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Medicine:
doi: 10.1097/MD.0b013e3181a5b42e
Article

Autoimmune Forms of Hypoglycemia

Lupsa, Beatrice C. MD; Chong, Angeline Y. MD; Cochran, Elaine K. MSN, CRNP; Soos, Maria A. PhD; Semple, Robert K. MB, PhD; Gorden, Phillip MD

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Author Information

From Clinical Endocrinology Branch (BCL, AYC, EKC, PG), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States; and University of Cambridge Metabolic Research Laboratories (MAS, RKS), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.

Received September 18, 2008, and in revised form December 18, 2008.

Accepted for publication January 5, 2009.

This work was supported by intramural research funding of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, Maryland, and by the Wellcome Trust.

Reprints: Phillip Gorden, MD, 10 Center Drive, MSC 1612, Room CRC 6-5940, Bethesda, MD 20892; (e-mail: phillipg@intra.niddk.nih.gov).

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Abstract

Autoimmune syndromes are a rare cause of hypoglycemia characterized by elevated levels of insulin in the presence of either anti-insulin antibodies (insulin autoimmune syndrome) or anti-insulin receptor antibodies (type B insulin resistance). Insulin autoimmune syndrome is the third leading cause of hypoglycemia in Japan, but has rarely been described in the non-Asian population.

In the current study, we report the clinical and biochemical characteristics and clinical course of 2 white patients with insulin autoimmune syndrome, and present a literature review of non-Asian patients reported with insulin autoimmune syndrome. Also, we describe the clinical and biochemical characteristics of patients reported in the literature with type B insulin resistance who manifested hypoglycemia. We compare the clinical and laboratory features of insulin autoimmune syndrome and type B insulin resistance with each other and with other forms of hyperinsulinemic hypoglycemia.

Autoimmune forms of hypoglycemia are uncommon. However, they should be considered in any patient with hypoglycemia in the setting of unsuppressed insulin levels associated with anti-insulin or anti-insulin receptor antibodies. Making the correct diagnosis may spare a hypoglycemic patient from an unnecessary pancreatic surgical procedure.

Abbreviations: BMI = body mass index, CRC = Clinical Research Center, HLA = human leukocyte antigen, NIH = National Institutes of Health, SLE = systemic lupus erythematosus.

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INTRODUCTION

Autoimmune forms of hypoglycemia are of 2 general types. In the first form antibodies are directed against endogenous insulin, and in the second form antibodies are directed against the cell surface insulin receptor. Both conditions may be associated with inappropriately elevated insulin, and both conditions may be associated with postprandial hypoglycemia, fasting hypoglycemia, or both. From a therapeutic perspective it is extremely important to distinguish these conditions from each other and from other forms of hypoglycemia associated with inappropriate insulin levels.

In the present report we do the following:

1) Describe the clinical characteristics of each syndrome with an emphasis on non-Asian patients with insulin autoimmune syndrome.

2) Compare and contrast insulin autoimmune syndrome with type B insulin resistance.

3) Describe the distinction between these autoimmune syndromes and other forms of insulin-induced hypoglycemia.

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PATIENTS AND METHODS

Patients

Two patients with the diagnosis of insulin autoimmune syndrome were admitted to the Clinical Research Center (CRC) of the National Institutes of Health (NIH) in Bethesda, Maryland, between July 2007 and July 2008. We evaluated the data gathered on these patients to draw conclusions about the clinical spectrum of this syndrome.

Thirty-four patients with type B insulin resistance were admitted to the CRC of the NIH between January 1973 and July 2008. We analyzed their data, and 8 of 34 patients were found to have hypoglycemia at some phase of their disease.

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Criteria for Inclusion

For a diagnosis of insulin autoimmune syndrome, patients were required to have demonstrable anti-insulin antibodies in association with hypoglycemia. For a diagnosis of type B insulin resistance, patients were required to demonstrate autoantibodies against the insulin receptor in association with hyperglycemia or hypoglycemia.

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Data Collection

Each patient underwent a detailed history and physical examination and was followed for months at the CRC. 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 response (resolution of glucose abnormalities) over the course of follow-up, current status, and mortality.

We used a similar approach to derive complete follow-up information on cases reported in the literature whenever possible. We searched PubMed (National Library of Medicine, Bethesda, MD) for publications in English, French, and Spanish, using the following keywords: autoimmune hypoglycemia, insulin autoimmune syndrome, and Hirata disease. To search for cases of type B insulin resistance manifesting hypoglycemia, we searched PubMed, Scopus (Elsevier, Amsterdam, The Netherlands), and Web of Science (Thomson Reuters, New York, NY) with the following keywords: type B insulin resistance, antibody, insulin receptor, and hypoglycemia.

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Laboratory Testing

All patients underwent a battery of routine hematologic, immunologic, and biochemical tests on initial examination, and on multiple subsequent time points.

The patients with insulin autoimmune syndrome underwent a diagnostic fast during hospitalization. Each patient was proven to have anti-insulin antibodies by radioimmunoassay, done at the Mayo Clinic laboratories. The free insulin was determined by polyethylene glycol precipitation. Blood glucose, insulin, C-peptide, hemoglobin A1c, antinuclear antibodies, anti-double-stranded DNA antibodies, complement C3 and C4, anticardiolipin antibodies, and human leukocyte antigen (HLA) typing were determined at the NIH laboratories. Proinsulin was measured at the Mayo Clinic laboratories.

In patients with type B insulin resistance, anti-insulin receptor autoantibodies were detected by immunoprecipitation of insulin receptor preparations using patients' sera followed by Western blotting.2,14 The methods for routine hematologic, immunologic, and biochemical tests were the same as those used in patients with insulin autoimmune syndrome. Most patients with type B insulin resistance underwent a standard oral glucose tolerance test, and those initially presenting with hypoglycemia underwent a diagnostic fast.

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INSULIN AUTOIMMUNE SYNDROME:CASE REPORTS

Case 1

A 67-year-old white man experienced episodes of fasting and postprandial hypoglycemia, alternating with postprandial hyperglycemia for about 9 months.

Because of these symptoms he was hospitalized and treated briefly with pre-meal insulin injections and glimepiride. Over the next 6 months he took no medication for blood glucose control, and in spite of a regular schedule of meals every 4 hours, he continued to have daily fasting and postprandial episodes of hypoglycemia with blood glucose levels of 40-50 mg/dL accompanied by adrenergic and neuroglycopenic symptoms. The symptoms of hypoglycemia resolved with food ingestion and glucose tablets.

His past medical history was significant for obesity, chronic obstructive pulmonary disease, hypertension, congestive heart failure, atrial fibrillation, and hyperlipidemia. His medications included ramipril, atenolol, warfarin, furosemide, tiotropium bromide, levalbuterol, and fluticasone/salmeterol inhaler. The patient denied any use of exogenous insulin or oral hypoglycemic medications.

Physical examination revealed an obese man with irregularly irregular heart rhythm and moderate leg edema bilaterally. Vital signs were normal except for a mildly elevated blood pressure of 146/81 mm Hg. The rest of the physical exam was unremarkable. Body mass index (BMI) was 32 kg/m2.

The results of the initial endocrine investigations are summarized in Table 1. Fasting blood sugar was 45 mg/dL (normal range, 70-115 mg/dL), with an insulin level of 164 μU/mL (normal range, 6-27 μU/mL) and a C-peptide level of 34 ng/mL (normal range, 0.9-4 ng/mL). Hemoglobin A1c was 7% (normal range, 4.8%-6.4%). Adiponectin level was 4 mg/L (normal adult range for a BMI of 20 kg/m2, 3-19 mg/L).69 The low adiponectin level in this overweight patient was consistent with the insulin resistance of obesity. Further laboratory studies showed a normal white count with monocytosis, anemia, and thrombocytopenia; normal electrolytes; normal kidney and liver function tests except for high total protein; and low albumin. Serum protein electrophoresis revealed monoclonal gammopathy of uncertain significance. Antinuclear antibodies were strongly positive, and anti-double-stranded DNA antibodies were mildly positive. Because of anemia and thrombocytopenia, the patient underwent a bone marrow biopsy, which suggested a myelodysplastic condition consistent with chronic myelomonocytic leukemia. Computed tomography of the chest showed mediastinal lymphadenopathy. Computed tomography and ultrasound of the abdomen failed to detect a pancreatic tumor. The serologic typing of HLA alleles showed that the patient was DRB1*0301 and DRB1*0404 positive.

Table 1
Table 1
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The patient underwent a supervised fast starting with a mixed meal. After 5 hours of fasting, the patient developed symptomatic hypoglycemia with a blood glucose of 49 mg/dL, accompanied by a high insulin level of 157 μU/mL, C-peptide level of 34.9 ng/mL, and proinsulin of 8100 pmol/L. Hypoglycemia persisted until the end of the test at 7 hours (Figure 1). The anti-insulin antibody level was 56% (normal range, 0%-2%). The antibodies were polyclonal and belonged to the IgG subclass. After polyethylene glycol precipitation of the insulin to remove the antibody-bound complexes, only 1%-3% of the insulin was recoverable.

Figure 1
Figure 1
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Based on the episodes of hypoglycemia, accompanied by extremely high levels of insulin, proinsulin, and C-peptide, and the presence of anti-insulin antibodies, the patient was diagnosed with insulin autoimmune syndrome. He was started on oral prednisone 60 mg/d, with slow tapering over 2 months. The patient responded well to the treatment with resolution of hypoglycemia and decline in the insulin autoantibody titers. When the prednisone was decreased to 5 mg a day, the antibody level increased again; however, the patient remained asymptomatic (Figure 2). Seven months after the time of diagnosis, the patient died from intractable thrombocytopenia related to chronic myelomonocytic leukemia.

Figure 2
Figure 2
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Case 2

A 71-year-old white man experienced episodes of hypoglycemia over a 9-month period with blood glucose levels of 30-40 mg/dL and without any obvious temporal pattern with meals.

Past medical history was significant for hypertension treated with nifedipine, metoprolol, and irbesartan/hydrochlorothiazide; benign prostatic hyperplasia treated with terazosin; and osteoporosis. The patient had a family history of diabetes mellitus in his niece and systemic lupus erythematosus (SLE) in his daughter.

The physical exam was unremarkable except for the patient being overweight with a BMI of 28.6 kg/m2.

Initial workup showed a fasting blood glucose of 90 mg/dL, an insulin level of 11.8 μU/mL, C-peptide of 1.8 ng/mL, proinsulin of 49 pmol/L, negative anti-glutamic acid decarboxylase (GAD) 65 antibodies, anti-islet cell IgG of <1:4, hemoglobin A1c of 5.5%, anti-insulin antibodies of 54% (normal, <3%) and negative oral hypoglycemic screening (Table 1). Complete blood count; chemistry; liver function; and rheumatologic workup that included anti-double-stranded DNA, anti-ENA panel, complement levels, erythrocyte sedimentation rate, and serum and urine protein electrophoresis were within the normal limits. Computed tomography of the abdomen was negative for insulinoma.

The patient underwent a supervised fast starting with a mixed meal. His blood glucose dropped to 53 mg/dL at 4 hours; however, it returned to normal for the rest of the test (Figure 3). The supervised fast was stopped after 32 hours due to lack of evidence of hypoglycemia. The following day he underwent an oral glucose tolerance test. Four hours after the administration of 75 g dextrose, his blood sugar dropped to 43 mg/dL with associated symptoms of hypoglycemia. Concurrent insulin was 55.1 μU/mL, C-peptide was 8.7 ng/mL, and proinsulin was 500 pmol/L. The results of the oral glucose tolerance test are illustrated in Figure 4.

Figure 3
Figure 3
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Figure 4
Figure 4
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The patient was placed on low carbohydrate meals and was started on prednisone 60 mg/d for 2 weeks. After starting prednisone, his blood glucose normalized. After 2 weeks of prednisone, his anti-insulin antibodies had decreased to 40%. The patient was tapered off prednisone and his symptoms have been stable since that time. One month after stopping the prednisone, the anti-insulin antibody titer was 29%.

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DISCUSSION

Clinical Characteristics of Insulin Autoimmune Syndrome in Non-Asian Patients

Insulin autoimmune syndrome or Hirata disease is a rare condition characterized by hyperinsulinemic hypoglycemia associated with high titer of antibodies to endogenous insulin, in the absence of pathologic abnormalities of the pancreatic islets and prior exposure to exogenous insulin.4

The syndrome was first described by Hirata in 1970.84 In Japan, insulin autoimmune syndrome is the third leading cause of severe hypoglycemia after insulinoma and extrapancreatic neoplasms. The Japanese experience with insulin autoimmune syndrome was summarized by Hirata and Uchigata in 1999.84 To our knowledge, no systematic review of non-Asian cases of insulin autoimmune syndrome has been undertaken so far.

The disease is extremely uncommon in Western countries. White people appear to be less prone than Japanese individuals to developing the syndrome. To date, 58 cases have been reported in the non-Asian population, including the 2 cases in the current report. The phenotype of insulin autoimmune syndrome is well illustrated by our 2 case reports and further amplified by the compilation of the non-Asian cases shown in Table 2.

Table 2
Table 2
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The vast majority of the patients reported outside Asia are white. Most of the cases come from Europe (50%) and the United States (41%). Overall, insulin autoimmune syndrome affects men and women equally and is seen more frequently in patients older than 40 years of age.

Insulin autoimmune syndrome is characterized by episodes of hyperinsulinemic hypoglycemia that occur most often postprandially, although fasting hypoglycemia and hypoglycemia exacerbated by exercise have been reported. Paradoxically, hyperglycemia may occur immediately following a meal or oral glucose challenge. This phenomenon was present in our Patient 1 with insulin autoimmune syndrome, who had an elevated hemoglobin A1c of 7% in spite of his hypoglycemic episodes.

Of the cases with data reported, 19 patients (42%) had reactive hypoglycemia and 14 patients (31%) had fasting hypoglycemia. In 11 patients (24%), the episodes of hypoglycemia occurred in both postprandial and fasting states.

Most of the patients diagnosed with insulin autoimmune syndrome had associated comorbidities or exposure to various medications. In non-Asian patients, this syndrome is often associated with rheumatologic diseases such as SLE or rheumatoid arthritis. Some of the patients who developed anti-insulin antibodies had an underlying hematologic disease, ranging from benign monoclonal gammopathy to multiple myeloma. Many patients had positive antinuclear antibodies, anti-double-stranded DNA, and rheumatoid factor, and had an abnormal blood count, urine and serum protein electrophoresis, and bone marrow examination.

A few case reports mention an association of anti-insulin antibodies with ulcerative colitis and pregnancy.4,31

In about 47% of the non-Asian patients, insulin autoimmune syndrome seemed to be triggered by exposure to different medications (captopril, penicillamine, pyritinol, carbimazole, imipenem, propylthiouracil, hydralazine, procainamide, isoniazid, penicillin G). In Japanese cases, a clear relation was demonstrated between medications containing the sulfhydryl group and the occurrence of this syndrome. In contrast, the association was not as evident in the non-Asian cases.

In the majority of patients, the hypoglycemia improved or resolved completely. In 2 cases, remission of insulin autoimmune syndrome was reported, with no treatment required.51,61 However, most patients were treated for symptomatic hypoglycemia. The first line of treatment was low carbohydrate meals to prevent postprandial hypoglycemia. Eleven patients (38%) were treated with steroids, mostly oral prednisone. Other medications such as acarbose, somatostatin, and diazoxide have been tried with variable results. In some cases where the hypoglycemia was induced by medication, discontinuing the incriminating drug led to resolution of the symptoms. Four patients (13%) underwent pancreatic surgery for suspected insulinoma, and 1 patient underwent subtotal pancreatectomy for intractable hypoglycemia.

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Pathophysiology of Insulin Autoimmune Syndrome

In insulin autoimmune syndrome, hypoglycemia is caused by antibodies against endogenous insulin, without prior exposure to exogenous insulin. In these cases, the binding kinetics of endogenous insulin by the antibodies are thought to lead to physiologically inappropriate levels of bioavailable insulin, causing either hyper- or hypoglycemia.

Anti-insulin antibodies can be measured by assessing binding by serum of 125I-labeled insulin, by ELISA, or more indirectly by determining recovery of immunoreactive insulin after polyethylene glycol precipitation of plasma. The vast majority of the anti-insulin antibodies belong to the IgG group with various ratios of kappa to lambda light chains. One non-Asian patient had IgA antibodies. These anti-insulin antibodies are classified as monoclonal and polyclonal based on affinity curves for binding to human insulin and presence of solitary light chains.31,60,84 Studies suggest that the type of amino acid at position 74 of the DR beta 1 chain may be important for determining the clonality of the insulin autoantibodies.13 Monoclonal anti-insulin antibodies are more prevalent in non-Asian patients. Of the cases with data reported, 8 non-Asian patients (67%) had monoclonal antibodies.

In insulin autoimmune syndrome, the insulin levels are markedly elevated, usually above 100 μU/mL. In some cases the insulin assay may give erroneous results because of the interference of the endogenous autoantibodies with the assay antibody. Free insulin levels are normal or high, the proinsulin and C-peptide levels are markedly elevated, and insulin antibodies show a high percentage of binding to insulin. Basu and others4,60 have suggested that the C-peptide and proinsulin concentrations can also be spuriously elevated because the insulin autoantibodies can interfere with the immunoassay by binding to C-peptide and proinsulin.

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Mechanism of Hypoglycemia in Insulin Autoimmune Syndrome

The hypoglycemic episodes in insulin autoimmune syndrome appear to be caused by the binding and release of the insulin from the antibodies, which occur out of synchrony with the prevailing glucose concentration. After a meal or oral glucose load, patients often demonstrate initial hyperglycemia, followed by hypoglycemia a few hours later. The hyperglycemia is caused by the anti-insulin antibodies that bind the insulin secreted in response to rising blood glucose levels after a meal. This binding reduces the availability of the secreted insulin to the receptors in the liver and peripheral tissues, resulting in hyperglycemia and further insulin secretion. This transient hyperglycemia explains the elevated hemoglobin A1c seen in some patients with insulin autoimmune syndrome, as in our Patient 1. As the blood glucose concentration begins to decrease and insulin secretion declines, the insulin bound to the antibodies is released, resulting in inappropriately high free insulin concentrations for the blood glucose, causing hypoglycemia.60

To investigate the mechanism of hypoglycemia in this disease, Dozio et al21 conducted an experiment in a patient with insulin autoimmune syndrome, looking at 125I-labeled insulin scintigraphic scans before and after treatment. After an intravenous injection of 125I-labeled insulin, the patient demonstrated persistent labeled insulin activity in the blood and absence of uptake of the labeled hormone in the liver or kidneys. After treatment with prednisone and plasmapheresis, insulin autoantibody levels decreased, and the clearance of 125I-labeled insulin from the blood pool increased.

Classically, this syndrome has been described in Japan in association with medications containing the sulfhydryl group. It has been postulated that the sulfhydryl group interacts with the disulfide bonds in the insulin molecule, making the insulin more immunogenic, either by hapten formation or by cleavage of the disulfide bonds of the insulin molecule. However, incubation of methimazole and insulin in vitro has no effect on the insulin structure and immunoreactivity.60 In most cases, discontinuing the sulfhydryl medications was associated with remission of the hypoglycemic episodes, and reintroducing the offending agents led to the recurrence of hypoglycemia. This finding suggests that the association between medications and the syndrome is more than coincidental.84

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Characteristics of Insulin Autoimmune Syndrome in Asian Patients

The Asian patients with insulin autoimmune syndrome reported by Hirata84 have different clinical characteristics compared with the non-Asian patients. In the Japanese cases, the peak age of onset was 60-69 years for both sexes, and there was no remarkable sex difference except in the group aged 20-29 years, in which 80% of the patients were female.

About 41% of the Asian patients with insulin autoimmune syndrome were exposed to medications containing the sulfhydryl group. Most of the patients received methimazole for treatment of Graves disease. However, other medications have been incriminated: glutathione used to treat urticaria and alpha-mercaptopropionyl glycine used to treat chronic hepatitis, dermatitis, cataracts, and rheumatoid arthritis. Other Japanese patients developed insulin autoimmune syndrome in response to tolbutamide used to treat diabetes, gold thioglucose used for asthma, interferon alpha used for renal cell carcinoma, aceglatone used for urinary bladder carcinoma, steroids used for polymyositis, antihypertensive drugs (captopril, diltiazem), nonsteroidal antiinflammatory drugs (loxoprofen sodium, giclofenac sodium), and tolperisone used for lumbar pain.83,84 A 2007 case report associated this syndrome with the use of alpha lipoic acid.82

In most of the Asian patients, the insulin autoantibodies were polyclonal IgGs with variable kappa and lambda light chains and 2 classes of insulin binding sites: high affinity/low capacity and low affinity/high capacity.31 Most of the Japanese patients had a prevalent Cw4/B62/DR4 allelic combination. These haplotypes are 10-20 times more common in Asians compared with non-Asian subjects and may account for the high frequency of these cases in Japan. The majority of the DR4-positive Japanese patients are DRB1*0406 positive (87% of the patients tested).13,84 The DRB1*0406 allele appears to play an important role in presenting insulin peptides to T cells.87

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Clinical Characteristics of Type B Insulin Resistance

Most patients with type B insulin resistance present with moderate to severe hyperglycemia that is usually associated with profound glucosuria, polyuria, and weight loss. However, in our experience, 24% (8/34) of patients manifested some form of hypoglycemia during the course of their illness (Table 3). We found 22 other cases in the literature of hypoglycemia caused by anti-insulin receptor antibodies. Some patients develop hypoglycemia after a period of hyperglycemia. The hypoglycemia may occur in the fasting or the postprandial state. Instead of having a preceding period of hyperglycemia, other patients with type B insulin resistance may initially present with spontaneous hypoglycemia and never manifest hyperglycemia. Of note, patients with hypoglycemia tend to present with a higher BMI than those who present with hyperglycemia. Arioglu et al2 reported that 62% of hyperglycemic patients at the NIH had a BMI <25 kg/m2 and only 19% had a BMI >30 kg/m2. In contrast, 33% of hypoglycemic patients had a BMI <25 kg/m2 and 67% had a BMI >30 kg/m2.

Table 3
Table 3
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The typical patient with type B insulin resistance is a middle-aged black woman. To date, our group at the NIH has followed 34 patients with type B insulin resistance. Twenty-nine of 34 (85%) were female and 29 of 34 (85%) were black. We have evaluated 5 male patients (15% of the total), and all of them were black. In our series of 34 patients, the average age of affected women at presentation was 41 years and the average age of affected men was 57 years. Considering only the hypoglycemic patients seen at the NIH, all 8 were female, and 6 of the 8 patients were black. Among the other hypoglycemic cases published in the literature, 17 of 22 (77%) were women. The patient's race was reported in 9 of those cases; 6 of the 9 (67%) patients were black.

Unlike insulin autoimmune syndrome, acanthosis nigricans is a striking clinical feature of type B insulin resistance.2 Of our 34 patients, 31 (92%) had acanthosis nigricans. The acanthosis nigricans most often affects the axillae, groin, and neck. A distinguishing feature of the acanthosis nigricans associated with type B insulin resistance is the involvement of the periocular, perioral, and labial regions. Because of this distinctive distribution of acanthosis nigricans, patients tend to have a characteristic facial appearance. In some patients, acanthosis nigricans can be found on the trunk, buttocks, lips, and vulva.

Ovarian enlargement and hyperandrogenism are also presenting characteristics in women with type B insulin resistance.2 In our NIH series, enlarged ovaries were seen in most of the premenopausal female patients and were usually cystic. In 2002, Arioglu et al2 reported that 7 of 13 female patients between the ages of 14 and 50 years seen at the NIH had elevated testosterone levels. Since the publication of that paper, we have seen 4 additional women younger than 50 years old with type B insulin resistance, and 3 of them had hypertestosteronemia. We observed a reduction in testosterone levels when the patients' autoantibody syndrome remits, suggesting that the hyperandrogenism is associated with the presence of the autoantibody or hyperinsulinemia.2

Another common feature of type B insulin resistance at presentation is the co-occurrence of autoimmune phenomena. Arioglu et al2 noted that the most common underlying autoimmune disorder in their series of 24 patients seen at the NIH was SLE. In that report, 11 of 24 patients (46%) met the criteria for SLE, and 6 of 24 patients (25%) had 3 of 4 criteria for SLE. Of the 10 additional patients we have seen at the NIH since that 2002 report, 3 patients met the criteria for SLE and 2 patients had 3 of 4 criteria for SLE. One patient of the 10 had mixed connective tissue disease. In other cases reported in the literature, type B insulin resistance has been associated with primary biliary cirrhosis, multiple myeloma, scleroderma, dermatomyositis, overlap syndrome, Hodgkin disease, Hashimoto thyroiditis, Sjögren syndrome, and autoimmune thrombocytopenia.2 Of note, the metabolic derangements caused by type B insulin resistance usually become manifest after the onset of the systemic autoimmune disease.

Type B insulin resistance has other metabolic features. Unlike other syndromes of insulin resistance, fasting triglyceride levels are low. In the 2002 NIH series,2 the average fasting triglyceride level was 54 mg/dL. Among our 10 additional patients, fasting serum triglycerides ranged from 25 to 68 mg/dL with an average of 49 mg/dL.

Another characteristic of type B insulin resistance is hyperadiponectinemia. Semple et al68 reported paradoxically high plasma adiponectin levels in patients with type B insulin resistance. Adiponectin is produced by adipose tissue, and levels are typically low in insulin-resistant patients. In type B resistance, adiponectin levels normalize as the titers of insulin receptor autoantibodies fall and insulin resistance resolves.

Autoantibodies against the insulin receptor are predominantly polyclonal IgGs.2,16,29,38 Several methods of detection have been used over the years with varying degrees of sensitivity and specificity; these methods include inhibition of insulin binding, immunoprecipitation of the insulin receptor, and stimulation of glucose oxidation.63

These antibodies can cause hypoglycemia by activating the receptor. When autoantibodies to the insulin receptor are injected into fasting rats, severe and persistent hypoglycemia is induced in a dose-dependent manner.20 The hypoglycemic effect occurs within 2-4 hours of injection and lasts 8-24 hours. Interestingly, when antibodies are administered at high doses for several days to fed rats, hyperglycemia is observed instead. In vitro, antireceptor antibodies stimulate 2-deoxyglucose uptake and glucose oxidation in murine fatty fibroblasts and rat adipocytes.20,41,75,85 In addition, they have been shown to stimulate autophosphorylation of the insulin receptor in purified receptor preparations from rat liver.93 In particular, phosphorylation of the beta subunit of the insulin receptor occurs.75 Human adipocytes incubated with antireceptor antibodies also show increased glucose oxidation.40 Thus, autoantibodies to the insulin receptor can mimic the effects of insulin when given acutely. However, with chronic administration, the antireceptor antibodies induce persistent hyperglycemia and insulin resistance. This observation is consistent with the concept that these autoantibodies are partial agonists for the insulin receptor. At high antibody titer, the antagonistic property is manifested, while at low titer, the agonistic effect is observed. This mechanism would explain the different clinical states of hyperglycemia followed by hypoglycemia. Other potential mechanisms include insulin receptor proliferation28 and a change in the qualitative form of the autoantibody from agonist to antagonist.

In contrast to the more benign course of insulin autoimmune syndrome, Type B insulin resistance is associated with high mortality. Arioglu et al2 reported that 13 of 24 patients followed over 28 years at the NIH died. The causes of death included hypoglycemia, lupus, myocardial infarction, end-stage renal disease, breast cancer, and stroke. The 3 patients in that series who initially presented with hyperglycemia and then later developed hypoglycemia died from complications of hypoglycemia. In other reports of type B insulin resistance, patients have died of hypoglycemia, bronchopneumonia, and gastrointestinal bleeding.2,10,57,86 It appears that the transition between a hyperglycemic to a hypoglycemic phase is associated with a poor prognosis. Furthermore, while insulin autoimmune syndrome responds to glucocorticoids, type B insulin resistance has been difficult to treat successfully with a variety of immunosuppressants.

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Clinical Distinction Between the 2 Types of Autoimmune Hypoglycemia

Insulin autoimmune syndrome and type B insulin resistance have overlapping forms of hypoglycemia; thus, both can present with fasting hypoglycemia, reactive hypoglycemia, or both. Differentiating between these 2 syndromes is usually based on clinical and biochemical evaluation (Table 4).

Table 4
Table 4
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In insulin autoimmune syndrome, hypoglycemia occurs fasting and/or more commonly after food ingestion. Hyperglycemia can also occur postprandially because the insulin is bound by the antibodies and is not available to be used immediately after a meal. In type B insulin resistance, the patients most commonly present with severe hyperglycemia. Some patients manifest fasting hypoglycemia following a period of hyperglycemia, while others present solely with severe fasting hypoglycemia. The hypoglycemia is thought to be caused by the binding of the insulin receptor by the antibodies. The degradation of insulin is dependent on the insulin receptor. The antibodies bound to the receptor prevent insulin from being degraded, leading to hyperinsulinemia and concurrent hypoglycemia. Hypoglycemia seems to be more common in patients with low anti-insulin receptor antibody titers.

In insulin autoimmune syndrome the insulin, C-peptide, and proinsulin levels are extremely high, much higher than in type B insulin resistance. All patients with insulin autoimmune syndrome have high titers of insulin-specific autoantibodies, and these antibodies cause false elevation in the insulin levels interfering with the commercially available assays. A diagnosis of insulin autoimmune syndrome can be made by measuring the anti-insulin antibodies, which are classically elevated. In type B insulin resistance, the antibodies against the insulin receptor are positive.

In non-Asian patients, insulin autoimmune syndrome occurs most frequently in men and women between the ages of 40 and 80 years and affects both sexes equally. The vast majority of non-Asian patients are white. Type B insulin resistance affects mostly black women between the ages of 40 and 50 years. Acanthosis nigricans and signs of hyperandrogenism are common in these patients and are not present in patients with insulin autoimmune syndrome.

Underlying rheumatologic or hematologic diseases are frequently seen in patients with both types of autoimmune hypoglycemia. Insulin autoimmune syndrome can be triggered by medications, especially drugs containing the sulfhydryl group. In these cases, the hypoglycemia usually subsides when the medication is discontinued. Most of the patients with insulin autoimmune syndrome respond well to steroids, with resolution of their symptoms. In patients with type B insulin resistance, the response to therapy is variable, and the disease is usually much more refractory to therapy.

Both types of antibodies have rarely been reported in the same patient.9 This could be due to the production of both autoantibodies, but in the era of animal insulins many patients with type B insulin resistance also had antibodies to exogenous animal insulin. Antibodies produced against exogenous insulin may produce mild insulin resistance. Rarely, high binding capacity antibodies can occur, and patients with such antibodies manifest severe insulin resistance. We have not seen examples of this syndrome since the introduction of human insulin.

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Comparing the 2 Types of Autoimmune Hypoglycemia With Other Causes of Hyperinsulinemic Hypoglycemia

Hypoglycemia can be classified as an insulin-mediated or a non-insulin-mediated condition. The most common cause of hyperinsulinemic hypoglycemia is insulinoma. However, other causes should be taken into consideration such as insulin autoimmune syndrome and type B insulin resistance. These conditions can usually be differentiated by measurements of plasma C-peptide, proinsulin, anti-insulin, and anti-insulin receptor antibodies (Table 5). Making the correct diagnosis is extremely important because it may spare a hypoglycemic patient from an unnecessary pancreatic surgical procedure.

Table 5
Table 5
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Typically, insulin secretion in a patient with an insulinoma fails to be suppressed in the presence of hypoglycemia. The hypoglycemic episodes occur in the fasting state, and the levels of insulin, C-peptide, and proinsulin are inappropriately high. Insulinomas are more frequently seen in patients with multiple endocrine neoplasia type 1. In these patients, insulin-secreting tumors account for 20%-35% of the functional pancreatic islet cell tumors.

In autoimmune hypoglycemia, the decrease in blood glucose can occur fasting or after food ingestion. The insulin, C-peptide, and proinsulin levels are extremely elevated. The correct diagnosis can be made by measuring the anti-insulin and anti-insulin receptor antibodies. The autoimmune forms of hypoglycemia are frequently seen in association with hematologic and rheumatologic diseases, or they may be medication induced.

There are a variety of other syndromes causing hyperinsulinemic hypoglycemia, such as noninsulinoma pancreatogenous hypoglycemia syndrome. This condition can occur with or without bariatric surgery and can manifest as postprandial hypoglycemia. In this syndrome, the anti-insulin and anti-insulin receptor antibodies are negative.

In a patient with hypoglycemia, a factitious cause should always be considered. The surreptitious administration of insulin should be suspected in patients who have access to insulin. Typically the insulin levels are high but the C-peptide and proinsulin levels are low. Before the marketing of human insulin, the most useful test to confirm the diagnosis was the demonstration of anti-insulin antibodies in response to exogenously administered insulin.34 The incidence of immunologic complications of insulin therapy has significantly decreased with the use of recombinant human insulin. These new preparations can still cause anti-insulin antibodies, but the titers are low and they are rarely associated with hypoglycemia. Seven case reports have been published of patients treated with human insulin who developed hypoglycemia as a result of antibodies against exogenous insulin. All these cases were reported from Japan, where insulin autoimmune syndrome is more prevalent.27

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CONCLUSION

Autoimmune forms of hypoglycemia are uncommon. However, they should be considered in any patient with hypoglycemia in the setting of unsuppressed insulin levels associated with anti-insulin or anti-insulin receptor antibodies.

These autoantibodies should be measured in all hypoglycemic patients because careful investigation of the autoimmune mechanism may spare a hypoglycemic patient from an unnecessary pancreatic surgical procedure.

Although not essential for the diagnosis, the coexistence of a separate autoimmune or hematologic disease should be sought in patients with a diagnosis of autoimmune hypoglycemia.

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REFERENCES

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