Clinical Course of the Syndrome of Autoantibodies to the Insulin Receptor (Type B Insulin Resistance)

Abstract

Introduction The type B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor. It is representative of a class of disease in which an autoantibody is produced against a cell surface receptor (9,79). Graves disease, caused by autoantibodies to the thyroid stimulating hormone receptor, and myasthenia gravis, caused by autoantibodies to the acetylcholine receptor at the myoneural junction, are typical of these diseases (30). Other rare syndromes include gonadal deficiencies and iron deficiencies (46,61). The exact prevalence of type B insulin resistance syndrome is not known; however, it is quite rare. There have been no population-based studies to answer the question of disease prevalence. Autoantibodies to the insulin receptor were first identified in middle-aged women with other autoimmune diseases (26,36). Subsequently, it was recognized that the disease also affects males and younger patients (4,15,24,53). The disease causes a spectrum of abnormalities in glucose homeostasis, ranging from extreme insulin resistance (30) to fasting hypoglycemia (30,69), and in some other cases a change from extreme insulin resistance to intractable hypoglycemia (1,67,69). In addition, the abnormalities in glucose homeostasis may remit in association with the disappearance of the antibody to the insulin receptor. While all these phenomena have been observed and reported over the years, little is known about the long-term prognosis of the patients. Furthermore, various treatment modalities have been employed to treat the syndrome without adequate appreciation of the disease course in the long run. In this paper we review the natural history of type B insulin resistance syndrome using clinical data from 24 patients followed for up to 28 years. Methods Patients and objective Twenty-four patients with the diagnosis of type B insulin resistance syndrome were admitted to the Clinical Center of the National Institutes of Health (NIH), Bethesda, Maryland, between January 1973 and December 2000. The data gathered on these patients were retrospectively evaluated to draw conclusions about the clinical outcomes. Criteria for inclusion Patients were required to have demonstrable autoantibodies against the insulin receptor in association with a clinical abnormality of glucose homeostasis, that is, hyperglycemia or hypoglycemia. Data collection Because of the wide geographic origins of these patients, it was not possible to follow each patient at the Clinical Center for the duration of time reported; therefore, we have supplemented our information by correspondence and telephone. Each patient underwent a detailed history and physical examination and in most cases they were followed for months or years at the Clinical Center. As retrospective information on each case was compiled, specific attention was given to delineate the onset of the syndrome, associated features, therapeutic interventions, outcome of therapy and metabolic responses (resolution of glucose abnormalities) over the course of follow-up, current status, and mortality. In addition, a similar approach was taken to derive complete follow-up information on cases reported in the literature wherever possible. Laboratory tests All patients underwent a battery of routine hematologic, immunologic, and biochemical tests on their initial examination, and on multiple subsequent time points. Most patients underwent a standard oral glucose tolerance test, and patients presenting with hypoglycemia underwent a diagnostic fast at least at the time of initial presentation. Each patient was proven to have an insulin receptor autoantibody by assays that measured either inhibition of insulin binding or blocking the biologic activity of insulin (30). A newer method detected antireceptor antibody by measuring immunoprecipitation of recombinant human insulin receptors. This method, developed in 1997, has improved specificity and sensitivity (Figure 1).Fig. 1: A newer method detected anti-insulin receptor antibody by measuring immunoprecipitation of recombinant human insulin receptors. Cos 7 cells were transfected with recombinant human insulin receptors using LipofectAMINE Plus according to manufacturer’s instructions (Life Technologies, Gaithersburg, MD). The cells were solubilized for 30 minutes on ice and insoluble debris removed by centrifugation (14,000 G for 20 minutes) at 4 °C. To test for the presence of the antireceptor antibody in the patients’ sera, 150 μL of extract was incubated with 2 μL of patient serum overnight at 4 °C. The antibody bound receptors were precipitated with peroxidase-affinity pure Fab′ 2 fragment goat antirabbit IgG −Fc fragment specific antibody (Jackson Immunological Research, West Grove, PA) and blotted with anti-insulin receptor β-subunit rabbit polyclonal antibody (C19) (Santa Cruz, CA). Nine samples were screened on the gel shown. Samples on Lane 1 and 8 are positive. Samples on lane 8 and 9 belong to the same patient at 2 different time points, 3 months apart. The autoantibody is detected from the sample on lane 8, whereas it cannot be detected from the sample on lane 9. Remission is defined as the complete disappearance of the autoantibody as shown on this immunoblot.Glucose and triglyceride levels were determined by standard methods using automated Hitachi equipment (Boehringer Mannheim, Indianapolis, IN). HbA1c was determined by high-pressure liquid chromatography (Bio-Rad; Hercules, CA). Insulin and leptin levels were determined by immunoassays using reagents provided by Abbott Imx Instrument (Abbott Park, IL) and Linco (St Charles, MO), respectively. Free fatty acid (FFA) levels were determined with a commercial kit (Wako; Richmond, VA) at the Mayo Clinical Laboratories. Body fat distribution Skin folds were measured (mean of 3 measurements) on the side of the dominant arm using Lange skinfold calipers (Cambridge Scientific Industries, London, UK). A nonstretch tape was used to measure circumferences (mean of 3 measurements) to the nearest mm. Percentage body fat was calculated from the sum of 4 skinfolds (triceps, biceps, subscapular, suprailiac) (21). Dual energy X-ray absorptiometry was also used to estimate fat and lean body mass (28). Therapeutic interventions and definitions of remission Therapeutic interventions are divided into 2 categories: therapy to correct metabolic syndrome and therapy to abrogate the autoimmune response. The first category includes standard therapy such as insulin and oral hypoglycemic agents. The second category includes a variety of therapeutic regimens employed to control the autoantibody production and to treat the underlying condition. The most commonly used therapeutic intervention in the second category was steroid therapy. This was given in 3 ways: high dose (for example, prednisone 1 mg/kg per day, max 60 mg/day, or dexamethasone 2–6 mg/day used more than 5 days); taper regimen; and maintenance (continuous use of steroids at doses equivalent to 5 mg/day prednisone therapy). Plasmapheresis was accomplished using a standard protocol, usually with 5 exchange sessions within a 2-week period. In the earlier cases, plasma exchange was used every 2–3 weeks over a period ranging from 6 weeks to 3 months. Cyclophosphamide was given either orally at a dose of 50 mg twice a day or intravenously at a dose ranging from 500 to 1,000 mg at 21- to 30-day intervals. Oral cyclosporine A was used at a dose of 250 mg twice a day for 6–8 weeks in 2 patients (B19 and B20). Oral azathioprine was used at a dose of 50 mg daily in patient B24 in order to spare steroid therapy. Remission was defined as amelioration of the glucose abnormality, that is, resolution of hyperglycemia or hypoglycemia and disappearance of the autoantibody as shown on Figure 1. We attempted to relate the metabolic response (the change in blood glucose parameter) to a therapeutic protocol or to a spontaneous outcome (that is, blood glucose change in the absence of a therapeutic intervention). If patients displayed a marked improvement in glucose responses within 6 weeks of administration of a therapy, we defined the response as a consequence of therapy and classified the amelioration as “remission in response to therapy.” If the amelioration was not related to a specific intervention within 6 weeks or was not preceded by a specific intervention, we classified the amelioration as “spontaneous remission.” Results General features Twenty-four patients with demonstrated autoantibodies to the insulin receptor were evaluated between January 1973 and December 2000 (Table 1). Twenty of 24 (83%) patients were female and 21 of 24 (88%) were African American. All 4 (17%) male patients were African American. The average age of the female patients at was years The average age of the male patients at was years case gathered from the literature with adequate case are also 1: of 24 (88%) patients a in of insulin The distribution of was in the and was a of this type of insulin resistance from other syndromes of insulin In the of and the in a typical (Figure In some cases, the and were and in other cases, such as the or may be physical of a patient with anti-insulin receptor The and in association with from the in typical The of patients presenting with hyperglycemia as shown in this were in most of the 20 female patients and were usually as detected by the not follow the typical disease The of was most as in Figure The was in 1 patient in with hormone and hormone patient with insulin receptor The of is was observed with levels in 7 of female patients between the of and 50 years age with the of from to in The association of the levels with age is demonstrated in Figure Furthermore, we observed a in levels to the the autoantibody syndrome that the of was related to the presence of the autoantibody the in insulin (Figure levels are in younger female patients with the anti-insulin receptor autoantibody levels at are shown as a of The levels patients into Data shown from 4 patients in 2 subsequent were features of the syndrome features were in these patients, in our case and in the literature cases (Table the most underlying syndrome was (Table It is that over the patients this most was related to as with a We not or in of our patients. case in the literature is reported to have a of and Clinical features of autoimmune disease and their disease in most patients demonstrated of autoimmune the syndrome was associated with multiple in 1 of the patients and with disease in 2 cases in the literature The metabolic of this syndrome usually the onset of a autoimmune of it was not possible to the specific at the onset of the metabolic example, the diagnosis of type B insulin resistance syndrome preceded the diagnosis of in 4 patients. All of these patients, however, multiple features with a the diagnosis of multiple was about months the of the autoantibody to the insulin receptor, and a were at the time of presentation. features of 24 patients with to average blood glucose at was and from to This was usually associated with high levels of and The patients usually with a onset of hyperglycemia and with Figure at was this be more for patient with a of in a period of 5 months. We have observed the presence of and in patients of presentation. The in the literature cases presenting with hyperglycemia was also in of 20 of the The HbA1c levels for the patients in this was measured from to at the time of presentation. patients were most with high doses of insulin to and In the more patients and we and in an to the daily doses of insulin insulin levels were high the of insulin therapy In to other syndromes of insulin resistance and the patients with type B insulin resistance an fasting triglyceride levels This was by levels of fatty in patients in fatty acid levels were measured This is similar to the of our patients with in the insulin receptor a period of spontaneous hypoglycemia in 3 of the 21 patients with hyperglycemia at the a similar was in the literature patients 1). In patient the hypoglycemia was and in of insulin therapy and therapy to blood glucose There was no change in either the or other of the antireceptor antibody from the to the hypoglycemic of In patients and of hypoglycemia a in the of the antireceptor In these patients, levels of autoantibody and the patients of hypoglycemia and It is that these patients insulin with of antireceptor they may hypoglycemic with of of the 24 patients were known to be with spontaneous hypoglycemia 1). of the patients and were on their for The of these patients is by the that they insulin in the presence of the presence of the antireceptor antibody insulin Body of patients 4 the body mass of patients. of the patients with hyperglycemia a In the patients with hypoglycemia with a which is with of hypoglycemic patients. While a patients in the or it is to the of reported by the of patients with hyperglycemia Dual energy X-ray absorptiometry that were in the 5 most patients presenting with hyperglycemia a in fat and lean body Body mass with to metabolic course of hyperglycemia we have complete data on the patients, we of long-term follow-up from patients In patients is information to their clinical course with to In 6 of these patients the antireceptor antibody from the over a period of months. 6 patients were to a of and up the “spontaneous in Figure not related to the of The time of follow-up remission is on the patients 6 more in association with is a of patients in no remission has been observed treatment with regimens to the 5 for therapy patients were with either high doses of cyclosporine or various of these (Table In 6 of the patients, a clinical remission in association with the therapy (that is, within 6 weeks of therapy). the autoantibody from the and the patient was to a of The 6 patients in a similar to have hyperglycemia of follow-up Figure Remission of and were and patient was not to abrogate the autoimmune response and has not been in follow-up on insulin therapy. of insulin on the clinical course of more patients treatment with in an to therapeutic were not in a clinical and the are to to the of the disease was with The dose was at mg/day and to This not in in daily insulin dose from to improved the of fasting hyperglycemia from to 3 weeks of therapy with Patients and B24 at a dose ranging from to displayed of remission within 4 weeks the diagnosis of the receptor autoantibody syndrome associated with therefore, the of not be was as an for 2 weeks and the follow-up information is not the fasting blood not change the first 2 patient B24 was with at mg/day and at 30 mg/day 6 In this not either the daily insulin dose at 1,000 or the of control fasting at to 2 weeks of therapy or 250 6 weeks of therapy). Clinical course of hypoglycemia has been followed for 28 years. to have a of antireceptor In initial test a fasting glucose with hypoglycemia 4 the glucose (Figure test years the fasting glucose is similar has a insulin was on initial test and by 2 In the second test, insulin is and the insulin response to the plasma glucose levels to at 2 In HbA1c is The patient is with to in glucose levels and to the The glucose and insulin a oral glucose tolerance test in patient in 1973 and 2000 to have a of anti-insulin receptor with hypoglycemia and a response to steroid therapy and 2 months of hypoglycemia and with hypoglycemic was with steroids for 4 months. The steroids to the plasma glucose in the however, was no in the of autoantibody at the time of was to Clinical course of 24 patients followed over 28 years The most of the follow-up was that of 24 patients have (Table the patients 4 a spontaneous remission from hyperglycemia and 3 remission on of the hypoglycemia patients also 8 of in patients from either or hypoglycemia. In we the age of and age of in the patients We also the associated at the time of within the period in is to that the 3 patients with hyperglycemia and on to hypoglycemia from of hypoglycemia. A similar was from the information reported on the literature (Table of in the the patients, 2 are to follow-up and 9 are 9 patients have been followed for ranging from months to 28 years. of these patients and are antibody positive. The in this paper a period of 28 years and the by and that the insulin receptor is a cell surface with the to be and by the to the insulin receptor as a of the 2 of patients with insulin resistance and identified 1 of the as that caused by autoantibodies against the insulin receptor. This has provided a to the and of the insulin receptor. We review the from these patients about their Autoantibodies to the insulin receptor are associated with other autoimmune disease is the most autoimmune disease associated with autoantibodies to the insulin receptor in our and also in the literature In our patients, the autoimmune features preceded the of the insulin receptor autoantibody of the Other autoimmune diseases have also been observed in our patients, such as and Other have observed an association with syndrome and autoimmune receptor autoantibodies as a manifestation We observed the autoantibodies in association with multiple in 1 The patient with and a on serum as typical of the insulin receptor autoantibody syndrome, this autoantibodies were polyclonal and not for the on serum months presenting with the diagnosis of multiple was by In this the of the autoantibody against the insulin receptor and multiple is however, it is to that autoantibodies to the insulin receptor have been as a of hypoglycemia in at least 4 patients with disease and 2 patients with it may be possible to this syndrome as a and are 2 presenting features and were in these patients. are for this syndrome are associated with other syndromes of insulin resistance such as in the insulin receptor and for the association of these clinical with insulin of these the insulin resistance with the disappearance of the autoantibody from the The in these patients a It has been that causes by a on the binding to other receptors in the In the of the syndrome was not as a that female patients in or years Because type B insulin resistance is observed in a wide age and in it was possible to the of with female and age years is also associated with by It is that the was observed without marked in 1 It is also to that and insulin resistance and the high levels of either or insulin were insulin resistance hypoglycemia or of antireceptor The autoantibodies to the insulin receptor in these patients and in are polyclonal with a of the G class (26,36). from the patients were in was a marked in binding to the cell surface In the cells were measuring binding of insulin The that binding inhibition the cells the high with which the antireceptor to receptors. the antibody is removed from the cells by an acid however, insulin binding is to that the receptor is While most patients’ antireceptor be detected by binding some not have been detected by their to solubilized insulin receptors the immunoprecipitation method is more specific to the presence of autoantibodies to the insulin receptor. autoantibodies are specific for the insulin receptor, some also with to the type 1 receptor for most are specific for the of the insulin receptor and little to to the receptors on To the that it has been autoantibodies to to a of the of the of the insulin receptor This is from the of the receptor that the of insulin binding in the of the If the autoantibodies are not binding to the same as they insulin There are 3 possible by by or by of binding The answer is not In to binding studies have shown that the autoantibodies the of receptor at the cell This to of the receptor and is a possible of receptor It is that were incubated with autoantibodies to the insulin receptor the the biologic of insulin the cell the autoantibodies were from the patients The required for the The were of the insulin studies to the between the of antireceptor in and their to insulin resistance in were incubated with antireceptor a time course was was a over the course of this response and cells more and more insulin It that the is to binding of the autoantibody to the receptor with of the this is followed by of the receptor and of receptors on the cell which the subsequent insulin resistance A similar response was observed in the anti-insulin receptor In the the antibody caused hypoglycemia in the administration a of insulin resistance over Clinical Autoantibodies to the insulin receptor were first identified as a of insulin it was recognized that they caused fasting hypoglycemia in some patients In addition, some cases with and on to fasting hypoglycemia a patient or fasting The answer is not may be at least 3 in not hypoglycemia is associated with of This was in the 3 patients with hypoglycemia it was typical of the patients from hyperglycemia to that is, this change was usually preceded by a in autoantibody This is a at the in dose response of the receptor antibody in to the dose response of The dose response for glucose is to the in to the binding inhibition to the in patients with of it is to that the of the and the patient hypoglycemia. in some patients be a change in the biologic of the autoantibody as in patients with Graves The of this type of is by the of that to as either or of insulin in our cases, we have been to a change in the biologic of the autoantibody using in assays the clinical from hyperglycemia to hypoglycemia. be a change in the insulin receptor production to other in patients with the autoantibody example, patient was reported to have a in the of receptors. This have the response to the a clinical fasting hypoglycemia to be a for the outcome of the In addition, these patients may diagnostic and therapeutic for of hyperglycemia and treatment of the is to the and control of This usually be with of The average insulin dose of the patient reported at the of their course was this of insulin is usually with The autoantibodies have been shown to glucose and also glucose by the using and are therapeutic The of these in hyperglycemia has not been in a The and our are to to the for has been reported to the of insulin to control hyperglycemia of our more patients, was with This not in in daily insulin improved the of fasting Patients and B24 The data on and are not to in glucose this to be in patient There are a of the on the of hyperglycemia using an of fatty acid and While the of this disease usually be by insulin oral the hypoglycemic is an The most therapy is and we have no with The of in hypoglycemia is usually within 24 and this is change in the of the antireceptor The of this therapeutic have not been prognosis and therapeutic The in this disease is high and to be determined by the of the underlying it is that patients spontaneous remission of the autoantibody syndrome without therapy. There are of remission in the literature using a variety of we used we were by the used to treat the underlying disease, such as be as the specific of the underlying disease are In our has and or have their of patients spontaneous remission of the and it from our that the more not either the onset of remission or the long-term course of the may be for the metabolic syndrome for patients have not within the typical time period. The of autoantibodies to the cell surface insulin receptor in a metabolic syndrome in This syndrome with an underlying disease such as The autoantibody in about of the patients with of the metabolic cases demonstrated that not have a on duration of the metabolic In addition, our that is a high of in A from hyperglycemia to hypoglycemia is an of prognosis and may to with intractable hypoglycemia. Autoantibodies to the cell surface receptors an of We the natural history of the disease caused by autoantibodies to the insulin receptor. We evaluated 24 patients age of with this disease between January 1973 and December 2000. patients (88%) were African American. and in were All 1 patient displayed was the most underlying of 24 patients most commonly associated with of 24 patients with spontaneous hypoglycemia. The 21 patients with hyperglycemia and to within 5 follow-up information is for of the 21 patients presenting with a period of hyperglycemia spontaneous hypoglycemia in 3 of the patients. Patients presenting with hyperglycemia high doses of insulin for therapy (mean The autoantibody in 7 of patients within months 30 patients various regimens and months of 6 of these patients within 6 weeks of The 6 patients similar not into remission months of of the more to was the high of of 24 patients at years. of the in patients into patients with hyperglycemia and developed hypoglycemia from of hypoglycemia. B insulin resistance is a metabolic syndrome in female patients with a high association with of patients remit not have a on duration of There is a high of in patients and a from hyperglycemia to hypoglycemia is an of We are to the and other in the Clinical Center of the National Institutes of Health have for the these patients over the 28 years. We are also to and for their in and the to the anti-insulin receptor