A case of systemic lupus erythematosus in a patient with Noonan syndrome with recurrent severe hypoglycaemia.

Noonan syndrome (NS) is a dominantly inherited genetic disorder with mutations in genes encoding components or regulators of the Rat sarcoma virus/mitogen-activated protein kinase pathway. Its diagnosis is based on characteristic features, including typical facial features, a short stature, congenital heart disease, mild developmental delay, and cryptorchidism. Patients with NS sometimes develop autoimmune diseases, such as Hashimoto's thyroiditis and, rarely, systemic lupus erythematosus (SLE). We herein present a 29-year-old Japanese female with NS complicated by SLE and repeated severe hypoglycaemia. The patient was diagnosed with SLE based on thrombocytopenia, nephritis, a positive antinuclear antibody titre (1:640), and a positive anti-dsDNA antibody. The patient was treated with a glucocorticoid, mycophenolate mofetil, and tacrolimus, which attenuated both SLE and hypoglycaemia. Since insulin receptor antibody levels were higher to the upper normal range and decreased after treatment, hypoglycaemia probably appeared to be attributed to type B insulin resistance syndrome. We herein present the first case of SLE in NS complicated by type B insulin resistance syndrome. Although NS is a rare disease, we need to consider the complication of autoimmune diseases, including SLE.

A Multicenter, Open-Label, Single-Arm Trial of the Efficacy and Safety of Empagliflozin Treatment for Refractory Diabetes Mellitus with Insulin Resistance (EMPIRE-01).

INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. METHODS: The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. RESULTS: By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. CONCLUSION: Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. TRIAL REGISTRATION: jRCTs2051190029 and NCT04018365.

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.

Clinical Features and Outcome Analysis of Type B Insulin Resistance Syndrome: A Single-Center Study in China.

CONTEXT: Type B insulin resistance syndrome (TBIRS) is a rare condition, for which effective treatment remains challenging. OBJECTIVE: This work aimed to summarize the clinical characteristics of TBIRS and explore effective therapeutic strategies. METHODS: The clinical manifestations, biochemical indices, and treatment of 8 patients (3 men and 5 women) with TBIRS from Peking Union Medical College Hospital were retrospectively analyzed and their clinical outcomes were evaluated. RESULTS: The average age of the patients was 49.5 ± 16.5 years, and the duration of the disease ranged from 2 months to 1 year. Seven patients with hyperglycemia had normal/lower triglycerides (TGs) and lower insulin-like growth factor 1 (IGF-1) levels. One patient complained of intractable hypoglycemia. Five patients had accompanied systemic lupus erythematosus, 2 had mixed connective tissue disease, and 1 had undifferentiated connective tissue disease. Five patients had acanthosis nigricans and 3 women of child-bearing age had hyperandrogenism. All 8 patients were treated with glucocorticoids combined with immunosuppressants, among whom, 5 received high-dose glucocorticoid pulse therapy followed by conventional-dose glucocorticoid therapy, all of whom achieved partial remission within 2 to 4 weeks. Among the 3 patients receiving conventional glucocorticoid therapy, 2 achieved partial remission within 2 to 4 weeks. Six patients were tracked for 10 weeks to 4 years; 4 and 2 achieved complete and partial remission, respectively. CONCLUSION: Decreased serum complement 3 and IGF-1 levels and normal/decreased TG levels act as striking biochemical features of TBIRS. High-dose glucocorticoid pulse therapy followed by conventional-dose long-term therapy combined with immunosuppressants achieves good clinical efficacy.

Polycystic ovary syndrome in a patient with type B insulin resistance syndrome can improve with glucocorticoid treatment: a case report and literature review.

Polycystic ovary syndrome (PCOS) frequently exhibits hyperinsulinemia due to insulin resistance, but there are many unknown aspects of this disease. This report presents the case of a 31-year-old woman with PCOS and type B insulin resistance syndrome (TBIRS). The patient had repeated hyperglycemia and hypoglycemia, and prominent hyperinsulinemia. The insulin receptor antibody was positive, leading to a diagnosis of TBIRS. She also had amenorrhea during the previous 3 months, high blood testosterone levels, and enlarged polycystic ovaries, leading to a diagnosis of PCOS at the same time. The patient was treated with glucocorticoid for TBIRS. The insulin receptor antibody eliminated at 8 weeks after initiation of glucocorticoid treatment, and the blood glucose levels and hyperinsulinemia improved at 9 weeks. Then, the enlargement of both ovaries diminished at 32 weeks, and the menstruation had normalized since 36 weeks. The blood testosterone level normalized at 41 weeks. To the best of our knowledge, this is the first report to demonstrate that enlarged polycystic ovaries and a menstrual disorder in TBIRS improved after glucocorticoid treatment. It is possible that elimination of insulin receptor antibodies by glucocorticoid treatment attenuated insulin resistance and subsequently improved PCOS in TBIRS.

Endogenous hyperinsulinemic hypoglycemia: case series and literature review.

PURPOSE: Endogenous hyperinsulinemic hypoglycemia (EHH) is an uncommon disease characterized by inappropriately high plasma insulin levels despite low plasma glucose levels. Some rare etiologies can lead to EHH. Correct diagnosis is a prerequisite for treatment. Hence, although challenging, it is crucial for patients with EHH to identify the different causes. METHODS: We describe a case series of three patients, all of whom had obvious hypoglycemic symptoms and extraordinary hyperinsulinemia. Their plasma glucose, insulin, and C-peptide levels were tested simultaneously when hypoglycemia occurred. Moreover, other biochemical indices and relevant antibody levels were measured and imaging examinations were conducted. RESULTS: According to their medical history, physical examination, laboratory results, and imaging findings, the three patients were diagnosed with insulinoma, type B insulin resistance syndrome, and insulin autoimmune syndrome. After precise treatments, hypoglycemia was ultimately eliminated. CONCLUSION: Although these diseases have similar symptoms and biochemical abnormalities, the treatment and prognosis are different. The case series presented here highlights the challenges in the differential diagnosis of EHH. An accurate diagnosis is necessary for hypoglycemia treatment.

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.

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.

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

BACKGROUND: 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. CONTENT: 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). SUMMARY: 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.

Effect of a multitarget therapy with prednisolone, mycophenolate mofetil, and tacrolimus in a patient with type B insulin resistance syndrome complicated by lupus nephritis.

Type B insulin resistance syndrome (TBIR) is a rare autoimmune disease characterised by autoantibodies targeting insulin receptors. TBIR is often complicated by systemic lupus erythematosus (SLE). We describe the case of a 59-year-old Japanese man with TBIR complicated with lupus nephritis (LN), who presented with nephrotic syndrome and severe hypoglycaemia. Treatment with prednisolone (PSL), mycophenolate mofetil (MMF), and tacrolimus (TAC) resulted in improved SLE activity and glucose intolerance with the reduction of anti-insulin receptor autoantibodies. To the best of our knowledge, this is the first reported case of TBIR complicated with LN that was successfully treated using multitarget therapy with PSL, MMF, and TAC.

Searching for the Culprit: When Diabetic Ketoacidosis Presents With Insulin Autoantibodies.

OBJECTIVE: The main objective was to describe and review a unique case that presented with diabetic ketoacidosis, positive insulin autoantibodies (IAAbs, which are found in Hirata disease and are usually present with hypoglycemia), and laboratory findings characteristic of type B insulin resistance syndrome (TBIRS) and systemic lupus erythematosus. Confirmation of TBIRS was obtained in Germany as immunoassay for insulin receptor antibodies (IRAbs) is not available in the United States. METHODS: A literature review on TBIRS and cases that present with IAAbs and IRAbs simultaneously was conducted. RESULTS: We found 6 cases presenting with hypoglycemia, both antibodies, and treatment attempts with various management approaches that were different from the proposed National Institutes of Health (NIH) protocol for TBIRS. Our case is distinct because of the demographic background, presentation with diabetic ketoacidosis, comparatively lower insulin requirement, and no significant hypoglycemic episodes in the third phase. CONCLUSION: We propose that access to IRAb immunoassays may be important for diagnosing milder cases of TBIRS, while IAAbs may provide prognostic and therapeutic insights. Despite completely different presentation from other TBIRS patients reviewed, we observed that the proposed NIH protocol consisting of dexamethasone, rituximab, and cyclophosphamide was successfully employed in our patient. Thus, we propose that our case and the findings regarding antibody testing and the NIH treatment regimen may assist clinicians with earlier recognition and effective management of milder cases of TBIRS.

Type B insulin resistance syndrome in a patient with type 1 diabetes.

SUMMARY: Type B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia. Described here is a patient who within a few months after the onset of autoimmune type 1 diabetes increased her insulin requirements more than 20-fold; despite this she had considerable difficulty maintaining a plasma glucose value of <40-60 mmol/L (720-1100 mg/dL). On suspicion of TBIRS, the patient was started on tapering dose of glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect. Within days, insulin requirements decreased by 80-90% and plasma glucose stabilized around 7-8 mmol/L (126-144 mg/dL). The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays. After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses and immune column treatments with temporarily remarkable effect. Mixed and transient results were seen with rituximab, mycophenolic acid and bortezomib, but the glycemic status remained suboptimal. Lack of compliance and recurrent infections may have contributed to this. LEARNING POINTS: Type B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with acquired polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia. We describe here a young patient in whom, a few months after the onset of a regular autoimmune diabetes, insulin requirements in a short time increased more than 20-fold, but despite this, the plasma glucose level could be kept at <40-60 mmol/L only with considerable difficulty. Did this patient have TBIRS? On suspicion of TBIRS, the patient was started on tapering glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect; within days insulin requirements decreased by 80-90% and plasma glucose stabilized around 7-8 mmol/L. The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays. After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses with temporarily remarkable effect. TBIRS should be considered in diabetic patients whose glycemia and/or insulin requirements are inexplicably and dramatically increased.

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.

Saibokuto as a Possible Therapy for Type B Insulin Resistance Syndrome: The Disappearance of Anti-insulin Receptor Antibody and a Marked Amelioration of Glycemic Control by Saibokuto Treatment.

Type B insulin resistance syndrome is a rare autoimmune disease and no effective therapy has yet been established. On the other hand, it is known that Saibokuto, one type of Japanese Kampo medicine, may have beneficial effects on various symptoms associated with this disease and it is therefore occasionally prescribed for various immune disorders. We herein describe a case of type B insulin resistance syndrome in which anti-insulin receptor antibody disappeared and the patient's glycemic control markedly improved after the administration of Saibokuto. At first, we administered various anti-oral diabetic drugs and insulin therapy, but the patient's glycemic control became further aggravated. In addition, Helicobacter pylori eradication therapy was not effective, although its benefit has been reported. Interestingly, after the patient started taking Saibokuto, her glycemic control markedly improved. In addition, the patient's plasma insulin levels markedly decreased and anti-insulin receptor antibody became negative after taking Saibokuto. Taken together, there is a possibility that Saibokuto may one of the options for type B insulin resistance syndrome therapy.

Effect of Liraglutide on Type B Insulin Resistance Syndrome and Insulin Allergy in Type 2 Diabetes: A Case Report.

INTRODUCTION: The appearance of anti-insulin antibodies or an allergy to insulin occasionally causes clinical problems with glycemic control in insulin users. METHODS: In the present report, we describe a therapeutic approach that was employed for a man with type 2 diabetes who had insulin allergy, anti-insulin antibodies, and anti-insulin receptor antibodies that developed during his insulin treatment. RESULTS: We started the patient on liraglutide, a glucagon-like peptide-1 receptor agonist, and attained glycemic control without incurring any side effects. Two years after liraglutide induction, his blood glucose was being maintained at a healthy level by liraglutide monotherapy. CONCLUSION: Liraglutide may be a therapeutic option for patients with insulin allergy, anti-insulin antibodies, and type B insulin resistance syndrome, as it represents an alternative strategy to insulin.

Efficacy of oral glucocorticoid and cyclosporine in a case of rituximab-refractory type B insulin resistance syndrome.

We describe a case of type B insulin resistance syndrome associated with systemic lupus erythematosus (SLE) that was refractory to rituximab and successfully treated with a combination of oral glucocorticoids and cyclosporine. Prior to treatment, insulin resistance was severe, and application of a hyperinsulinemic euglycemic clamp was not possible despite the continuous intravenous infusion of insulin at a maximum rate of 9.0 mU/kg/min. The addition of cyclosporine to oral glucocorticoid therapy resulted in remission of insulin resistance. The combination of oral prednisolone and cyclosporine might be effective in treating type B insulin resistance syndrome, particularly in rituximab-resistant cases. However, nephrotoxicity is a particular concern for patients receiving long-term cyclosporine therapy.

Successful control of a case of severe insulin allergy with liraglutide.

A 72-year-old woman presented with repeated hypoglycemic and hyperglycemic episodes because of an insulin allergy. On admission, she was diagnosed with type B insulin resistance syndrome. She was also found to have anti-insulin antibodies. After steroid therapy, glycemic control improved dramatically accompanied by the disappearance of the insulin allergy. We then introduced liraglutide, which successfully stabilized her glycemic episodes without allergic reactions. Liraglutide might be useful to treat patients with severe insulin allergy.