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A, Anti-INSR autoantibody assay for our patient (P1070) before and after treatment (25-min exposure). Lane 1, Negative control serum (2 L), negative for anti-INSR autoantibody; lane 2, positive control serum (2 L), positive for anti-INSR autoantibody; lane 3, positive control serum (0.2 L), positive for anti-INSR autoantibody; lane 4, P1070 serum before therapy (2 L); lane 5, P1070 before therapy (0.2 L); lane 6, P1070 after therapy (2 L); lane 7, P1070 after therapy (0.2 L); lane 8, cell lysate containing insulin receptor 1:3 dilution; and lane 9, cell lysate containing insulin receptor. INSR, insulin-receptor. B, Time line (weeks) for fasting glucose (mg/dL; solid line), daily insulin dose (IU/d; dashed line), and HbA1c (%; dotted line) as well as white blood cell (WBC) and B cell count. The arrows indicate application of rituximab/cyclophosphamide/prednisone, the short lines indicate the Ig treatment and plasmapheresis, and the dots indicate timing of insulin receptor antibody tests. ab, antibodies; Ig, immunoglobulins; IR, insulin-receptor; Tx, treatment.
Source publication
Context:
Type B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high (>50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and pred...
Contexts in source publication
Context 1
... ever, an initial insulin receptor antibody assay was nega- tive. Finally, an immunoprecipitation assay was strongly positive for anti-insulin-receptor antibodies (Figure 2A), confirming the diagnosis of type B insulin resistance. ...
Context 2
... Ig iv (Intratect 20 g/d; Biotest Pharma GmbH) over 6 days nor plasmapheresis (five times in 14 d) im- proved her blood glucose or allowed reduction of the daily insulin dose. We therefore started the patient on a com- bination protocol of rituximab (750 mg/m 2 in two doses 2 wk apart), cyclophosphamide (100 mg/d orally, contin- uously), and dexamethasone (40 mg/d for 4 days every month), in accordance with the NIH protocol ( Figure 2B) (6), which was well tolerated. B cells were depleted already 2 weeks after the first rituximab application but returned Figure 1. ...
Context 3
... cells were depleted already 2 weeks after the first rituximab application but returned Figure 1. A 45-year-old female patient with acanthosis nigricans due to type B insulin resistance at diagnosis (A) and 4 months after rituximab treatment (B). to almost normal levels 4 months later without relapse ( Figure 2B). Cyclophosphamide was temporarily with- drawn due to low white blood cells. ...
Context 4
... months after her initial rituximab dose, insulin treat- ment could be withdrawn completely, and blood glucose levels remained within the normal range from 66 to 107 mg/dL. HbA1c continued to decrease to 6.5% ( Figure 2B). The acanthosis nigricans improved ( Figure 1B). ...
Context 5
... acanthosis nigricans improved ( Figure 1B). Congru- ent with the complete clinical remission, insulin receptor autoantibodies were now negative (Figure 2A). We there- fore discontinued cyclophosphamide and dexamethasone and started her on a maintenance regime with azathio- prine 100 mg daily for 1 year. ...
Similar publications
Type 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...
Citations
... Both states may be seen at different times during the natural history of the condition in the same patient as antibody titers and/or affinity fluctuate. Many immunosuppressive treatments for TBIR have been reported (7)(8)(9), encompassing different combinations of plasmapheresis, potent glucocorticoids, cyclophosphamide, cyclosporin A, azathioprine, and rituximab (10,11). The most extensive evidence to date is related to a combination of rituximab, high-dose pulsed steroids, and cyclophosphamide (12). ...
Type B insulin resistance (TBIR) is a rare, often fulminant form of insulin resistance caused by autoantibodies against the insulin receptor. If left untreated, its mortality is high. Various immunosuppressive regimens have shown efficacy, but treatment effects are variable and time-delayed, and drug-induced complications may arise. We report a patient with TBIR arising as a complication of Wiskott–Aldrich syndrome. Stable remission of TBIR was achieved through allogeneic peripheral blood stem cell transplantation (PBSCT) over a follow-up period of more than 1.5 years. We thus demonstrate that PBSCT can be considered a treatment option in TBIR where conventional immunosuppressive therapy is ineffective or contraindicated.
... Cyclophosphamide and mycophenolate mofetil have been trialed in TBIRs but not shown consistent benefit (8). Rituximab may be beneficial in TBIRs when given in combination with cyclophosphamide and glucocorticoids (36,37), but to date we are not aware of use of this combination in the IHLI group. ...
Objective:
Type B insulin resistance syndrome is a rare autoimmune disorder affecting glucose homeostasis, characterised by serum autoantibodies to the insulin receptor (AIRAb). Patients typically present with severe insulin resistance. A mixed hyper- and hypo-glycaemia phenotype may also occur, as can isolated hypoglycemia. The classic biochemical pattern comprises elevated insulin levels despite hypoglycemia, however a small proportion of cases demonstrate 'isolated hypoglycemia with low insulin'. The primary objectives of this systematic review were to identify the clinical characteristics and outcome of this subgroup.
Design:
Systematic review of cases with hypoglycemia with suppressed insulin. Exclusions: hyperglycemia, elevated insulin, AIRAbs not confirmed.
Methods:
PubMed, Medline and Embase databases were searched up until February 2023 and complemented by manual citation search. JBI critical appraisal checklist for case reports was used to assess bias.
Results:
A total of 5342 articles were identified after duplicate removal. Eleven, all case reports, met all inclusion criteria and were included. Cases belonging to this subgroup were more diverse in sex, age and ethnicity when compared with type B insulin resistance as a whole. Of the 11 cases, 3 developed lymphoma. High dose corticosteroid therapy appeared to be effective therapy for the hypoglycemia with often rapid response.
Conclusions:
Isolated hypoglycemia with low insulin forms a rare subgroup of type B insulin resistance. These patients lack the common characteristics of hyperinsulinemic hypoglycemia and hyperglycemia/insulin resistance. Furthermore, whilst coexisting autoimmune disease is commonly observed, there is potentially an association with aggressive lymphoma, the onset of which may be delayed.
... The clinical features of TBIR can vary from severe IR with uncontrolled diabetes and ovarian hyperandrogenism, to spontaneous hypoglycemia (4,5). TBIR belongs to the growing family of autoimmune diseases amenable to immunosuppressive treatment (6,7). As the correct diagnosis of TBIR and monitoring of treatment pose considerable problems in daily practice, we decided to develop a novel sensitive in vitro assay for InsR-aAb quantification. ...
Context:
Severe insulin resistance 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.
Objective:
To establish a robust in vitro method for InsR-Ab quantification.
Design, setting, patients, outcome measures:
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.
Results:
The novel assay proved sensitive, robust, and passed quality control. The measured InsR-aAb from TBIR patients associated with disease severity, decreased upon treatment, and inhibited insulin signalling in vitro. Titers of InsR-aAb correlated positively to fasting insulin in patients.
Conclusions:
Quantification of InsR-aAb from serum samples via the novel in vitro assay enables identification of TBIR and monitoring of successful therapy.
... e patient finally improved after rituximab 750 mg/m 2 divided into two doses two weeks apart, associated with oral cyclophosphamide 100 mg/day and dexamethasone 40 mg/day for 4 days. Fasting glucose improved down to 80-100 mg/dL, HbA1c was reduced from 11.8% to 6.5%, and perioral, periocular, and periauricular acanthosis nigricans improved as well [37]. ...
e association of type B insulin resistance syndrome (TBIRS) due to autoimmune diseases such as systemic lupus erythematosus (SLE) is uncommon. is is partly due to the lack of established criteria for the diagnosis of this resistance. However, some clinical aspects may suggest that the diagnosis does not necessarily have to be positive insulin receptor antibodies as such patients could respond to immunosuppressive treatment. Methods. We describe a case and have performed a literature review on PubMed/ MEDLINE, EMBASE, and Google Scholar bibliographic databases to identify all case reports. All available studies from January 1975 through December 2020 were included. Data collected were tabulated, and outcomes were analyzed cumulatively. Results. irty-one cases of TBIRS associated with SLE have been described. ese patients presented with catabolic symptoms and hyperglycemia in most cases, with an average time from the onset of symptoms of four months. In addition to that clinical characteristics related to SLE were variable, along with certain common characteristics such as acanthosis in 60% of patients. Almost all the patients had antibodies against insulin receptors. e insulin doses required by the patients ranged from 450 to 25,000 U daily. Remission was achieved in 80% of the patients with a two-year follow-up. Most patients associated with late-onset SLE, like our patient, achieved metabolic control after immunosuppressive treatment. Conclusion. High insulin resistance in patients with de novo diabetes mellitus (DM) without obesity should be considered as a possible clinical manifestation of an autoimmune disease such as SLE, with a good metabolic response to the immunosuppressive management established.
... The development of CGM systems with hypoglycemia alarm capability was a major advance for patients at risk of severe hypoglycemia of any cause and has been an invaluable diagnostic and therapeutic tool in this case. In addition, advances in immunosuppression including rituximab have resulted in improved rates of remission in the literature [6,18,19]. The role of maintenance immunosuppression (eg, azathioprine) following remission is unknown, but has been used in some reports [6,19]. ...
... In addition, advances in immunosuppression including rituximab have resulted in improved rates of remission in the literature [6,18,19]. The role of maintenance immunosuppression (eg, azathioprine) following remission is unknown, but has been used in some reports [6,19]. ...
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 IGF-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.
... 7,8,11 Pathophysiological hypotheses have involved the coexistence of activating and blocking autoantibodies and/or modifications in antibody titers leading to insulin-like or desensitization effects. 11,14 Return to baseline blood glucose levels was achieved after rituximab administration and was concomitant to antibody disappearance in the serum. [12][13][14][15] This latter point suggests that the observed hyperglycemic state was, at least partially, linked to the effect of the antibody. ...
... 11,14 Return to baseline blood glucose levels was achieved after rituximab administration and was concomitant to antibody disappearance in the serum. [12][13][14][15] This latter point suggests that the observed hyperglycemic state was, at least partially, linked to the effect of the antibody. ...
... On the other hand, HHV8 1 MCD should also be ruled out in patients presenting with fever and unexplained hypoglycemia. Rituximab is effective in the treatment of type B insulin resistance syndrome 14 and is also the preferred treatment of HHV8 1 MCD. This justified the use of the drug in this particular setting, which was shown to be an effective and safe strategy. ...
Key Points
Autoimmune hypoglycemia belongs to the clinical spectrum of HHV8+ MCD and rituximab is an effective treatment of this condition. This rare complication is related to autoantibodies directed toward the insulin receptor and activating the insulin signaling pathway.
... Various modalities have been employed in the past, albeit with extremely inconsistent remission and high mortality rates. These include high-dose corticosteroids, plasmapheresis, intravenous immunoglobulins, and other immunosuppressants, such as mycophenolate mofetil, cyclophosphamide, cyclosporine, and azathioprine [1,9,[19][20]. More recently, a standardised protocol has been developed by the NIH consisting of high-dose corticosteroids, cyclophosphamide, and rituximab as induction agents, followed by maintenance therapy with azathioprine or cyclosporine. ...
A 47-year-old Asian Indian woman presented with uncontrolled hyperglycaemia and osmotic symptoms despite multiple oral antidiabetic medications and insulin. She had a history of recurrent oral ulcers, profound weight loss, and intermittent fever for one and a half years before the presentation. She had severe acanthosis nigricans, although her body mass index (BMI) was 14.6 kg/m².
Her blood glucose remained uncontrolled despite very large dosages of intravenous insulin (more than 12,000 units daily). Evaluation for possible underlying collagen vascular diseases and malignancies were negative. Her serum insulin levels were high. She tested negative for anti-insulin antibodies but positive for anti-insulin-receptor antibodies. She improved with a pulse dose of intravenous methylprednisolone but relapsed within one month. A second pulse dose was given following which a complete remission of diabetes and regression of acanthosis was observed.
Type B insulin resistance, a rare cause of severe insulin resistance, may respond favourably to immunosuppressive therapy with high-dose methylprednisolone.
... Cases are uncommon in Latin America, and only two have been previously reported in Peru (6). The mortality rate is around 50% without treatment, and is mainly attributed to hypoglycaemia (3,7). ...
... We used the protocol established by Klubo-Gwiezdzinska et al. (8), using immunosuppressive therapy based on cycles of methylprednisolone 1 g IV for 2 days and cyclophosphamide 50 mg (one tablet) BID. Rituximab, a monoclonal anti-CD20 antibody, was included in this protocol, since it previously showed high efficacy and safety in inducing initial remission (1,7,13); however, it was not administered in the present case since it is not covered for this disease by Peruvian health insurance and patients cannot obtain it due to its high cost, restricting its use significantly. This protocol led to a significant reduction in previously reported mortality rates (14). ...
Type 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.
... Cases are uncommon in Latin America, and only two have been previously reported in Peru (6). The mortality rate is around 50% without treatment, and is mainly attributed to hypoglycaemia (3,7). ...
... We used the protocol established by Klubo-Gwiezdzinska et al. (8), using immunosuppressive therapy based on cycles of methylprednisolone 1 g IV for 2 days and cyclophosphamide 50 mg (one tablet) BID. Rituximab, a monoclonal anti-CD20 antibody, was included in this protocol, since it previously showed high efficacy and safety in inducing initial remission (1,7,13); however, it was not administered in the present case since it is not covered for this disease by Peruvian health insurance and patients cannot obtain it due to its high cost, restricting its use significantly. This protocol led to a significant reduction in previously reported mortality rates (14). ...
Type 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.
... There is no standard treatment for TBIR because of the differences in antibody titers, antibody effects, and underlying diseases; therefore, treatment is tailored to each case [5]. The reported examples of treatments include steroids [4], immunosuppressants [6], Helicobacter pylori eradication therapy [7], plasma exchange therapy [6], anti-CD20 monoclonal antibodies [8], combination of a steroid-immunosuppressant drug and anti-CD20 monoclonal antibody [5,[9][10][11], and insulin-like growth factor-1 [6,12,13]. ...
Type B insulin resistance (TBIR) is an extremely rare disease characterized by marked hyperglycemia and insulin resistance and often coexists with autoimmune diseases. The characteristics, symptoms, blood glucose patterns, comorbidities, and treatments of TBIR all vary and are not defined. In this study, we described a case of TBIR that developed 6 months after DPP-4 inhibitor administration and immediately after the patient caught a cold. Treatment using prednisolone and insulin-like growth factor-1 was effective. We also conducted an observational survey-based case series study in a Japanese cohort comprising 21 cases. The average age of onset of TBIR was 62.3±14.8 (17–84) years, and 61.9% of subjects were male. The majority of patients (90.4%) were 50 years old and over. During the study period, there was a high percentage (85.7%) of episodes of hypoglycemia, which was the trigger for diagnosis in more than 50% of cases. Glycemic patterns included 7 cases of hyperglycemia (33.3%), 10 cases of hypoglycemia (47.6%), and 4 cases of both hyperglycemia and hypoglycemia (19.1%). In the hypoglycemic group, 90.0% of patients were male. Furthermore, 71.4% of cases were antinuclear antibody positive, and 81.0% of cases were complicated with autoimmune disease. Systemic lupus erythematosus (38.1%) and Sjögren’s syndrome (23.8%) were relatively common as coexisting autoimmune diseases. Treatment was based on prednisolone use, which was used in 88.9% of patients. On the other hand, the effect of IGF-1 was limited. Overall, the prognosis of TBIR was good.
