieving a significant reduction in hypoglycemic events and a lasting response to treatment over 3 months.Eine 69-jährige Patientin mit rezidivierenden schweren Hypoglykämien wurde zur weiteren Diagnostik der Medizinischen Hochschule Hannover zugewiesen. Zuvor hatte die Patientin nach einem Stenting, das aufgrund einer peripheren arteriellen Verschlusskrankheit (pAVK) erforderlich war, mit einer Clopidogreleinnahme begonnen. Das Vorliegen eines Insulinoms und eines paraneoplastischen Syndroms wurde ausgeschlossen. Trotz niedrig normaler Blutzuckerkonzentrationen fanden sich erhöhte Insulin- und Insulinautoantikörperkonzentrationen. Diagnostiziert wurde ein Insulinautoimmunsyndrom, a.e. (am ehesten) ausgelöst durch vorausgegangene Clopidogreleinnahme. Eine Behandlung mithilfe der Immunadsorption wurde initiiert; diese erzielte eine signifikante Reduktion der hypoglykämischen Ereignisse und ein anhaltendes Therapieansprechen über 3 Monate.
2021-01-04 | Insulin Autoimmune Syndrome: A Case of Clopidogrel-induced Autoimmune Hypoglycemia.
Insulin autoimmune syndrome (IAS) is characterized by hyperinsulinemic hypoglycemia with elevated anti-insulin antibodies. Most commonly observed in the Japanese population, elsewhere it is rare and associated with autoimmune diseases, plasma cell dyscrasias, or sulfhydryl group medications. The active metabolite of clopidogrel has a sulfhydryl group and here we report a case of clopidogrel-induced IAS. A 67-year-old man was admitted with severe hyperinsulinemic hypoglycemia requiring continuous intravenous infusion of 10% dextrose to sustain euglycemia. His symptoms of hypoglycemia had started after commencing dual antiplatelet therapy (including clopidogrel) for ischemic heart disease 9 months earlier. The hypoglycemia was associated with elevated insulin, proinsulin, c-peptide, and anti-insulin antibody titers as well as the HLA-DRB1*04 haplotype. Multiple localizing studies were negative for an insulinoma. A diagnosis of IAS was thus made. Clopidogrel cessation, oral dexamethasone, and diazoxide therapy were not sufficient to safely wean the dextrose infusion. Plasma exchange was ultimately effective. This case highlights a case of severe IAS. Given the ubiquity of clopidogrel, IAS should be remembered as a rare adverse effect.
2020-12-09 | A combination of plasma exchange and steroids in the treatment of a-lipoic acid-induced insulin autoimmune syndrome
Not required for Clinical Vignette.
2020-02-22 | Insulin Autoimmune Syndrome Treated with Plasmapharesis
A 66-year male with a history of Central Serous Retinopathy presented with recurrent episodes of hypoglycemia. On evaluation, he was found to have insulin-mediated hypoglycemia with serum insulin of 300uIU/ml, C peptide 27.51ng/ml, when the blood glucose was 46mg/dl. High insulin levels above 100uIU/ml, led to suspicion of Autoimmune hypoglycemia and were confirmed by a high anti-insulin antibody titer of 300U/ml. Imaging was negative for Insulinoma. The patient was started on low dose oral prednisolone under ophthalmological monitoring, but as there was no symptomatic improvement, the dose was increased following which there was a flare-up of CSR. The patient was initiated on plasmapheresis following which his hypoglycemia improved with drop in anti-insulin antibody titers to 29U/ml. The patient was maintained on low dose steroids, which were tapered and stopped over the next six months with complete resolution of hypoglycemia and normalization of anti-insulin antibody titers.
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2026-05-29 | Refractory severe type B insulin resistance treated with daratumumab.
Type B insulin resistance syndrome (TBIRS) is a rare autoimmune condition characterized by insulin receptor autoantibodies, often in association with systemic lupus erythematosus (SLE). It can cause extreme insulin resistance, with fewer than 200 cases described worldwide. A 24-year-old man with no prior autoimmune history presented with diabetic ketoacidosis and severe insulin resistance, requiring up to 215 000 units of insulin daily. Laboratory studies revealed high-titer antinuclear antibodies, hypocomplementemia, lupus-specific autoantibodies, and mesangial proliferative lupus nephritis, confirming new-onset SLE. His management was complicated by latent tuberculosis, neutropenia, and cyclophosphamide-induced hearing loss. Despite intensive therapy with corticosteroids, rituximab, cyclophosphamide, obinutuzumab, plasmapheresis, and intravenous immunoglobulin, he remained profoundly insulin resistant, requiring very high daily insulin doses, with persistently elevated insulin receptor antibody titers. Initiation of daratumumab, a CD38 monoclonal antibody, resulted in marked clinical improvement, with progressive decline in insulin requirements and eventual discontinuation of insulin 17 months after presentation. He achieved durable remission with normalization of hemoglobin A1c. This unusually severe case of TBIRS highlights the limitations of conventional B-cell-directed therapies, where long-lived plasma cells sustain pathogenic autoantibodies. Plasma cell-targeted strategies such as daratumumab may represent an effective therapeutic option in refractory cases.
2026-03-13 | Clinical Characteristics and Risk Factors of Exogenous Insulin Antibody Syndrome in Patients with Diabetes: A Retrospective Cross-Sectional Study.
Insulin autoimmune syndrome (IAS) is a rare hypoglycemic disorder often confused with insulinoma or insulin overdose. Patients with diabetes on insulin therapy increasingly show insulin autoantibodies (IAAs), presenting symptoms similar to classic IAS, termed exogenous insulin antibody syndrome (EIAS). This study examines EIAS clinical features and risk factors. Patients with diabetes with IAA test results, admitted to our hospital between June 2023 and March 2024 were retrospectively enrolled. Participants were stratified into control and EIAS groups on the basis of IAA status. Clinical characteristics were compared between groups, independent risk factors for EIAS were identified by multivariate logistic regression, and the diagnostic utility of fasting insulin for predicting EIAS was assessed with receiver-operating-characteristic (ROC) curve analysis. Of 120 patients with diabetes and available IAAs results, 37 met criteria for EIAS. Compared with controls, EIAS patients were older, had longer diabetes duration, were more often treated with insulin aspart or premixed human insulin, and received higher daily insulin doses. Paradoxically, EIAS patients had markedly lower levels of fasting blood glucose and HbA1c, while higher fasting and 2-h post-prandial insulin concentrations, as well as HOMA-IR. Multivariate logistic regression analysis showed that elevated fasting insulin levels were independently associated with increased risk of EIAS. For every 1 uU/mL increase in fasting insulin, the risk of EIAS increased by 3% (OR = 1.03, 95% CI: 1.00-1.05). The fasting insulin level demonstrated high overall diagnostic and predictive efficacy for EIAS, with an area under the curve (AUC) of 0.782 (95% CI: 0.691-0.872). The optimal diagnostic cutoff value was 6.975 uU/mL, with a sensitivity of 73.0% and a specificity of 81.9%. EIAS patients were identified with advanced age, prolonged diabetes duration, high insulin dosage, hypoglycemia, and hyperinsulinemia. Fasting insulin level is independently associated with EIAS risk and demonstrates good diagnostic performance.
2026-02-05 | Three Interesting Cases of Hypoglycemia: A Case Series.
Hypoglycemia can be due to exogenous hyperinsulinemic hypoglycemia or endogenous hyperinsulinemic hypoglycemia (ENHH). ENHH is a rare entity characterized by inappropriately elevated plasma insulin in the background of low plasma glucose levels. ENHH, being an uncommon disease, is caused by many rare entities, with drug-induced being the most common cause of hypoglycemia. Other causes include insulinoma, insulin autoimmune syndrome, and nesidioblastosis. Here, we report three rare cases of non-diabetic hypoglycemia referred to the endocrinology clinic who had signs and symptoms of hypoglycemia fulfilling Whipple's triad with evidence of hyperinsulinemia despite low plasma glucose. All the appropriate biochemical investigations along with imaging studies were conducted to find out the etiology of hypoglycemia. After taking detailed medical history and clinical examination with biochemical and radiological investigations, patients were diagnosed with insulin autoimmune syndrome, insulinoma, and drug-induced hypoglycemia. Appropriate management was started, and patients were relieved of hypoglycemia. Diseases causing hypoglycemia have similar manifestation, but the diagnosis and management are always a challenging task. Hence, an accurate and early diagnosis is always a deciding factor for further prognosis.
2026-01-01 | Case Report on Hypoglycemia – Beyond Diet, Drugs and Diabetes
Hypoglycemia is a common presentation for various conditions presenting to the emergency department. After ruling out drugs as a cause, especially in nondiabetic individuals, classification to hyperinsulinemic or non-hyper insulinemic hypoglycemia is the next step. Since insulinoma is one of the most common causes of hyperinsulinemia, several imaging modalities are typically used in the search for it. However, in the presence of autoimmune autoantibody syndrome should be thought of. Here we report a case of an elderly non diabetic female with recurrent hypoglycemia. She was noticed to have late postprandial hypoglycemia. Investigation revealed raised insulin levels, raised C peptide levels, and high titers of insulin auto-antibodies. The patient was diagnosed with Insulin antibody syndrome (IAS). IAS may not be a rare syndrome; physicians need to be more vigilant to diagnose and manage such patients.
2025-07-23 | Successful treatment with rituximab of a type 2 diabetes patient with antibody-mediated insulin resistance syndrome: A case report.
Insulin antibody-mediated insulin resistance is a rare autoimmune mechanism that can cause severe hyperglycemia. A 52-year-old male patient was admitted to our hospital with complaints of polydipsia, polyuria, and weight loss (8 kg in 6 months). He was diagnosed with type 2 diabetes mellitus at age 33. Type 2 diabetes mellitus with antibody-mediated insulin resistance syndrome. Rituximab infusion in a 500 mg dose was given 2 times in a 2-week interval. A significant response was achieved 1 month later with fasting plasma glucose: 120 mg/dL (6.7 mmol/L), glycosylated hemoglobin A1c: 7.6% (59.6 mmol/mol), and anti-insulin antibodies: 0.001 U/mL. Clinically improved response persisted for about 6 months. Clinicians should be aware of the antibody-mediated insulin resistance, recognize suggestive signs and symptoms, pursue appropriate diagnostic evaluation, and treatment approach.
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Drug Discovery Landscape
1 orphan drug designation for Insulin autoimmune syndrome.
1 orphan drug designation for Insulin autoimmune syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Glucagon analogue linked to a human immunoglobulin Fc fragment | antibodies | EMA | 2020-04-22 | — | JVM Europe B.V. |
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