Anti-insulin Receptor Antibodies Research Articles

Autoimmunity in Type 2 Diabetes: When the Only Effective Therapy Becomes Immunosuppressive.

Type B insulin resistance syndrome is a rare form of diabetes due to the presence of anti-insulin receptor antibodies [1, 2], which causes glycemic decompensation and antidiabetic therapy failure and instead responds to immunosuppressive therapy. A 67-year-old patient was admitted to the hospital due to autoimmune hemolytic anemia and glycemic decompensation. We first prescribed subcutaneous basal-bolus insulin and then intravenous insulin without improvement in blood sugar levels (between 300 and 500 mg/dL). Considering the non-response to therapy and the autoimmune diathesis of the patient (hemolytic anemia and mixed connective tissue disease), we suspected an autoimmune etiopathogenesis of glycemic decompensation; we excluded type 1 diabetes mellitus (specific antibodies were negative), and we considered the anti-insulin-antibodies-(-assayed and negative) and anti-insulin receptor antibodies (not assayed due to the lack of a center specialized in this assay in the area). Therefore, we decided to start Rituximab. After 2 weeks from the infusion, the patient improved glycemic compensation, reducing insulin requirement. Further, 2 months after the first infusion, the patient stopped insulin, returning to oral therapy with Metformin. To date, the patient has completed 3 cycles of Rituximab with the benefit of glycemic control (HbA1c 6.7%). The brilliant response to Rituximab supports the hypothesis of an autoimmune pathogenesis. The anti-insulin receptor antibodies (in the type B insulin resistance syndrome) affect mostly middle-aged adults, especially women, in the context of other autoimmune diseases. Hence, it is necessary to consider the diagnosis of this rare disease in order to perform timely and effective treatment.

PSUN275 Autoimmune Dysglycemia Syndrome (ADS) Associated with Multiple Rheumatological Conditions

Abstract Background Autoimmune dysglycemia syndrome is rare entity that can be induced by drugs or associated with rheumatic diseases. This syndrome includes the insulin autoimmune syndrome caused by anti-insulin antibodies; and type B insulin resistance syndrome caused by anti-insulin receptor antibodies. Patients may present with hyperglycemia, hypoglycemia, or both. Clinical case A 41-year-old Peruvian woman; pulmonary tuberculosis at age 14. In 2008 she presented polyarthritis, elevated ESR and CRP, she received methotrexate and deflazacort for 3 months, presenting remission and suspending medication. In 2009, she was admitted to the emergency room with seizures that resolved after intravenous administration of 33% dextrose. She was hospitalized for study, during her stay she presented episodes of fasting hypoglycemia and postprandial hyperglycemia. She reported hyporexia, weight loss, alopecia, and joint pain. On examination: she presented malar and soft palate erythema, mild pretibial edema. Laboratory tests: fasting blood glucose: 52-69mg/dl, albumin 1,6g/L; fasting insulin: 69.3uIU/mL, C-peptide: 3ng/mL; Anti-insulin antibodies: 4,7 (NV < 0,5), proteinuria 4,2 g/24h, ANA 1/2560 mottled pattern. Anti-cardiolipin, Anti-Sm and Anti-DNA (-). Hemoglobin: 10.6, Leukocytes: 3,160, lymphocytes: 1,540, platelets: 166,000. Renal biopsy showed membranous glomerulonephritis. The determination of antibodies against the insulin receptor is not available in Peru. With the diagnosis of autoimmune dysglycemia associated with SLE, she received prednisone 30mg/d, azathioprine 125mg/d, hydroxychloroquine 400mg/d; fractionated normocaloric diet, NPH + crystalline insulin on a correction scale, she was discharged with a progressive decrease in NPH insulin and metformin 850mg bid. Her glucose levels stabilized, control of proteinuria and joint symptoms was achieved with azathioprine, hydroxychloroquine, prednisone 10mg. The patient remained asymptomatic with rheumatological treatment, she suspended metformin and endocrinological follow-up in 2011. In 2013 she presented recurrent episodes of Raynaud's phenomenon and symptoms of proximal muscle weakness, crusted ulcers on the pads of the fingers of both hands, malar rash and exanthema in heliotrope. Laboratory tests: CPK: 8347U/L. Electromyogram: Spontaneous activity with polyphasic short small motor unit potential and early recruitment. Muscle biopsy showed perifascicular atrophy, perivascular and perimysial inflammatory infiltrate with CD4+ T lymphocytes and B lymphocytes. Glucose, insulin, C3, and C4 levels were normal, and anti-insulin antibodies (-). The diagnosis of dermatomyositis was established. She received prednisone 60mg, hydroxychloroquine, methotrexate 10mg, and nifedipine. In August 2020, telemedicine care in endocrinology and rheumatology concluded that there were no episodes of hypoglycemia, glucose: 86 mg/dl, insulin: 12uIU/ml; anti-insulin antibodies (-); CPK levels 136IU/L, C3, C4 normal, no proteinuria and anti ds-DNA (-). Conclusion Autoimmune conditions could cause dysglycemia mainly through different autoantibodies which may cause hyperglycemia and in rare cases hypoglycemia. This case report emphasizes the importance of long-term follow-up in patients with autoimmune conditions including SLE and ADS. Many of these patients are prompt to develope a new autoimmune disease over time. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

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.

Improvement of hepatocyte engraftment by co-transplantation with pancreatic islets in hepatocyte transplantation.

Because of the fragility of isolated hepatocytes, extremely poor engraftment of transplanted hepatocytes remains a severe issue in hepatocyte transplantation. Therefore, improving hepatocyte engraftment is necessary to establish hepatocyte transplantation as a standard therapy. Since the pancreatic islets are known to have favorable autocrine effects, we hypothesized that the transplanted islets might influence not only the islets but also the nearby hepatocytes, subsequently promoting engraftment. We evaluated the effects of islet co‐transplantation using an analbuminemic rat model (in vivo model). Furthermore, we established a mimicking in vitro model to investigate the underlying mechanisms. In an in vivo model, the hepatocyte engraftment was significantly improved only when the islets were co‐transplanted to the nearby hepatocytes (p < 0.001). Moreover, the transplanted hepatocytes appeared to penetrate the renal parenchyma together with the co‐transplanted islets. In an in vitro model, the viability of cultured hepatocytes was also improved by coculture with pancreatic islets. Of particular interest, the coculture supernatant alone could also exert beneficial effects comparable to islet coculture. Although insulin, VEGF, and GLP‐1 were selected as candidate crucial factors using the Bio‐Plex system, beneficial effects were partially counteracted by anti‐insulin receptor antibodies. In conclusion, this study demonstrated that islet co‐transplantation improves hepatocyte engraftment, most likely due to continuously secreted crucial factors, such as insulin, in combination with providing favorable circumstances for hepatocyte engraftment. Further refinements of this approach, especially regarding substitutes for islets, could be a promising strategy for improving the outcomes of hepatocyte transplantation.

Successful remission of type B insulin resistance syndrome without rituximab in an elderly male.

SummaryType B insulin resistance syndrome (TBIR) is a rare autoimmune disease caused by antibodies against the insulin receptor. It should be considered in patients with dysglycaemia and severe insulin resistance when other more common causes have been ruled out. We report a case of a 72-year-old male with a 4-year history of type 2 diabetes who presented with hypercatabolism, vitiligo, acanthosis nigricans, and hyperglycaemia resistant to massive doses of insulin (up to 1000 U/day). Detection of anti-insulin receptor antibodies confirmed TBIR. The patient received six pulses of methylprednisolone and daily treatment with cyclophosphamide for 6 months. Response to treatment was evident after the fourth pulse of methylprednisolone, as indicated by weight gain, decreased glycosylated haemoglobin and decreased requirement of exogenous insulin that was later discontinued due to episodes of hypoglycaemia. Remission was eventually achieved and the patient is currently asymptomatic, does not require insulin therapy, has normal glycaemia and is awaiting initiation of maintenance therapy with azathioprine. Thus, TBIR remitted without the use of rituximab. This case highlights the importance of diagnosis and treatment in a timely fashion, as well as the significance of clinical features, available laboratory findings and medication. Large controlled studies are required to standardise a therapeutic protocol, particularly in resource-constrained settings where access to rituximab is limited.Learning points:Type B insulin resistance syndrome is a rare autoimmune disorder that should be considered in patients with dysglycaemia, severe insulin resistance and a concomitant autoimmune disease. Serological confirmation of antibodies against the insulin receptor is not necessary in all cases due to the high associated mortality without timely treatment.Although there is no standardised immunosuppressive treatment, a protocol containing rituximab, cyclophosphamide and steroids has shown a significant reduction in previously reported mortality rates.The present case, reports successful remission in an atypical patient using cyclophosphamide and methylprednisolone, which is an effective therapy in countries in which rituximab is not covered by health insurance.When there is improvement in the hypercatabolic phase, the insulin dose should be reduced and/or discontinued to prevent hypoglycaemia; a mild postprandial hyperglycaemic state should be acceptable.

Type B insulin resistance syndrome associated with connective tissue disease and psoriasis.

SummaryType B insulin resistance syndrome (TBIR) is characterised by the rapid onset of severe insulin resistance due to circulating anti-insulin receptor antibodies (AIRAs). Widespread acanthosis nigricans is normally seen, and co-occurrence with other autoimmune diseases is common. We report a 27-year-old Caucasian man with psoriasis and connective tissue disease who presented with unexplained rapid weight loss, severe acanthosis nigricans, and hyperglycaemia punctuated by fasting hypoglycaemia. Severe insulin resistance was confirmed by hyperinsulinaemic euglycaemic clamping, and immunoprecipitation assay demonstrated AIRAs, confirming TBIR. Treatment with corticosteroids, metformin and hydroxychloroquine allowed withdrawal of insulin therapy, with stabilisation of glycaemia and diminished signs of insulin resistance; however, morning fasting hypoglycaemic episodes persisted. Over three years of follow-up, metabolic control remained satisfactory on a regimen of metformin, hydroxychloroquine and methotrexate; however, psoriatic arthritis developed. This case illustrates TBIR as a rare but severe form of acquired insulin resistance and describes an effective multidisciplinary approach to treatment.Learning points:We describe an unusual case of type B insulin resistance syndrome (TBIR) in association with mixed connective tissue disease and psoriasis.Clinical evidence of severe insulin resistance was corroborated by euglycaemic hyperinsulinaemic clamp, and anti-insulin receptor autoantibodies were confirmed by immunoprecipitation assay.Treatment with metformin, hydroxychloroquine and methotrexate ameliorated extreme insulin resistance.

Anti-Insulin Receptor Antibodies in the Pathology and Therapy of Diabetes Mellitus.

Diabetes mellitus (DM) is recognized as the most common and the world's fastest-growing chronic disease with severe complications leading to increased mortality. Many strategies exist for the management of DM and its control, including treatment with insulin and insulin analogs, oral hypoglycemic therapy such as insulin secretion stimulators and insulin sensitizers, and diet and physical training. Over the years, many types of drugs and molecules with an interesting pharmacological diversity have been developed and proposed for their anti-diabetic potential. Such molecules target diverse key receptors, enzymes, and regulatory/signaling proteins known to be directly or indirectly involved in the pathophysiology of DM. Among them, insulin receptor (IR) is undoubtedly the target of choice for its central role in insulin-mediated glucose homeostasis and its utilization by the major insulin-sensitive tissues such as skeletal muscles, adipose tissue, and the liver. In this review, we focus on the implication of antibodies targeting IR in the pathology of DM as well as the recent advances in the development of IR antibodies as promising anti-diabetic drugs. The challenge still entails development of more powerful, highly selective, and safer anti-diabetic drugs.

Type B insulin resistance syndrome: a systematic review.

A literature review on the clinical, laboratory, and treatment features of type B insulin resistance syndrome (TBIRS). Data from PubMed, the Virtual Health Library and Cochrane database were selected and analyzed using the REDCap application and R statistical program. From 182 papers, 65 were selected, which assessed 119 clinical cases, 76.5% in females and 42.9% in African-Americans, with an average age of 44 years. A common feature of TBIRS is co-occurrence of autoimmune diseases, such as systemic lupus erythematosus (most frequently reported). Hyperglycemia of difficult control was the mostly reported condition. Tests for anti-insulin receptor antibodies were positive in 44.2% of the cases. Disease management comprised fractional diet, insulin therapy (maximum dose given was 57 600 IU/day), plasmapheresis and immunosuppression with several classes of drugs, mainly glucocorticoids. Remission occurred in 69.7% of cases, in 30.3% of these spontaneously. The mortality rate was 15.38%. There was an inverse relationship between anti-insulin antibodies and remission (p = 0.033); and a positive correlation between combined immunosuppressive therapy and remission (p = 0.002). Relapse occurred in 7.6% of the cases. This rare syndrome has difficult-to-control diabetes, even with high doses of insulin, and it is usually associated with autoimmune diseases. Therapeutic advances using immunomodulatory therapy have led to significant improvements in the rate of remission.

Association Between Type B Insulin Resistance Syndrome and Mixed Connective Tissue Disease in an Arab African Man

Type B insulin resistance syndrome (TBIRS) has not been previously reported in Arab populations. We report a case of TBIRS in an Arab patient with mixed connective tissue disease (MCTD). Investigations revealed a clinical condition marked by positive anti-insulin receptor and ribonucleoprotein antibodies. The patient presented with severe hyperglycemia, weight loss, arthralgia, and acanthosis nigricans. He was managed successfully with an intensive pulsed combination regimen of cyclophosphamide and plasmapheresis augmented with high doses of prednisolone, which normalized his blood sugar levels without insulin therapy. MCTD was controlled by hydroxychloroquine. During the course of his treatment, the patient developed diabetic ketoacidosis secondary to the gluteal abscess, leukopenia, and recurrent hypoglycemia. Here, we showed that immunosuppressive agents and plasmapheresis can induce remission of TBIRS and can be used to normalize the blood sugar levels of Arab patients with this condition.

MON-686 Insulin Autoimmune Syndrome as a Rare Cause of Hypoglycemia

Background:Insulin Autoimmune Syndrome (IAS) or Hirata disease is reported more in Asians. We report the case of a patient with acute onset hypoglycemia secondary to IAS.Case Presentation:A 64 year old ARAB male physician presented with 2 weeks history of episodic hypoglycaemia with blood glucose (BG) 40–60 mg/dl, unrelated to food and occurring throughout the day. His attacks were associated with sweating, dizziness and palpitations, relieved by intake of juice. He reported 3 kg weight gain since the beginning of his symptoms.Past medical history revealed hypertension, past HCV infection with negative PCR and history of allergy to sulfa drugs. His medications included bisoprolol 2.5 mg daily.Physical exam showed no acanthosis nigericans. Laboratory investigations: Normal hepatic, renal and thyroid functions. 72 Hours fasting test was performed. at hour 3, the BG was 2.27 mmol (40.86 mg/dl), insulin > 1000 mU/ml (N: 2.6–24.9), c- peptide 15 ng/ml (N: 1.1–4.4), negative beta-hydroxybutyrate, with good glycemia response to glucagon 1mg. Urine sulfonylurea (SU) screen was negative. Insulin antibodies titre was high 8.9 nmol/L (N: 0–0.02) and Proinsulin >700 pmol/L (N: 3.6–22). MRI Abdomen showed only 3 mm lesion in the pancreatic head, likely a cyst.During hospitalization, the patient continued to have episodic hypoglycaemia and received dextrose 10% and octreotide injection. Bisoprolol was changed to amlodipine as it may mask his symptoms.Episodes of hypoglycaemia improved with octreotide but did not resolve completely. Prednisolone 30 mg daily was started with improvement and was tapered slowly after 16 weeks after mild hyperglycemia developed. Repeat work up showed reduction in insulin 67.4 mcunit/ml, C- peptide 2.66 ng/ml and insulin antibody titres to 0.24 nmol/L and remission of hypoglycemia.Discussion:Autoimmune hypoglycaemia is rare resulting from insulin antibodies(IAS), or anti-insulin receptor antibodies (Type B insulin Resistance). IAS can be triggered by drugs or viruses including hepatitis C and is associated with autoimmune diseases and hematologic malignancies. the differential diagnosis of hyperinsulinemic hypoglycemia include insulinoma, the presence of extreme levels of insulin, c-peptide and proinsulin and insulin antibodies is diagnostic of AIS. Short-term treatment with steroids was effective in treating hypoglycaemia and careful follow-up is ongoing. If the patient recurs, rituximab will be employed.

Induction of LTM following an Insulin Injection.

The pond snail Lymnaea stagnalis learns conditioned taste aversion (CTA) and consolidates it into long-term memory (LTM). One-day food-deprived snails (day 1 snails) show the best CTA learning and memory, whereas more severely food-deprived snails (5 d) do not express good memory. However, previous studies showed that CTA-LTM was indeed formed in 5-d food-deprived snails (day 5 snails), but its recall was prevented by the effects of food deprivation. CTA-LTM recall in day 5 snails was expressed following 7 d of feeding and then 1 d of food deprivation (day 13 snails). In the present study, we thus hypothesized that memory recall occurs because day 13 snails are in an optimal internal state. One day of food deprivation before the memory test in day 13 snails increased the mRNA level of molluscan insulin-related peptide (MIP) in the CNS. Thus, we further hypothesized that an injection of insulin into day 5 snails following seven additional days with access to food (day 12 snails) activates CTA neurons and mimics the food deprivation state before the memory test in day 13 snails. Day 12 snails injected with insulin could recall the memory. In addition, the simultaneous injection of an anti-insulin receptor antibody and insulin into day 12 snails did not allow memory recall. Insulin injection also decreased the hemolymph glucose concentration. Together, the results suggest that an optimal internal state (i.e., a spike in insulin release and specific glucose levels) are necessary for LTM recall following CTA training in snails.

A case of type B insulin resistance syndrome treated with low-dose glucocorticoids.

SummaryType B insulin resistance syndrome is characterized by the presence of autoantibodies to the insulin receptor. We present a 57-year-old male admitted to a hospital due to body weight loss of 16 kg and hyperglycemia of 13.6 mmol/L. He was diagnosed with type B insulin resistance syndrome because the anti-insulin receptor antibodies were positive. We informed him that some hyperglycemic cases of this syndrome had been reported to be spontaneously remitted in 5 years, and he did not agree to be treated with high-dose glucocorticoids and/or immunosuppressive agents due to his concern for their adverse effects such as hyperglycemia and immunosuppression. He chose to be treated with insulin and voglibose, but fair glucose control could not be obtained. Six years later, he agreed to be treated with low-dose glucocorticoids practicable in outpatient settings. One milligram per day of betamethasone was tried orally and reduced gradually according to the values of glycated hemoglobin. After 30 months of glucocorticoid treatment, the anti-insulin receptor antibodies became undetectable and his fasting plasma glucose and glycated hemoglobin were normalized. This case suggests that low-dose glucocorticoids could be a choice to treat type B insulin resistance syndrome in outpatient settings.Learning points:Type B insulin resistance syndrome is an acquired autoimmune disease for insulin receptors.This case suggested the possibility of long-lasting, low-dose glucocorticoid therapy for the syndrome as an alternative for high-dose glucocorticoids or immunosuppressive agents.Since the prevalence of autoimmune nephritis is high in the syndrome, a delay of immunosuppressive therapy initiation might result in an exacerbation of nephropathy.

Case reports of immunosuppression therapy for anti-insulin receptor and anti-insulin antibodies in patients attending the national severe insulin resistance service

Case reports of immunosuppression therapy for anti-insulin receptor and anti-insulin antibodies in patients attending the national severe insulin resistance service

SUN-182 When Insulin Is Not Enough...

Introduction: Multiple factors contribute to hyperglycemia in hospitalized patients, such as underlying medical conditions, pathophysiological stress, and medications. The development of transient insulin resistance is a known cause of hyperglycemia in both diabetic and non-diabetic patients. Rarely, patients can develop extreme insulin resistance, defined as having an insulin requirement of more than 3 units/kg/day. We report a case of extreme insulin resistance in a patient admitted with diabetic ketoacidosis (DKA) mediated by anti-insulin receptor antibodies. Case: 91 y/o F with history of CLL and IDDM (diagnosed three months prior, Last Hemoglobin A1C 14.2%) that was brought to the ED by EMS after being found covered in urine, lethargic and confused. On admission, she was found to be tachycardic, afebrile, normotensive, BMI 28.71. On physical exam she was diaphoretic and altered, but moving all extremities. She showed no findings consistent with acromegaly, hirsutism, red striae, moon-like facies, buffalo hump, or acanthosis nigricans. Initial labs included pronounced leukocytosis of 29.24, potassium of 5.9, glucose of 655, Anion Gap 25, HCO3 4, Beta Hydroxybutyrate 91.55, Lactic Acid 4.1, BUN 33, and a serum Cr of 1.49. UA showed: +30 protein, +80 ketones, Glucose >500, (-) nitrite and leukocyte esterase, & 2+ WBCs. The urine was positive for Bence Jones Protein Lambda Type. Her Kappa/Lambda Ratio was WNLs at 1.42 mg/L. UCx & BCx were negative. Patient was admitted to the ICU with an insulin drip following our hospital’s DKA protocol. After admission, she became hypotensive with increase work of breathing, for which she was intubated and started on vasopressin. On the second day of admission, Endocrinology was consulted due to inability to control blood glucose levels despite maximizing the rate of IV insulin infusion and persistent acidosis. Additional labs revealed a normal TSH, FT4, AM cortisol, IGF-1 27 ng/mL, AM Glucagon, Troponin, CEA and CA-125. Hemoglobin A1C was 8.9%. On the third day of admission, patient’s blood glucose levels persisted in the 400s-500s despite increasing her insulin infusion to 21 units/h and adding 15 units of HumuLIN R/per hour plus Insulin Glargine 40 units twice daily. She received over 900,000 U of insulin in the first 72 hours of hospitalization. In the setting of critical condition without a clear path to recovery, the family decided to pursue palliative care with comfort measures. Patient expired two hours after palliative extubation. Four days after patient expired, the blood work for the antibodies was received. The results were consistent with Negative Islet Cell Antibody, Negative GAD-65 Ab, & Positive Insulin Autoantibody (more than 50 U/ML). Conclusion: This case highlights the importance of considering immune-mediated IR along with other more common causes of IR in hospitalized patients with marked insulin demands.

Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models

Aims/hypothesisBi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies.MethodsTen naturally occurring mutant human INSRs with defects affecting different aspects of receptor function were modelled and assessed for response to insulin and anti-INSR antibodies. A novel 3T3-L1 adipocyte model of insulin receptoropathy was generated, permitting conditional knockdown of endogenous mouse Insr by lentiviral expression of species-specific short hairpin (sh)RNAs with simultaneous expression of human mutant INSR transgenes.ResultsAll expressed mutant INSR bound to all antibodies tested. Eight mutants showed antibody-induced autophosphorylation, while co-treatment with antibody and insulin increased maximal phosphorylation compared with insulin alone. After knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes, two antibodies (83-7 and 83-14) activated signalling via protein kinase B (Akt) preferentially over signalling via extracellular signal-regulated kinase 1/2 (ERK1/2) for seven mutants. These antibodies stimulated glucose uptake via P193L, S323L, F382V and D707A mutant INSRs, with antibody response greater than insulin response for D707A.Conclusions/interpretationAnti-INSR monoclonal antibodies can activate selected naturally occurring mutant human insulin receptors, bringing closer the prospect of novel therapy for severe insulin resistance caused by recessive mutations.

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.

IntroductionThe appearance of anti-insulin antibodies or an allergy to insulin occasionally causes clinical problems with glycemic control in insulin users.MethodsIn 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.ResultsWe 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.ConclusionLiraglutide 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.

Hypoinsulinemic Hypoglycemia Followed By The Onset Of Severe Insulin Resistance With Hyperglycemia And Circulating Anti-Insulin Receptor Antibodies In A Patient Suffering Systemic Lupus Erythematosus: A Case Report And Literature Review

ABSTRACT Objective: We report an atypical case of autoimmune hypoglycemia due to anti-insulin receptor antibodies after initiation of human monoclonal antibody denosumab and review the literature on this unusual disorder. Methods: We cite the history of a 30-year-old female treated for systemic lupus erythematosus (SLE) who presented with persistent hypoglycemia. This manifestation first appeared after administration of the anti-osteoporotic drug denosumab. Results: The patient's laboratory evaluation initially showed suppression of insulin and C-peptide levels. After ruling out all possible causes of hypoglycemia with decreased insulin levels, we resolved that the temporal relationship between the administration of denosumab and the occurrence of symptoms suggested the involvement of this drug in the disorder. However, in the course of the disease, laboratory tests showed a switch to hyperglycemia accompanied by markedly elevated insulin and C-peptide levels. A diagnosis of type B insulin resistance was ...

Hierarchical glucocorticoid-endocannabinoid interplay regulates the activation of the nucleus accumbens by insulin.

Here we asked if insulin activation of the nucleus accumbens in vitro is reflected by an increase in (3)H-deoxyglucose ([(3)H]DG) uptake, thus subserving a new model to study molecular mechanisms of central insulin actions. Additionally, we investigated the dependence of this insulin effect on endocannabinoids and corticosteroids, two major culprits in insulin resistance. We found that in acute accumbal slices, insulin (3 and 300nM but not at 0.3nM) produced an increase in [(3)H]DG uptake. The synthetic cannabinoid agonist, WIN55212-2 (500nM) and the glucocorticoid dexamethasone (10μM), impaired insulin (300nM) action on [(3)H]DG uptake. The glucocorticoid receptor (GcR) antagonist, mifepristone (10μM) prevented dexamethasone from inhibiting insulin's action. Strikingly, this anti-insulin action of dexamethasone was also blocked by two CB1 cannabinoid receptor (CB1R) antagonists, O-2050 (500nM) and SR141716A (500nM), as well as by tetrahydrolipstatin (10μM), an inhibitor of diacylglycerol lipases-the enzymes responsible for the synthesis of the endocannabinoid, 2-arachidonoyl-glycerol (2-AG). On the other hand, the blockade of the post-synaptic 2-AG metabolizing enzymes, α,β-serine hydrolase domain 6/12 by WWL70 (1μM) also prevented the action of insulin, probably via increasing endogenous 2-AG tone. Additionally, an anti-insulin receptor (InsR) antibody immunoprecipitated CB1Rs from accumbal homogenates, indicating a physical complexing of CB1Rs with InsRs that supports their functional interaction. Altogether, insulin stimulates glucose uptake in the nucleus accumbens. Accumbal GcR activation triggers the synthesis of 2-AG that in turn binds to the known CB1R-InsR heteromer, thus impeding insulin signaling.

Type B insulin resistance syndrome with fasting hypoglycemia and postprandial hyperglycemia

Type B insulin resistance syndrome is a rare disease that manifests as severe insulin resistance and hyperglycemia. Few cases with hypoglycemia are reported. We describe a patient with type B insulin resistance syndrome with the presence of insulin receptor antibodies that showed severe hypoglycemia and hyperglycemia and review the clinical features. The patient was a 65-year-old Japanese male diagnosed with type 2 diabetes in June 2012. In August, he was admitted to an emergency room after suffering a hypoglycemic coma several times and then referred to our medical center. His HbA1c was 7.9 %, fasting plasma glucose was 46 mg/dl, and serum insulin level was 310 µU/ml; however, the postprandial glucose level was high (200–400 mg/dl). Plasma glucose decreased slightly after an intravenous 0.1 U/kg insulin challenge test. The findings suggested severe insulin resistance. As anti-insulin receptor antibody was detected (93.3 %, radio-receptor assay), we diagnosed type B insulin resistance syndrome. The patient was administered prednisolone, and the symptoms disappeared. This report details a case of type B insulin resistance syndrome with both hypoglycemia and hyperglycemia, which was successfully treated with only prednisolone.