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:
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.
2026-05-29 | 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.
2026-02-27 | 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.
2026-07-13 | 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.
2026-05-29 | 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.
2026-02-27 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
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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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