Persistent Insulin Autoimmune Syndrome in a Caucasian Male in the Absence of Triggers.

Insulin autoimmune syndrome (IAS) or Hirata disease is a rare condition presenting as recurrent hypoglycemia, and associated with elevated insulin levels in the presence of insulin autoantibodies (IAAs) in patients who were never exposed to exogenous insulin and with no evidence of pancreatic abnormalities. IAS is much more frequent in East Asians, especially the Japanese population, compared to the lower incidence in Caucasians. However, it can be associated with other autoimmune diseases or drug use like methimazole and alpha-lipoic acid (ALA). We report a case of a 47-year-old Caucasian male presenting with a 12-month history of worsening episodes of fasting and post-prandial hypoglycemia associated with symptoms of dizziness, tremors, palpitations, and unconsciousness associated with hypoglycemia. Symptoms resolved with the administration of carbohydrate-containing foods, establishing Whipple's triad. At an outside facility, he had initial labs that showed elevated insulin levels (141 µU/ml) with normal glucose, C-peptide, and proinsulin levels, but there was no availability of an IAA lab assay. Given his symptoms, severity, and frequency of hypoglycemia, he was admitted to the hospital for a 72-hour fast, which showed the lowest glucose level of 64 mg/dl with inappropriately high insulin of 22.2 µU/ml, low C-peptide of 0.57 ng/ml, and undetectable proinsulin of <1.6 pmol/L, but with IAA being >50 U/ml (0.0-0.4 U/ml). He was treated with intensive dietary counseling with a low-carbohydrate diet and prednisone 20 mg twice daily initially. Additionally, he could not tolerate octreotide, diazoxide, and acarbose due to side effects. He is currently on prednisone 10 mg daily and nifedipine with no further hypoglycemic episodes, but still has a high IAA of >50 U/ml and serum insulin levels of 70-112 µU/ml. Our case highlights the importance of recognizing hypoglycemia and checking for IAA levels as first-line diagnostic tests, in the absence of which there could be a delay in diagnosis and leading to unnecessary lab and imaging testing. Our case is unique since it happened in a Caucasian without any prior exposure to a triggering factor and has not undergone self-remission yet, which happens in most of IAS cases.

An Unusual Case of Hypoglycemia in a Non-diabetic Individual due to Hirata Disease.

Hypoglycemia is common in diabetic populations using insulin or insulin secretagogues, but rare in non-diabetics. A 60-year-old non-diabetic male presented with repeated episodes of abnormal behavior persisting for 10-15 minutes for seven days, associated with sweating, intense hunger, and relief on food intake, with no history of insulin or secretagogue intake, with stable vitals and normal systemic examination. Laboratory tests during attacks revealed low blood sugar, high serum insulin, and normal C-peptide levels, with no evidence of pancreatic or extrapancreatic hyperinsulinism, and serum anti-insulin antibody levels >100 U/ml. Based on these results, he was diagnosed with autoimmune insulin syndrome (AIS). Treatment with low-carb meals, oral prednisolone, and acarbose led to the resolution of symptoms. Hirata syndrome, though rare in India, requires consideration as a differential diagnosis to avoid unnecessary invasive procedures.

Systematic Review-Type B Insulin Resistance With Isolated Hypoglycemia and Suppressed Insulin.

OBJECTIVE: Type B insulin resistance syndrome is a rare autoimmune disorder affecting glucose homeostasis, characterized by serum autoantibodies to the insulin receptor (AIRAbs). Patients typically present with severe insulin resistance. A mixed hyper- and hypoglycemia phenotype may also occur, as may isolated hypoglycemia. The classic biochemical pattern comprises elevated insulin levels despite hypoglycemia; however, a small proportion of cases demonstrate "isolated hypoglycemia with low insulin." The primary objectives of this systematic review were to identify the clinical characteristics and outcome of this subgroup. DESIGN: Systematic review of cases with hypoglycemia with suppressed insulin. Exclusions: hyperglycemia, elevated insulin, AIRAbs not confirmed. METHODS: PubMed, Medline, and Embase databases were searched up until February 2023 and complemented by manual citation search. The Joanna Briggs Institute critical appraisal checklist for case reports was used to assess bias. RESULTS: A total of 5342 articles were identified after duplicate removal. Eleven, all case reports, met all inclusion criteria and were included. Cases belonging to this subgroup were more diverse in sex, age, and ethnicity when compared with type B insulin resistance as a whole. Of the 11 cases, 3 developed lymphoma. High-dose corticosteroid therapy appeared to be effective therapy for the hypoglycemia, with often rapid response. CONCLUSIONS: Isolated hypoglycemia with low insulin forms a rare subgroup of type B insulin resistance. These patients lack the common characteristics of hyperinsulinemic hypoglycemia and hyperglycemia/insulin resistance. Furthermore, while coexisting autoimmune disease is commonly observed, there is potentially an association with aggressive lymphoma, the onset of which may be delayed.

Type B Insulin Resistance Syndrome: A Rare Cause of Hypoglycemia.

We describe a case of a Black female patient with a history of type 2 diabetes mellitus and systemic lupus erythematosus, who had a subacute onset of severe hypoglycemia that persisted after cessation of insulin therapy. Biochemical testing revealed hyperinsulinemic hypoglycemia, normal serum triglycerides, and high-normal serum adiponectin levels. Abdominal imaging demonstrated an 11-mm cystic pancreatic lesion. Her clinical history and biochemical test results raised suspicion for type B insulin resistance syndrome (TBIRS), which was confirmed on anti-insulin receptor antibody testing. The patient's hypoglycemia was managed with dietary modification therapy and continuous glucose monitoring. The severity and frequency of hypoglycemic episodes decreased spontaneously. We describe TBIRS and its uncommon hypoglycemic presentation, analyze factors that put TBIRS among the differential diagnosis, and discuss the treatment of TBIRS-associated hypoglycemia.

Clopidogrel as a Distinctive Cause of Insulin Autoimmune Syndrome: A Systematic Case Review.

The sulfhydryl group of clopidogrel metabolite could induce insulin autoimmune syndrome (IAS) with hypoglycemia as the major symptom. For patients with cardiovascular disease taking clopidogrel for vascular protection, this adverse event hypoglycemia increases the risk of cardiovascular events. However, discontinuing clopidogrel leaves patients without appropriate antiplatelet therapy. Treating IAS with glucocorticoids is also risky for these patients' primary cardiovascular diseases. Early recognition and appropriate treatment of clopidogrel-induced IAS (CIAS) would be beneficial for patients. This research aimed to discover the clinical features and investigate optimal therapeutic management of CIAS. We systematically searched for cases of CIAS in PubMed and Embase and performed data mining in Food and Drug Administration Adverse Event Reporting System (FAERS). In the CIAS series, clinical features were summarized and compared to 287 IAS cases, including demographic information, HLA alleles, onset, and symptoms. The therapeutic effect of glucocorticoids was compared between the receiving group and the not-receiving group. The possibilities of common antiplatelet drugs to induce hypoglycemia/IAS were investigated with chemical structure and FAERS reports. A CIAS series of 51 patients was established. CIAS had an onset age of 74.8±8.6 years old, 92.2% male, and a balanced proportion of East Asians and non-East Asians. Confusion occurred more frequently in CIAS than in IAS from various causes, while the other symptoms and hypoglycemia types were similar. The recovery time was approximately the same whether using glucocorticoids/immunotherapy in CIAS or not. Among common antiplatelet drugs, ticagrelor and rivaroxaban were unlikely to induce hypoglycemia/IAS. Clopidogrel is a distinctive cause of IAS featuring an elderly male presenting confusion as the symptom of hypoglycemia. Glucocorticoids/immunotherapy might not be necessary for the long-term recovery of CIAS. To balance the risks of hypoglycemia and cardiovascular events, substituting clopidogrel with ticagrelor and rivaroxaban might be considered.

Enfermedades endocrinas asociadas a vacunación por la COVID-19: Reporte de Casoss / Endocrine diseases associated with COVID-19 vaccination: case reports

La vacunación contra el SARS-CoV-2 no está exenta de efectos adversos. Se presenta dos casos de afectación endocrina asociada a la vacunación por la COVID-19. Mujer de 46 años que, luego de la primera dosis, presentó fiebre persistente y signos de tirotoxicosis, tras el diagnóstico de tiroiditis subaguda asociada a vacunación por la COVID-19, el cuadro remitió con el uso de corticoides. Varón de 71 años, que luego de la vacunación por la COVID-19, presentó hipoglicemias hiperinsulinemicas, con resultado positivo de anticuerpos antiinsulina. Se le diagnosticó con una hipoglicemia autoinmune asociada a la vacunación por la COVID-19 y recibió tratamiento con prednisona, controlando los episodios de hipoglicemia. En conclusión, las enfermedades endocrinas asociadas a vacunación por la COVID-19 son extremadamente raras y su detección oportuna permite su tratamiento adecuado.

SARS-CoV-2 vaccination is not free of adverse effects. We present two cases of endocrine involvement associated with COVID-19 vaccination. A 46-year-old woman who, after receiving the first COVID-19 vaccination dose, presented persistent fever and signs of thyrotoxicosis after being diagnosed with subacute thyroiditis associated with COVID-19 vaccination; the condition remitted with the use of corticoids. A 71-year-old male, who after COVID-19 vaccination, presented hyperinsulinemic hypoglycemia, testing positive for anti-insulin antibodies; he was diagnosed with autoimmune hypoglycemia associated with COVID-19 vaccination and received treatment with prednisone, controlling the episodes of hypoglycemia. In conclusion, endocrine diseases associated with COVID-19 vaccination are extremely rare and their timely detection allows adequate treatment.

Hypoglycemia Caused by Exogenous Insulin Antibody Syndrome: A Large Single-Center Case Series From China.

CONTEXT: Exogenous insulin antibody syndrome (EIAS) can lead to unexpected and potentially life-threatening recurrent hypoglycemia. OBJECTIVE: We aimed to better define autoimmune hypoglycemia caused by EIAS in patients with diabetes and shed light on the improvements in the identification and intervention for this rare but possibly life-threatening condition. METHODS: We summarized the clinical characteristics of autoimmune hypoglycemia caused by EIAS in 23 patients with diabetes. Furthermore, we performed human leukocyte antigen (HLA) genotyping of 10 patients. RESULTS: We identified a high frequency of autoimmune comorbidities (21.7%), food or drug allergy (48%), insulin allergy (30%), lipodystrophy at the insulin injection sites (22%), and antinuclear antibodies (25%) in the patients. Alternation between hyperglycemia and hypoglycemia was observed in more than 90% of the patients. Most patients showed a high insulin autoantibody titer (>90%) and inappropriately increased insulin concentration (insulin/C-peptide molar ratio >7, >85%). We detected similar frequencies of DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 compared with previously reported frequencies in type 1 diabetes, and a lower frequency of DRB1*0406 compared with insulin autoimmune syndrome. The spontaneous remission rate exceeded 70%. CONCLUSION: Predisposing factors for autoimmune hypoglycemia caused by EIAS include a strong autoimmune background. Susceptible HLA genotypes for type 1 diabetes or insulin autoimmune syndrome might not explain susceptibility to this condition. Additionally, insulin autoantibodies and the insulin/C-peptide molar ratio are reliable screening options. The prognosis for this condition is favorable. Monitoring of insulin and insulin autoantibodies may contribute to treatment effectiveness.

Insulin Receptor Autoantibody-mediated Hypoglycemia in a Woman With Mixed Connective Tissue Disease.

Autoantibodies to the insulin receptor are rare and typically cause severe insulin resistance and hyperglycemia, a condition termed type B insulin resistance. Uncommonly, antibodies to the insulin receptor can cause hypoglycemia. We present the case of a woman who developed recurrent severe hypoglycemia and myopathy, was found to have insulin receptor autoantibodies and mixed connective tissue disease, and had resolution of hypoglycemia with immunosuppression. A 55-year-old woman with a history of obesity, hypertension, and prior hemorrhagic stroke presented with recurrent severe hypoglycemia. A diagnostic fast resulted in hypoinsulinemic hypoketotic hypoglycemia. Adrenal function was intact. Progressive myopathy had developed simultaneously with her hypoglycemia, and rheumatologic evaluation revealed mixed connective tissue disease. The plasma acylcarnitine profile was normal, extensive oncologic evaluation including insulin-like growth factor 2 measurement was unrevealing, and anti-insulin antibody testing was negative. Ultimately, anti-insulin receptor antibodies were found to be present. The patient was treated with glucocorticoids and rituximab. Eight weeks after initiation of immunosuppression, the insulin receptor antibody titer had decreased and hypoglycemia had resolved. Eight months after diagnosis, the patient remained free of severe hypoglycemia despite tapering of glucocorticoids to a near-physiologic dose. Though antibodies to the insulin receptor typically cause severe insulin resistance, this patient had no evidence of insulin resistance and instead presented with recurrent severe hypoglycemia, which responded to glucocorticoids and rituximab. The diagnosis of insulin receptor antibody-mediated hypoglycemia is rare but should be considered in patients with systemic autoimmune disease, including mixed connective tissue disease, in the appropriate clinical context.

Insulin Autoimmune Syndrome as Part of Pre-Clinical LADA.

Hypoglycemia presents relatively typical symptoms. However, when it occurs spontaneously - like in insulin autoimmune syndrome - it is difficult to perform scheduled biochemical tests at the laboratory. The study presents the case of a 31-year-old Caucasian female whose recurrent hypoglycemia symptoms were the reason for further diagnostics. The final results revealed a positive test for insulin autoantibody and glutamic acid decarboxylase autoantibody. Therefore, not only the potential causes of hypoglycemia but also an active autoimmune process typical for latent autoimmune diabetes in adults were confirmed. It was concluded that autoimmune hypoglycemia can be a part of the autoimmune process associated with diabetes and pre-diabetes in adults.

Systemic lupus erythematosus complicated with autoimmune hypoglycemia with pancytopenia as first manifestation: A case report and literature review / 吉林大学学报(医学版)

Objetive: To analyze the hematological changes of systemic lupus erythematosus (SLE) and the clinical characteristics of immune-related hypoglycemia, and to provide the basis for the diagnosis and treatment of SLE complicated with autoimmune hypoglycemia (AIH). Methods: The clinical data a patient with SLE complicated with AIH with pancytopenia as the first manifestation were collected and the relevant literatures were reviewed. Results: A 70-year-old man was admitted to hospital because of dizziness and fatigue, and suffered from more than 3 months, aggravated for 2 weeks. The physical examination results showed pale conjunctiva, moist rales over the both lower lung and there were no other obvious positive signs. The blood test showed pancytopenia and the fasting blood glucose 2. 34 mmol · L-1 The pathomorphology of tissue was observed by bone marrow puncture; rheumatism examinations, glucose metabolism indexes, insulin autoantibodies (IAA) and other assistant examinations were performed, and the patient received the related treatment. The patient had a history of photosensitivity. Admission examinations indicated multiple serous effusions, urinary protein >). 5 g · 24 h-1, pancytopenia, abnormal antinuclear antibody (ANA) titer, pancreatic CT (-), and the patient was diagnosed as SLE complicated AIH finally. After treatment of prednisone, the symptoms of the patient were improved; the the whole blood count and fasting blood glucose responded well to the therapy of prednisone. After discharge from the hospital, the patient was treated with prednisone continuously and was required to regularly monitor the blood test and the blood glucose level. The patient's whole blood count was gradually increased and no hypoglycemia occurred. Conclusion: SLE with hematological changes as the first manifestation is easily misdiagnosed. And autoantibody-mediated glucose homeostasis should be considered when SLE is complicated with hypoglycemia.

Pseudoinsulinoma in a white man with autoimmune hypoglycemia due to anti-insulin antibodies: value of the free C-Peptide assay.

OBJECTIVES: Insulin autoimmune syndrome (IAS) is an extremely rare cause of hypoglycemia, particularly in non-Asian populations. METHODS: In this report, we describe a white male patient with elevated total insulin (>100.0 µIU/mL), C-peptide, and proinsulin levels who was diagnosed with IAS due to anti-insulin antibodies. He also had a small IgG κ M-protein. RESULTS: We show that anti-insulin antibodies and/or the monoclonal protein can significantly interfere with insulin and C-peptide immunoassays and propose polyethylene glycol precipitation to quantitate free C-peptide levels as a useful assay in differentiating IAS due to anti-insulin antibodies from insulinoma. CONCLUSIONS: In patients presenting with hypoglycemia with excessively high insulin levels, consideration needs to be given to autoimmune hypoglycemia due to anti-insulin antibodies as a cause. Additionally, if total C-peptide levels are increased, free C-peptide needs to be quantitated following polyethylene glycol precipitation.

Type B insulin-resistance syndrome presenting as autoimmune hypoglycemia, associated with systemic lupus erythematosus and interstitial lung disease.

We describe an unusual case of systemic lupus erythematosus with pulmonary manifestations presenting as hypoglycemia due to anti-insulin receptor antibodies. A 38-year-old female suffered an episode of unconsciousness and was admitted to hospital where her blood glucose was found to be 18 mg/dL. During the hypoglycemic episode, her serum insulin level was inappropriately high (2,207.1 pmol/L; normal range, 18 to 173) and C-peptide level was elevated (1.7 nmol/L; normal range, 0.37 to 1.47). Further blood tests revealed the presence of antinuclear antibodies, anti-double-stranded DNA antibodies, and anti-Ro/SSA, anti-La/SSB, anti-ribonucleoprotein, and anti-insulin receptor antibodies. A computed tomography scan of the abdomen, aimed at tumor localization, such as an insulinoma, instead revealed ground-glass opacities in both lower lungs, and no abnormal finding in the abdomen. For a definitive diagnosis of the lung lesion, video-associated thoracoscopic surgery was performed and histopathological findings showed a pattern of fibrotic non-specific interstitial pneumonia.

A case of autoimmune hypoglycemia outside Japan: Rare, but in the era of expanding drug-list, important to suspect.

We are hereby reporting a case of a 72-year-old Indian man, who, in the absence of a detectable tumor, presented with symptomatic hypoglycemia in the postabsorptive state (3-5 h after meal). His serum levels of insulin and C-peptide were very high. He was not taking any hypoglycemic drug. Hypoglycemic episodes completely subsided after withdrawal of pentoprazole and incorporation of small frequent meals in the dietary plan. Six months after the initial presentation, the subject became free of hypoglycemic episodes. Although insulin autoimmune syndrome (IAS) is the third leading cause of spontaneous hypoglycemia in Japan, it is extremely uncommon in the Western Countries. Till 2009, more than 200 cases from Japan and as many as 58 cases outside Asia have been reported. To the best of our knowledge, this is the first case of IAS reported from India.

Type B insulin-resistance syndrome presenting as autoimmune hypoglycemia, associated with systemic lupus erythematosus and interstitial lung disease

We describe an unusual case of systemic lupus erythematosus with pulmonary manifestations presenting as hypoglycemia due to anti-insulin receptor antibodies. A 38-year-old female suffered an episode of unconsciousness and was admitted to hospital where her blood glucose was found to be 18 mg/dL. During the hypoglycemic episode, her serum insulin level was inappropriately high (2,207.1 pmol/L; normal range, 18 to 173) and C-peptide level was elevated (1.7 nmol/L; normal range, 0.37 to 1.47). Further blood tests revealed the presence of antinuclear antibodies, anti-double-stranded DNA antibodies, and anti-Ro/SSA, anti-La/SSB, anti-ribonucleoprotein, and anti-insulin receptor antibodies. A computed tomography scan of the abdomen, aimed at tumor localization, such as an insulinoma, instead revealed ground-glass opacities in both lower lungs, and no abnormal finding in the abdomen. For a definitive diagnosis of the lung lesion, video-associated thoracoscopic surgery was performed and histopathological findings showed a pattern of fibrotic non-specific interstitial pneumonia.

Hiperparatiroidismo primario asociado a pancreatitis autoinmune, colangitis esclerosante y posible hipoglucemia autoinmune / Primary hyperparathyroidism associated with autoimmune pancreatitis, sclerosing cholangitis and probable autoimmune hypoglycemia

Se informa el caso de una mujer de 42 años quien desarrolla pancreatitis autoinmune, colangitis esclerosante y probable hipoglucemia autoinmune, asociada con hiperparatiroidismo primario. (Acta Med Colomb 2012; 37: 80-82).

Abstract We report the case of a 42 year old woman who developed autoimmune pancreatitis, sclerosing cholangitis and probable autoimmune hypoglycemia associated with primary hyperparathyroidism. (Acta Med Colomb 2012; 37: 80-82).

Autoimmune hypoglycemia in a patient with characterization of insulin receptor autoantibodies.

BACKGROUND: Type B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor that results in severe hyperglycemia and acanthosis nigricans. However, the mechanisms by which these autoantibodies induce hypoglycemia are largely unknown. In this paper, we report the case of patient with type B insulin resistance syndrome who presented with frequent severe fasting hypoglycemia and acanthosis nigricans. METHODS: To evaluate the mechanism of hypoglycemia, we measured the inhibition of insulin binding to erythrocytes and IM9 lymphocytes in a sample of the patient's dialyzed serum before and after immunosuppressive therapy. RESULTS: In the patient's pre-treatment serum IgG, the binding of (125)I-insulin to erythrocytes was markedly inhibited in a dose-dependent manner until the cold insulin level reached 10(-9) mol/L. We also observed dose-dependent inhibition of insulin binding to IM9 lymphocytes, which reached approximately 82% inhibition and persisted even when diluted 1:20. After treatment with glucocorticoids, insulin-erythrocyte binding activity returned to between 70% and 80% of normal, while the inhibition of insulin-lymphocyte binding was reduced by 17%. CONCLUSION: We treated a patient with type B insulin resistance syndrome showing recurrent fasting hypoglycemia with steroids and azathioprine. We characterized the patient's insulin receptor antibodies by measuring the inhibition of insulin binding.

Autoimmune Hypoglycemia in a Patient with Characterization of Insulin Receptor Autoantibodies

BACKGROUND: Type B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor that results in severe hyperglycemia and acanthosis nigricans. However, the mechanisms by which these autoantibodies induce hypoglycemia are largely unknown. In this paper, we report the case of patient with type B insulin resistance syndrome who presented with frequent severe fasting hypoglycemia and acanthosis nigricans. METHODS: To evaluate the mechanism of hypoglycemia, we measured the inhibition of insulin binding to erythrocytes and IM9 lymphocytes in a sample of the patient's dialyzed serum before and after immunosuppressive therapy. RESULTS: In the patient's pre-treatment serum IgG, the binding of 125I-insulin to erythrocytes was markedly inhibited in a dose-dependent manner until the cold insulin level reached 10-9 mol/L. We also observed dose-dependent inhibition of insulin binding to IM9 lymphocytes, which reached approximately 82% inhibition and persisted even when diluted 1:20. After treatment with glucocorticoids, insulin-erythrocyte binding activity returned to between 70% and 80% of normal, while the inhibition of insulin-lymphocyte binding was reduced by 17%. CONCLUSION: We treated a patient with type B insulin resistance syndrome showing recurrent fasting hypoglycemia with steroids and azathioprine. We characterized the patient's insulin receptor antibodies by measuring the inhibition of insulin binding.

A case of autoimmune hypoglycemia during treatment with anti-tuberculosis drugs / 대한내과학회지

Autoimmune hypoglycemia is characterized by insulin autoantibody, hyperinsulinemia and fasting hypoglycemia without previous insulin immunization. Negative results on the anatomic studies of the pancreas and an inability to reproduce hypoglycemia during a prolonged fast may be helpful in excluding insulinoma. Autoimmune hypoglycemia is self-limited disorder. We recently experienced a case of autoimmune hypoglycemia in a patient with insulin antibody, and the patient was without previous insulin injection therapy or any evidence of insulinoma, during treatment with anti-tuberculosis drugs. We present this case along with a review of the literature.