Insulin Receptor Autoantibodies Research Articles

THU381 A Case of Severe Type B Insulin Resistance Successfully Treated With Combined Immunosuppressive Therapy

Abstract Disclosure: A.K. Sumal: None. D.S. Martinez: None. Background: Type B insulin resistance is a rare autoimmune disorder caused by autoantibodies against the insulin receptor and is characterized by markedly high insulin requirements, severe catabolism, and a mortality rate over 50%. Clinical Case: A 50-year-old woman with Sjogren’s syndrome and a one-year history of diabetes treated with insulin presented with diabetic ketoacidosis (DKA) and was found to have type B insulin resistance. Initial laboratory workup demonstrated DKA with a blood glucose of 464 mg/dL (n: 65–99 mg/dL), CO2 8 mmol/L (n: 20–30 mmol/L), anion gap 16 (n: 8–12), pH 7.08 (n: 7.30–7.40) on venous blood gas, 2+ ketonuria, and a hemoglobin A1c of 11.7% (n: <5.7%). Additional workup revealed negative glutamic acid decarboxylase-65, insulin antigen-2, and insulin antibodies, positive C-peptide 2.7 ng/mL (n: 1.1–4.3 ng/mL), and elevated adiponectin 41 ug/mL (n: 5–28 ug/mL). Her physical exam was notable for 100 lb weight loss and extensive acanthosis nigricans, facial acne, and hirsutism. She was started on IV insulin infusion with resolution of her DKA but required more than 5000 units of insulin per day to obtain glycemic control. Due to the suspicion of type B insulin resistance, she was treated with metformin 1000 mg twice daily and pioglitazone 45 mg daily to reverse her hypercatabolic state and combined immunosuppressive therapy consisting of 2 cycles of rituximab 750 mg/m2 infusion, cyclophosphamide 100 mg daily, and dexamethasone 40 mg for 4 days administered 14 days apart based on a 2018 NIH protocol. Her serum was sent for confirmatory insulin receptor autoantibody testing, which is pending. Over the next 30 days, her insulin requirements improved immensely, and she was ultimately discharged without insulin in clinical remission. To prevent recurrence and hypoglycemia associated with low titers of insulin receptor autoantibodies, she was started on azathioprine 100 mg daily as maintenance therapy. Three months later, she was seen in endocrine clinic in sustained remission with a hemoglobin A1c of 6.0% and resolution of her acanthosis nigricans and hyperandrogenism. Review of her continuous glucose monitor showed no episodes of hypoglycemia. Conclusion: This rare case demonstrates the successful treatment of type B insulin resistance using metformin, pioglitazone, and combination immunosuppressive therapy with rituximab, cyclophosphamide, and pulse-dose steroids, followed by maintenance azathioprine. With a mortality rate over 50%, the use of combined immunosuppressive therapy has transformed this condition into a curable form of diabetes and should be recommended in all patients with type B insulin resistance. Presentation: Thursday, June 15, 2023

THU267 A Novel In Vitro Assay Correlates Insulin Receptor Autoantibodies To Fasting Insulin In Type B Insulin Resistance

Abstract Disclosure: B. Abel: None. W. Minich: Stock Owner; Self; ImmunometriX GmbH. C. Schwiebert: Employee; Self; Bruker Corporation. T. Welsink: Employee; Self; Bruker Corporation. P. Seemann: Stock Owner; Self; ImmunometriX GmbH, selenOmed GmbH. L. Schomburg: Stock Owner; Self; selenOmed GmbH. R.J. Brown: None. Severe insulin resistance (IR) in the presence of insulin receptor autoantibodies (InsR-aAb) is known as type B IR (TBIR). TBIR has a spectrum of phenotypes, including severe IR with uncontrolled diabetes (DM), milder IR without uncontrolled DM, hypoglycemia, and remission states. Considerable progress in therapy has been achieved, but diagnosis and monitoring of InsR-aAb remains a challenge. We aimed to develop a robust in vitro method for InsR-Ab quantification and correlate it with clinical outcomes. 28 longitudinal serum samples from 9 patients with TBIR were collected before, during, and after immunosuppression. Samples included 11 in states of remission, 4 in hypoglycemia, 6 in mild IR, and 7 in severe IR. Samples from 8 patients with IR not due to TBIR (type 1 DM, N=1; type 2 DM, N=4; lipodystrophy, N=2; and INSR mutation, N=1) were used as controls. A bridge-assay for InsR-aAb detection was established using recombinant human insulin receptor as bait and detector and validated using monoclonal antibodies as positive controls. The assay consists of an immobilized recombinant InsR at a plastic surface and an InsR-Luc fusion protein for detection of InsR-aAb. There was dose-dependent increase in intensity over >2 orders of magnitude with InsR-specific commercial mAb, but not with control mAb. In the presence of insulin, strong InsR phosphorylation was observed in cells incubated with Ig from control sera, but not those incubated with Ig from TBIR patient sera. Fasting insulin was highest in severe TBIR (median 1000 [IQR 273-1000] mcU/mL), followed by mild (71[32-230]), and lower in hypoglycemia (6 [3,103]) and remission (14[6,35]), P=0.0014, and was moderately elevated in insulin resistant controls (55[11,120]). A1c was elevated in severe TBIR & controls (9.9±3.0 & 9.1±3.8%) and near-normal in mild, hypoglycemic, and remission states of TBIR (5.7±1.3, 6.0±0.7, 5.7±1.1). InsR-aAb titers changed in parallel to changes in TBIR state and severity: highest in severe TBIR (median 700 [IQR 365-977]), followed by mild (176[98-254]), and lower in hypoglycemia (14[1.3-189]) and remission (17[3-28]). All TBIR samples showed clearly elevated signal intensities versus controls (0.9[0.7-1.1], Bonferroni corrected P<0.05 for all TBIR states vs controls). During treatment, InsR-aAb for each subject declined with amelioration of disease symptoms. Fasting insulin strongly correlated with InsR-aAb titers (r=0.825, p<0.001). The assay correctly identified all samples from patients with TBIR vs controls with non-autoimmune IR, and thus is an easy to interpret diagnostic tool. InsR-aAb titers correlated with fasting insulin, supporting direct relevance of InsR-aAb as causal for disease severity and as therapeutic targets for Ab depletion. By easing diagnosis and monitoring of TBIR, the new assay for InsR-aAb quantification should enhance access to timely and effective treatment for TBIR. Presentation: Thursday, June 15, 2023

A Novel In Vitro Assay Correlates Insulin Receptor Autoantibodies With Fasting Insulin in Type B Insulin Resistance.

Severe insulin resistance (IR) in the presence of insulin receptor autoantibodies (InsR-aAb) is known as type B insulin resistance (TBIR). Considerable progress in therapy has been achieved, but diagnosis and monitoring of InsR-aAb remains a challenge. This work aimed to establish a robust in vitro method for InsR-Ab quantification. Longitudinal serum samples from patients with TBIR at the National Institutes of Health were collected. A bridge-assay for InsR-aAb detection was established using recombinant human insulin receptor as bait and detector. Monoclonal antibodies served as positive controls for validation. The novel assay proved sensitive, robust, and passed quality control. The measured InsR-aAb from TBIR patients was associated with disease severity, decreased on treatment, and inhibited insulin signaling in vitro. Titers of InsR-aAb correlated positively to fasting insulin in patients. Quantification of InsR-aAb from serum samples via the novel in vitro assay enables identification of TBIR and monitoring of successful therapy.

204-LB: An Unusual Case of Autoantibody-Negative Ketosis-Prone Diabetes (KPD) Secondary to Marked Insulin Resistance

KPD is classically regarded as an atypical form of diabetes caused by near-complete beta-cell failure. A 37-year-old Egyptian man (BMI: 27.7 Kg/m2) presented with hyperglycemia (362 mg/dL) and DKA (arterial pH 7.20, ketonemia 5.0 mmol/L, ketonuria 80 mg/dL) . He was afebrile, with recent polyuria, polydipsia and weight loss. HbA1c was 107 mmol/mol (11.9%) and blood tests excluded diabetes secondary to endocrinopathies. SARS-CoV-2 RT-PCR test was negative. IV insulin infusion (0.1 IU/kg/h) and IV fluid therapy were started. He was shortly transitioned to a sc basal-bolus insulin regimen (0.7 IU/kg/day) . Mixed-meal tolerance test (MMTT) revealed a peak 120-min stimulated C-peptide of 12.3 ng/mL, suggesting marked insulin resistance. Islet autoantibodies (ICA, IAA, GADA, IA-2A, ZnT8A) and insulin receptor autoantibodies (IgG/IgM) were negative. HLA genotyping detected the following haplotypes: DRB1*01,*04; DQA1*01:01P,*03:01P; DQB1*03:02P,*05:01P. Insulin dose was gradually reduced and insulin therapy was discontinued after 4 months in favor of metformin (2550 mg/day) plus sc semaglutide (up to 1 mg/week) . After one year, MMTT revealed a peak 60-min stimulated C-peptide of 8.25 ng/mL. During the 18-month follow-up period, fasting capillary beta-hydroxybutyrate values were <0.2 mmol/L and HbA1c remained <48 mmol/mol (<6.5%) , indicating disease remission. This case suggests the existence of an autoantibody-negative KPD subtype driven by marked insulin resistance rather than by insulinopenia. Disclosure M. Infante: None. P. Diperna: None. M. Passeri: None. R. Monetta: None. F. Papola: None. F. Brancati: None. M. Caprio: None. A. Fabbri: None.

Practical Clinical Applications of Islet Autoantibody Testing in Type 1 Diabetes.

The distinction between type 1 diabetes (T1D) and type 2 diabetes (T2D) is extremely important for the choice of therapy, body weight and dietary management, screening for coexistent autoimmune diseases and comorbidities, anticipated prognosis, and risk assessment in relatives. Not uncommonly, the presentation of the patient may not allow an unambiguous discrimination between T1D and T2D. To help resolve this challenge, the detection of islet autoantibodies can support the diagnosis of T1D. The presence of islet autoantibodies in a person with diabetes indicates an autoimmune etiology therefore establishing the diagnosis of T1D. Presently 5 islet autoantibodies are available for routine clinical use: islet cell cytoplasmic autoantibodies (ICA), insulin autoantibodies (IAA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma associated-2 autoantibodies (IA-2A), and zinc transporter-8 autoantibodies (ZnT8A). There are caveats to the selection of which islet autoantibodies should be measured. Islet autoantibodies can also predict the development of T1D. Therefore, once safe and effective therapies are available to prevent T1D, islet autoantibody testing is expected to become a routine part of medical practice. A very rare cause of autoimmune diabetes is the type B insulin resistance syndrome resulting from antagonistic autoantibodies to the insulin receptor. Rarely hypoglycemia can result from agonistic insulin receptor autoantibodies, or high-titer IAA causing the autoimmune insulin syndrome (i.e., Hirata disease). In summary, autoimmune causes of dysglycemia are increasing in clinical importance requiring the scrutiny of laboratorians. The determination of islet autoantibodies can greatly aid in the diagnosis and the prediction of T1D.

New classification and diagnostic criteria for insulin resistance syndrome.

This report of a working group established by the Japan Diabetes Society proposes a new classification and diagnostic criteria for insulin resistance syndrome. Insulin resistance syndrome is defined as a condition characterized by severe attenuation of insulin action due to functional impairment of the insulin receptor or its downstream signaling molecules. This syndrome is classified into two types: genetic insulin resistance syndrome, caused by gene abnormalities, and type B insulin resistance syndrome, caused by autoantibodies to the insulin receptor. Genetic insulin resistance syndrome includes type A insulin resistance as well as Donohue and Rabson-Mendenhall syndromes, all of which are caused by abnormalities of the insulin receptor gene; conditions such as SHORT syndrome caused by abnormalities of PIK3R1, which encodes a regulatory subunit of phosphatidylinositol 3-kinase; conditions caused by abnormalities of AKT2, TBC1D4, or PRKCE; and conditions in which a causative gene has not yet been identified. Type B insulin resistance syndrome is characterized by severe impairment of insulin action due to the presence of insulin receptor autoantibodies. Cases in which hypoglycemia alone is induced by autoantibodies that stimulate insulin receptor were not included in Type B insulin resistance syndrome.

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.

An African American Male Patient with Rare Type B Insulin Resistance Syndrome.

Syndromes of severe insulin resistance can result from mutations in the insulin receptor gene or autoantibodies to the insulin receptor. The type B syndrome of insulin resistance results from autoantibodies to the insulin receptor and occurs predominantly in women under age 50 years. Here we report on a 64 year old African American man with systemic lupus erythematosus (SLE) and acanthosis nigricans who had severe insulin resistance requiring up to 5000 units of insulin per day. He was diagnosed with type B insulin resistance syndrome based on his clinical presentation and demonstration of autoantibodies to the insulin receptor in his serum. This case study underscores the importance of assaying for autoantibodies to the insulin receptors especially in African American patients with severe insulin resistance and diabetes requiring excessive doses of insulin, in the setting of an autoimmune disease like SLE. It also behooves reference laboratories to develop and offer this assay because these patients have a very high mortality.

SAT-131 Asymptomatic Severe Hypoglycemia with Lactic Acidosis in a Case of Non-Hodgkin’s Lymphoma - an Unusual Phenomenon of Hyper-Warburgism

INTRODUCTIONHypoglycemia in malignancy is well known with several etiologies; impaired liver function, insulin receptor autoantibodies, production of insulin-like substance by malignant cells or large tumor burden. Another possible mechanism is the Warburg effect where metabolism shifts towards glycolytic pathways over oxidative phosphorylation even under aerobic conditions leading to excess lactate production. This leads to glucose consumption due to shunting of glucose away from normal cells to cancer cells. Very few cases of lactic acidosis and severe hypoglycemia in Non-Hodgkin’s Lymphoma have been described in the literature. We report such an unusual case here.CASE DISCUSSIONA 52-year-old, African-American male was admitted for severe malnutrition with 80 lb. weight loss, severe hypoglycemia and progressively increasing right chest wall mass. On arrival, he had no classic symptoms of hypoglycemia. Physical exam revealed persistent tachycardia, white patches on oral mucosa and posterior tongue, and an indurated mass on right chest wall with extensive swelling of right upper limb. Lab work was significant for blood glucose (BG) of 41 mg/dL (60–100), lactate 16 mmol/L (0.5 to 2), anion gap 26 mEq/L (3–10), albumin 2.3 g/dL (3.4 to 5.4) and normal renal and liver function tests. Fingerstick sugar readings were persistently in the 20s with no response to multiple boluses of dextrose and glucagon. He was started on dextrose 5% (D5) drip and intravenous solumedrol. Solumedrol was weaned off and D5 titrated down to investigate causes of hypoglycemia. BG dropped to 39 and corresponding labs showed insulin level of < 2 mcUnit/mL (2–20), C-peptide of 0.2 ng/mL (0.8–6.0) and ketone level of 0.2 mmol/L (<0.4). IGF-1 and IGF-2 were both low at 26 ng/mL (61–200) and 113 ng/mL (333–967) respectively. A CT torso with contrast showed bilateral pleural effusions, moderate pericardial effusions and a large ill-defined heterogeneous mass along anterior chest wall. He underwent ultrasound guided biopsy of the chest wall mass and diagnosed with diffuse large B-cell lymphoma. He also tested positive for HIV/AIDS and Hepatitis C. PET scan showed diffuse FDG (fluorodeoxyglucose) uptake consistent with advanced disease. He was started on chemotherapy and lactate and BG normalized soon after 1st cycle.CONCLUSIONIn our case; suppressed insulin, low C-peptide and IGF-2 levels indicate non-insulin mediated hypoglycemia due to rapid glucose utilization by cancer cells. Severe hypoglycemia with lack of neuroglycopenic symptoms suggests use of lactate (rather than glucose) as an alternative metabolic fuel for brain, thus preserving its function. Our patient presented with an exaggerated Warburg effect (hyper-Warburgism) as evident by extreme glucose consumption, severe lactic acidosis and large tumor burden on FDG/PET. Chemotherapy must be instituted timely to correct these abnormalities.

MON-124 Antibody-Mediated Extreme Insulin Resistance: The Importance of Pre-Treatment Screening

Background: Antibody-mediated extreme insulin resistance is characterized by hyperglycemia despite the use of >200 units of insulin/day and is often divided into two subtypes, insulin receptor antibody-mediated (Type B insulin resistance) and insulin antibody-mediated insulin resistance. The National Institutes of Health (NIH) published an immunomodulatory protocol for the treatment of Type B insulin resistance (1). However, there is scarce data on immunomodulatory therapy use for insulin antibody-mediated insulin resistance, and little has been documented to guide pretreatment screening. Clinical Case: We report the case of a 56 year-old Hispanic male with a 10-year history of well-controlled type 2 diabetes, who presented with abrupt onset hyperglycemia/diabetic ketoacidosis resistant to escalating doses of intravenous insulin infusion (>2500 units daily). He was diagnosed with antibody-mediated insulin resistance due to hyperglycemia requiring very high doses of insulin, lack of identifiable precipitants for diabetic ketoacidosis or hyperosmolar hyperglycemic state, and elevated insulin antibody levels. He underwent pre-immunomodulatory therapy screening for infections, rheumatologic disorders, and malignancy, which uncovered a new diagnosis of latent tuberculosis. He was started on treatment for latent tuberculosis, and began immunomodulatory therapy using the protocol developed by the NIH with rituximab, dexamethasone, and cyclophosphamide. One month after the second therapy cycle, insulin was no longer required for glycemic control, and he maintained appropriate glycemic control on oral diabetic agents alone (metformin and pioglitazone). Conclusion: This case validates the use of immunomodulatory therapy for the treatment of insulin antibody-mediated insulin resistance. It also highlights the importance of pre-immunomodulatory therapy screening to uncover occult infection prior to immunosuppression, and to investigate for possible causal neoplastic or rheumatologic disease. We propose an algorithm for pre-immunomodulatory screening prior to therapy in patients with antibody-mediated insulin resistance. Reference: (1) Malek R, Chong AY, Lupsa BC, et al. Treatment of Type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies. The Journal of Clinical Endocrinology & Metabolism. 2010;95(8):3641-3647.

Влияние комплексной терапии с включением неспецифической иммунокоррекции беременных женщин с сахарным диабетом 1 типа на состояние здоровья их детей

Цель. Влияние комплексной терапии с включением неспецифической иммунокоррекции (ингаляции гепарина в гестационном периоде у женщин с сахарным диабетом 1-го типа (СД1) с установленной гиперпродукцией аутоантител к инсулину и его рецепторам), на здоровье рожденных ими детей. Материалы и методы. Проведен сравнительный анализ нервно-психического развития, соматического состояния и иммунологических особенностей у детей от рождения до 3 лет от матерей с СД1, получавших традиционную терапию (основная группа, n = 101) и детей от матерей с СД1, получавших во время беременности в составе комплексной терапии ингаляции гепарином (экспериментальная группа, n = 40). Контрольную группу (n = 30) составили дети от соматически здоровых матерей без инфекционной и эндокринной патологии. Результаты. При анализе частоты регистрируемой у детей в период новорожденности патологии ЦНС установлено увеличение данного показателя по сравнению с контролем обеих группах детей, рождённых от матерей с СД1. Однако по результатам балльной оценки (методика «ГНОМ») выявлено, что в экспериментальной группе было достоверно больше здоровых детей и, наоборот, меньше детей с патологией нервной системы, нуждающихся в лечении. При этом что уровень антител к инсулину у детей экспериментальной группы в возрасте 1 год оказался значимо ниже (р &lt; 0,05), чем в основной группе. Заключение. Своевременное применение неспецифической иммунокоррекции в период беременности в составе комплексной терапии беременных женщин с СД1 позволяет нормализовать уровень органоспецифических аутоантител, улучшить клиническое состояние новорожденных детей и прогноз их последующего неврологического развития. Aim. To study the effect of a complex therapy including a nonspecific immune correction (heparin inhalation in the gestational period of women with type 1 diabetes mellitus (DM1) with documented overproduction of insulin and insulin receptor autoantibodies) on the health of their children. Methods. A comparative analysis of neuropsychic development, somatic status, and immunological features was performed in children from birth to three years born by mothers with DM1 who received a standard complex therapy (main group, n = 101) and children from mothers with DM1 who received heparin inhalation as a part of the complex therapy during pregnancy (study group, n = 40). The control group (n = 30) consisted of children from somatically healthy mothers without infectious and endocrine pathology. Results. Analysis of the incidence of CNS pathology observed in newborns during the neonatal period showed an increase in this index in both groups of children born from mothers with DM1 compared to the control. However, according to the results of scoring (GNOM method) the number of healthy children was significantly greater whereas the number of children with CNS pathology who needed treatment was significantly less. Moreover, the level of insulin antibodies was significantly lower (p &lt;0.05) in children of the experimental group at the age of one year than in the main group. Conclusion. The timely use of nonspecific immune correction as a part of the complex therapy of pregnant women with DM1 allows to normalize the level of organ-specific autoantibodies, improve both the clinical condition of newborns and the prediction for their subsequent neurological development.

Insulin autoimmune syndrome: from diagnosis to clinical management.

Autoimmune forms of hypoglycemia are a rare cause of low blood sugar levels among Caucasians, and often go misdiagnosed, exposing patients to lengthy series of pointless, potentially harmful and expensive tests. There are two types of autoimmune hypoglycemia. One is insulin autoimmune syndrome (IAS), which is characterized by hyperinsulinemic hypoglycemia, elevated insulin autoantibody (IAA) titers, no prior exposure to exogenous insulin, and no of pathological abnormalities of the pancreatic islets. This condition is also known as "Hirata's disease". The other is type B insulin resistance syndrome (TBIRS), a rare autoimmune disorder resulting in a broad array of abnormalities in glucose homeostasis-from hypoglycemia to extremely insulin-resistant hyperglycemia-caused by the presence of insulin receptor autoantibodies (IRAbs). This review focuses on these two syndromes, describing their epidemiology, possible genetic background, clinical presentation, pathophysiology, diagnosis and treatment.

Type B Insulin Resistance in Peru

Type B insulin resistance (IR) is a rare autoimmune disease characterized by the presence of insulin receptor autoantibodies, resulting in a marked IR inducing hyperglycemia. Our first case is a 42-year-old female with a history of RA, SLE and Hashimoto-thyroiditis that presented with cachexia, acanthosis-nigricans, hirsutism, negative anti-insulin-ab and glucose level between 400 to 700 mg/dl, despite a total insulin dose of 1000 IU/day. She received pulses of cyclophosphamide along with prednisone. One year later the patient was off insulin and with HbA1c of 5.6%. The second case is a 42-year-old female patient that presented with polyuria, polydipsia, cachexia, acanthosis-nigricans, negative glutamic-acid-decarboxilase-ab and positive TPO-ab. She received IV infusion of regular insulin at a rate of 500 UI/d. Two years later she was off insulin with HbA1C of 5.6%. As summary, we reported a case of a disease remitted after receiving immunosuppressive therapy and a case of disease remitted spontaneously.

A case of extreme insulin resistance due to high levels of insulin receptor autoantibodies (type B insulin resistance)

A case of extreme insulin resistance due to high levels of insulin receptor autoantibodies (type B insulin resistance)

MANAGEMENT OF ENDOCRINE DISEASE: A clinical update on tumor-induced hypoglycemia

Tumor-induced hypoglycemia (TIH) is a rare clinical entity that may occur in patients with diverse kinds of tumor lineages and that may be caused by different mechanisms. These pathogenic mechanisms include the eutopic insulin secretion by a pancreatic islet β-cell tumor, and also the ectopic tumor insulin secretion by non-islet-cell tumor, such as bronchial carcinoids and gastrointestinal stromal tumors. Insulinoma is, by far, the most common tumor associated with clinical and biochemical hypoglycemia. Insulinomas are usually single, small, sporadic, and intrapancreatic benign tumors. Only 5-10% of insulinomas are malignant. Insulinoma may be associated with the multiple endocrine neoplasia type 1 in 4-6% of patients. Medical therapy with diazoxide or somatostatin analogs has been used to control hypoglycemic symptoms in patients with insulinoma, but only surgical excision by enucleation or partial pancreatectomy is curative. Other mechanisms that may, more uncommonly, account for tumor-associated hypoglycemia without excess insulin secretion are the tumor secretion of peptides capable of causing glucose consumption by different mechanisms. These are the cases of tumors producing IGF2 precursors, IGF1, somatostatin, and glucagon-like peptide 1. Tumor autoimmune hypoglycemia occurs due to the production of insulin by tumor cells or insulin receptor autoantibodies. Lastly, massive tumor burden with glucose consumption, massive tumor liver infiltration, and pituitary or adrenal glands destruction by tumor are other mechanisms for TIH in cases of large and aggressive neoplasias.

Approach to the patient with type B insulin resistance

Type B insulin resistance (TBIR) is a rare disease caused by the presence of insulin receptor autoantibodies (IRA).African middle-aged women are predisposed to it.Most patients have an underlying autoimmune disease,most commonly systemic lupus erythematosus (SLE).The patients predominantly present with abnormalities of glucose homeostasis ranging from extreme insulin resistance and symptomatic hyperglycemia to lifethreatening hypoglycemia,usually accompanied with manifestation of insulin resistance such as acanthosis nigricans,hyperandrogenism,and polycystic ovary.The diagnosis can be established by the elevation of IRA.We herewith report a ease of TBIR complicated with SLE,and the clinical features,diagnosis and treatment of TBIR are reviewed. Key words: Type B insulin resistance; Systemic lupus erythematosus; Diagnosis; Treatment

Type B Insulin Resistance Syndrome Associated with an Immune Reconstitution Inflammatory Syndrome in an HIV-Infected Woman

Type B insulin resistance syndrome is a rare condition characterized by the presence of autoantibodies directed against the insulin receptor. It has been reported in association with autoimmune diseases such as systemic lupus erythematosus. We report a case of type B insulin resistance syndrome in a patient with HIV infection on highly active antiretroviral therapy (HAART). A 27-yr-old African woman with ketosis-prone diabetes and HIV infection developed severe insulin resistance after the initiation of HAART. Standard oral glucose tolerance tests using 75 g of glucose performed 1, 2, and 3 months after the initiation of HAART showed severe hyperinsulinemia and hypoglycemia. Six months later, she developed symptomatic hyperglycemia resistant to high-dose insulin therapy. To determine the cause of insulin resistance, we assayed the titer of insulin receptor autoantibodies in the serum of the patient. Plasma insulin receptor autoantibodies were present at the time of marked hyperglycemia and insulin resistance, confirming the diagnosis of type B insulin resistance syndrome. Simultaneously the diagnosis of immune reconstitution inflammatory syndrome was established according to increased CD4 T cell count, decreased plasma HIV1-RNA level, and tuberculosis reactivation, shortly after institution of HAART. Corticosteroid therapy improved insulin resistance and hyperglycemia. We report the first case of type B insulin resistance syndrome associated with immune reconstitution inflammatory syndrome in an HIV-infected patient.

A Case of the Type B Insulin Resistance Syndrome with Chronic Hepatitis B

Type B insulin resistance syndrome is rare autoimmune disease that is characterized by various abnormalities of glycemic homeostasis, from hyperglycemia caused by extreme insulin resistance to fasting hypoglycemia. It can combine with other autoimmune diseases, most commonly systemic lupus erythematosus. It usually occurs in women and accompanies acanthosis nigricans, hyperandrogenism, and, in many cases, ovary dysfunction. The diagnosis of type B insulin resistance syndrome is based largely on the presence of insulin receptor autoantibodies and hyperglycemia, or hypoglycemia and hyperinsulinemia. In some cases, patients with the type B insulin resistance have been successfully treated with immunosuppressive therapy and plasmapheresis. We experienced type B insulin resistance syndrome in a patient with chronic hepatitis B and used only plasmapheresis for treatment. The immunosuppressive therapy was omitted due to the state of activation of chronic hepatitis B. We present this case with a review of relevant literature. (Endocrinol Metab 26:360-363, 2011)

Treatment of Type B Insulin Resistance: A Novel Approach to Reduce Insulin Receptor Autoantibodies

Type B insulin resistance belongs to a class of diseases caused by an autoantibody to a cell surface receptor. Blockade of insulin action results in hyperglycemia, hypercatabolism, severe acanthosis nigricans, and hyperandrogenism in women. This rare autoimmune disorder has been treated with various forms of immunosuppression with mixed success. We describe 14 patients with type B insulin resistance referred to the National Institutes of Health, adding to an existing cohort of 24 patients. This report focuses on seven patients who were treated with an intensive combination protocol of rituximab, cyclophosphamide, and pulse corticosteroids aimed at control of pathogenic autoantibody production. Hematological, metabolic, and endocrine parameters, including fasting glucose, glycated hemoglobin, insulin dose, lipids, and testosterone, were monitored before and after treatment. All seven treated patients achieved remission, defined as amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Glycated hemoglobin has normalized in all seven treated patients. Remission was achieved on average in 8 months from initiation of treatment. The medication regimen was well tolerated, with no serious adverse events. In seven patients with type B insulin resistance, standardized treatment with rituximab, cyclophosphamide, and pulse steroids results in remission of the disease. Future studies will determine whether this treatment protocol can be applied to other autoantibody/cell surface receptor disease states.

Insulin Receptor Autoimmunity and Insulin Resistance

The frequency of insulin receptor autoantibodies (IR-ab) was determined among adolescents and young adults with documented insulin resistance syndrome (IRS) with and without concomitant autoimmunity. The study population was comprised of 61 patients with obesity, acanthosis nigricans and insulin resistance (simple IRS); 12 with IRS and other autoimmune problems (lupus erythematosus, rheumatoid arthritis, dermatomyositis) (type B insulin resistance); six with autoimmune polyglandular syndrome type 2; and 40 healthy controls. Using our newly developed radiobinding assay system, we found no control positive while 25% of the patients with type B IRS (3/12) were positive, as expected. However, we found that 9.8% of the patients with simple IRS (6/61) were also reproducibly positive. All the latter patients with positive IR-ab were female with ovarian hyperandrogenism. The phenotype of those affected was otherwise unremarkably different from those without IR-ab. Our findings suggest that autoimmunity to insulin receptors may be causal in IRS especially for females with ovarian hyperandrogenism, and that IR-ab may be found in IRS besides those previously defined by the type B phenotype. Determining the level of IR-ab in childhood onset IRS may provide mechanistic insights into the genesis of insulin resistance and lead to novel treatment approaches.