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%.
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.
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.
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.
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
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
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.
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.
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).
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.
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.
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
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.
1. Archambeaud-Mouveroux F, Canivet B, Fressinaud C, de Buhan B, Treves R, Laubie B. Autoimmune hypoglycemia: the fault of pyritinol? Presse Med
2. Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden P. Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective. Medicine (Baltimore)
3. Arnqvist HJ, Halban PA, Mathiesen UL, Zahnd G, von Schenck H. Hypoglycaemia caused by atypical insulin antibodies in a patient with benign monoclonal gammopathy. J Intern Med
4. Basu A, Service FJ, Yu L, Heser D, Ferries LM, Eisenbarth G. Insulin autoimmunity and hypoglycemia in seven white patients. Endocr Pract
5. Benson EA, Healey LA, Barron EJ. Insulin antibodies in patients receiving penicillamine. Am J Med
6. Benson EA, Ho P, Wang C, Wu PC, Fredlund PN, Yueng RT. Insulin autoimmunity as a cause of hypoglycemia. Arch Intern Med
7. Blackshear PJ, Rotner HE, Kriauciunas KA, Kahn CR. Reactive hypoglycemia and insulin autoantibodies in drug-induced lupus erythematosus. Ann Intern Med
8. Bloise W, Wajchenberg BL, Moncada VY, Marcus-Samuels B, Taylor SI. Atypical antiinsulin receptor antibodies in a patient with type B insulin resistance and scleroderma. J Clin Endocrinol Metab
9. Bortolotti D, Mothe-Satney I, Ferrari P, Gautier N, Sonke J, Palle S, Bernard G, Badetti JL, Fredenrich A, Van Obberghen E, Canivet B. Spontaneous hypoglycaemia in the presence of both anti-insulin antibody and anti-insulin receptor antibody. Diabetes Metab
10. Braund WJ, Naylor BA, Williamson DH, Buley ID, Clark A, Chapel HM, Turner RC. Autoimmunity to insulin receptor and hypoglycaemia in patient with Hodgkin's disease. Lancet
11. Burch HB, Clement S, Sokol MS, Landry F. Reactive hypoglycemic coma due to insulin autoimmune syndrome: case report and literature review. Am J Med
12. Casesnoves A, Mauri M, Dominguez JR, Alfayate R, Pico AM. Influence of anti-insulin antibodies on insulin immunoassays in the autoimmune insulin syndrome. Ann Clin Biochem
13. Cavaco B, Uchigata Y, Porto T, Amparo-Santos M, Sobrinho L, Leite V. Hypoglycaemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin autoantibodies. Eur J Endocrinol
14. Coll AP, Morganstein D, Jayne D, Soos MA, O'Rahilly S, Burke J. Successful treatment of Type B insulin resistance in a patient with otherwise quiescent systemic lupus erythematosus. Diabet Med
15. Cresto JC, Abdenur JE, Chamoles N, Bresciani P, Ruiz M, Massa B, Camberos MC, Basabe JC. Autoimmune hypoglycemia syndrome with specific anti-human insulin antibodies. Medicina (B Aires)
16. De Pirro R, Roth RA, Rossetti L, Goldfine ID. Characterization of the serum from a patient with insulin resistance and hypoglycemia. Evidence for multiple populations of insulin receptor antibodies with different receptor binding and insulin-mimicking activities. Diabetes
17. Di Cerbo A, Tassi V, Scillitani A, Zoppetti G, De Filippis V. Characterization of insulin autoantibodies in a patient with autoimmune hypoglycemia. J Endocrinol Invest
18. Di Paolo S, Giorgino R. Insulin resistance and hypoglycemia in a patient with systemic lupus erythematosus: description of antiinsulin receptor antibodies that enhance insulin binding and inhibit insulin action. J Clin Endocrinol Metab
19. Discher T, Seipke G, Friedmann E, Velcovsky HG, Federlin K. Recurrent hypoglycemia in the insulin autoimmune syndrome. Dtsch Med Wochenschr
20. Dons RF, Havlik R, Taylor SI, Baird KL, Chernick SS, Gorden P. Clinical disorders associated with autoantibodies to the insulin receptor. Simulation by passive transfer of immunoglobulins to rats. J Clin Invest
21. Dozio N, Scavini M, Beretta A, Sarugeri E, Sartori S, Belloni C, Dosio F, Savi A, Fazio F, Sodoyez JC, Pozza G. Imaging of the buffering effect of insulin antibodies in the autoimmune hypoglycemic syndrome. J Clin Endocrinol Metab
22. Dozio N, Sodoyez-Goffaux F, Koch M, Ziegler B, Sodoyez JC. Polymorphism of insulin antibodies in six patients with insulin-immune hypoglycaemic syndrome. Clin Exp Immunol
23. Elias D, Cohen IR, Schechter Y, Spirer Z, Golander A. Antibodies to insulin receptor followed by anti-idiotype. Antibodies to insulin in child with hypoglycemia. Diabetes
24. Eriksson JW, Bremell T, Eliasson B, Fowelin J, Fredriksson L, Yu ZW. Successful treatment with plasmapheresis, cyclophosphamide, and cyclosporin A in type B syndrome of insulin resistance. Case report. Diabetes Care
25. Faguer de Moustier B, Burgard M, Boitard C, Desplanque N, Fanjoux J, Tchobroutsky G. Auto-immune hypoglycemic syndrome induced by pyritinol. Diabetes Metab
26. Fareau GG, Maldonado M, Oral E, Balasubramanyam A. Regression of acanthosis nigricans correlates with disappearance of anti-insulin receptor autoantibodies and achievement of euglycemia in type B insulin resistance syndrome. Metabolism
27. Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. Immunological responses to exogenous insulin. Endocr Rev
28. Flier JS, Bar RS, Muggeo M, Kahn CR, Roth J, Gorden P. The evolving clinical course of patients with insulin receptor autoantibodies: spontaneous remission or receptor proliferation with hypoglycemia. J Clin Endocrinol Metab
29. Flier JS, Kahn CR, Jarrett DB, Roth J. Characterization of antibodies to the insulin receptor: a cause of insulin-resistant diabetes in man. J Clin Invest
30. Gehi A, Webb A, Nolte M, Davis J Jr. Treatment of systemic lupus erythematosus-associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil. Arthritis Rheum
31. Goldman J, Baldwin D, Rubenstein AH, Klink DD, Blackard WG, Fisher LK, Roe TF, Schnure JJ. Characterization of circulating insulin and proinsulin-binding antibodies in autoimmune hypoglycemia. J Clin Invest
32. Gorden P, Collier E, Roach P. Autoimmune mechanisms of insulin resistance and hypoglycemia. In: Moller DE, ed. Insulin Resistance
. Chichester: John Wiley; 1993:123-142.
33. Gregersen G, Dinesen B, Pedersen OB. Autoimmune insulin syndrome. The first Danish case report. Ugeskr Laeger
. 1998;160: 4539-4540.
34. Grunberger G, Weiner JL, Silverman R, Taylor S, Gorden P. Factitious hypoglycemia due to surreptitious administration of insulin. Diagnosis, treatment, and long-term follow-up. Ann Intern Med
35. Halsall DJ, Mangi M, Soos M, Fahie-Wilson MN, Wark G, Mainwaring-Burton R, O'Rahilly S. Hypoglycemia due to aninsulin binding antibody in a patient with an IgA-kappa myeloma. J Clin Endocrinol Metab
36. Herranz L, Rovira A, Grande C, Suarez A, Martinez-Ara J, Pallardo LF, Gomez-Pan A. Autoimmune insulin syndrome in a patient with progressive systemic sclerosis receiving penicillamine. Horm Res
37. Howard RL, Beck LK, Schneebaum A. Systemic lupus erythematosus presenting as hypoglycemia with insulin receptor antibodies. West J Med
38. Kahn CR, Baird KL, Flier JS, Jarrett DB. Effects of autoantibodies to the insulin receptor on isolated adipocytes. J Clin Invest
39. Kar P, Price P, Sawers S, Bhattacharya S, Reznek RH, Grossman AB. Insulinomas may present with normoglycemia after prolonged fasting but glucose-stimulated hypoglycemia. J Clin Endocrinol Metab
40. Kasuga M, Akanuma Y, Tsushima T, Iwamoto Y, Kosaka K, Kibata M, Kawanishi K. Effects of anti-insulin receptor autoantibodies on the metabolism of human adipocytes. Diabetes
41. Kasuga M, Akanuma Y, Tsushima T, Suzuki K, Kosaka K, Kibata M. Effects of antiinsulin receptor autoantibody on the metabolism of rat adipocytes. J Clin Endocrinol Metab
42. Kato T, Itoh M, Hanashita J, Itoi T, Matsumoto T, Ono Y, Imamura S, Hayakawa N, Suzuki A, Mizutani Y, Uchigata Y, Oda N. Severe hypoglycaemia in a person with insulin autoimmune syndrome accompanied by insulin receptor anomaly type B. Diabet Med
43. Kato Y, Ichiki Y, Kitajima Y. A case of systemic lupus erythematosus presenting as hypoglycemia due to anti-insulin receptor antibodies. Rheumatol Int
44. Khant M, Florkowski C, Livesey J, Elston M. Insulin autoimmune syndrome due to IgG kappa paraprotein. Pathology
45. Khoo TK, Service FJ. Hyperinsulinemic hypoglycemia. Endocr Pract
46. Kim CH, Park JH, Park TS, Baek HS. Autoimmune hypoglycemia in a type 2 diabetic patient with anti-insulin and insulin receptor antibodies. Diabetes Care
47. Kiyokawa H, Kono N, Hamaguchi T, Kawachi M, Tajima K, Mineo I, Yamada Y, Shimizu T, Kuwajima M, Tarui S. Hyperinsulinemia due to impaired insulin clearance associated with fasting hypoglycemia and postprandial hyperglycemia: an analysis of a patient with antiinsulin receptor antibodies. J Clin Endocrinol Metab
48. Konijnendijk MA, Zandbergen AA, Verheul FE, Baggen MG. Insulin autoimmune syndrome: the second Dutch case. Neth J Med
49. Le Dantec P, Veillard E, Guggenbuhl P, Perdriger A, Chales G, Pawlotsky Y. Autoimmune hypoglycemia occurring in tiopronin-treated rheumatoid arthritis. Rev Rhum Engl Ed
50. Lidar M, Rachmani R, Half E, Ravid M. Insulin autoimmune syndrome after therapy with imipenem. Diabetes Care
51. Lohmann T, Kratzsch J, Kellner K, Witzigmann H, Hauss J, Paschke R. Severe hypoglycemia due to insulin autoimmune syndrome with insulin autoantibodies crossreactive to proinsulin. Exp Clin Endocrinol Diabetes
52. Merlo C, Wimpfheimer C, Muser J, Keller U. Hypoglycemia and multiple myeloma. Schweiz Med Wochenschr
53. Meschi F, Dozio N, Bognetti E, Carra M, Cofano D, Chiumello G. An unusual case of recurrent hypoglycaemia: 10-year follow up of a child with insulin auto-immunity. Eur J Pediatr
54. Moller DE, Ratner RE, Borenstein DG, Taylor SI. Autoantibodies to the insulin receptor as a cause of autoimmune hypoglycemia in systemic lupus erythematosus. Am J Med
55. Moreira RO, Lima GA, Peixoto PC, Farias ML, Vaisman M. Insulin autoimmune syndrome: case report. Sao Paulo Med J
56. Nagayama Y, Morita H, Komukai D, Watanabe S, Yoshimura A. Type B insulin resistance syndrome induced by increased activity of systemic lupus erythematosus in a hemodialysis patient. Clin Nephrol
57. O'Brien TD, Rizza RA, Carney JA, Butler PC. Islet amyloidosis in a patient with chronic massive insulin resistance due to antiinsulin receptor antibodies. J Clin Endocrinol Metab
58. Paiva ES, Pereira AE, Lombardi MT, Nishida SK, Tachibana TT, Ferrer C, Hauache OM, Vieira JG, Reis AF. Insulin autoimmune syndrome (Hirata disease) as differential diagnosis in patients with hyperinsulinemic hypoglycemia. Pancreas
59. Redmon B, Pyzdrowski KL, Elson MK, Kay NE, Dalmasso AP, Nuttall FQ. Hypoglycemia due to an insulin-binding monoclonal antibody in multiple myeloma. N Engl J Med
60. Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am
61. Reisch N, Zwermann O, Reincke M. Hypoglycemia and transient diabetes mellitus in an insulin autoimmune syndrome. Dtsch Med Wochenschr
62. Rochet N, Blanche S, Carel JC, Fischer A, Deist FL, Griscelli C, Van Obberghen E, Le Marchand-Brustel Y. Hypoglycaemia induced by antibodies to insulin receptor following a bone marrow transplantation in an immunodeficient child. Diabetologia
63. Rodriguez O, Collier E, Arakaki R, Gorden P. Characterization of purified autoantibodies to the insulin receptor from six patients with type B insulin resistance. Metabolism
64. Rouabhia S, Ramanoelina J, Godmer P, Reach G, Dutel JL, Guillevin L. Insulin autoimmune syndrome revealing systemic lupus erythematosus. Ann Med Interne (Paris)
65. Ruiz-Giardin JM, Cremades C, Romero J, Marazuela M. Insulin autoimmune syndrome in a patient with viral hepatitis C. Clin Endocrinol (Oxf)
66. Schlemper RJ, Uchigata Y, Frolich M, Vingerhoeds AC, Meinders AE. Recurrent hypoglycaemia caused by the insulin autoimmune syndrome: the first Dutch case. Neth J Med
67. Selinger S, Tsai J, Pulini M, Saperstein A, Taylor S. Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. A case report. Ann Intern Med
68. Semple RK, Halberg NH, Burling K, Soos MA, Schraw T, Luan J, Cochran EK, Dunger DB, Wareham NJ, Scherer PE, Gorden P, O'Rahilly S. Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. Diabetes
69. Semple RK, Soos MA, Luan J, Mitchell CS, Wilson JC, Gurnell M, Cochran EK, Gorden P, Chatterjee VK, Wareham NJ, O'Rahilly S. Elevated plasma adiponectin in humans with genetically defective insulin receptors. J Clin Endocrinol Metab
70. Shah P, Mares D, Fineberg E, Pescovitz M, Filo R, Jindal R, Mahoney S, Lumeng L. Insulin autoimmune syndrome as a cause of spontaneous hypoglycemia in alcoholic cirrhosis. Gastroenterology
71. Shim MS, Kim MY, Kim MJ, Lee Y, Lee BJ, Chung CH, Shin YG. A case of autoimmune hypoglycemia complicated with diabetic ketoacidosis. Yonsei Med J
72. Sims RE, Rushford FE, Huston DP, Cunningham GR. Successful immunosuppressive therapy in a patient with autoantibodies to insulin receptors and immune complex glomerulonephritis. South Med J
73. Sklenar I, Wilkin TJ, Diaz JL, Erb P, Keller U. Spontaneous hypoglycemia associated with autoimmunity specific to human insulin. Diabetes Care
74. Spinas GA, Keller U. Insulin autoimmune syndrome and HLA-DR4. Lancet
75. Takayama-Hasumi S, Tobe K, Momomura K, Koshio O,Tashiro-Hashimoto Y, Akanuma Y, Hirata Y, Takaku F, Kasuga M. Autoantibodies to the insulin receptor (B-10) can stimulate tyrosine phosphorylation of the beta-subunit of the insulin receptor and a 185,000 molecular weight protein in rat hepatoma cells. J Clin Endocrinol Metab
76. Tardella L, Rossetti L, De Pirro R, Camagna A, Leonetti F, Tamburrano G, Merli M, Rossi Fanelli F, Lauro R. Circulating anti-insulin receptor antibodies in a patient suffering from lupus nephritis and hypoinsulinemic hypoglycaemia. J Clin Lab Immunol
77. Taylor SI, Grunberger G, Marcus-Samuels B, Underhill LH, Dons RF, Ryan J, Roddam RF, Rupe CE, Gorden P. Hypoglycemia associated with antibodies to the insulin receptor. N Engl J Med
78. Thieblot P, Boyer-Medeville C, Moinade S, Chambenois F, Cotisson A, Ville G. A French case of autoimmune hypoglycemia. Ann Med Interne (Paris)
79. Toyota T, Suzuki H, Sugawara H, Umezu M, Fujiya H, Suzuki S, Goto Y. Remission of insulin resistant diabetes in two patients with anti-insulin receptor antibodies. Tohoku J Exp Med
80. Trenn G, Eysselein V, Mellinghoff HU, Muller R, Benker G, Reinwein D, Federlin K. Clinical and biochemical aspects of the insulin autoimmune syndrome (IAIS). Klin Wochenschr
81. Tsushima T, Omori Y, Murakami H, Hirata Y, Shizume K. Demonstration of heterogeneity of autoantibodies to insulin receptors in type B insulin resistance by isoelectric focusing. Diabetes
82. Uchigata Y. The novel agent, alpha lipoic acid, can cause the development of insulin autoimmune syndrome. Intern Med
83. Uchigata Y, Eguchi Y, Takayama-Hasumi S, Omori Y. Insulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan. Diabetes Res Clin Pract
84. Uchigata Y, Hirata Y. Insulin autoimmune syndrome (IAS, Hirata disease). Ann Med Interne (Paris)
85. Van Obberghen E, Spooner PM, Kahn CR, Chernick SS, Garrison MM, Karlsson FA, Grunfeld C. Insulin-receptor antibodies mimic a late insulin effect. Nature
86. Varga J, Lopatin M, Boden G. Hypoglycemia due to antiinsulin receptor antibodies in systemic lupus erythematosus. J Rheumatol
87. Virally ML, Timsit J, Chanson P, Warnet A, Guillausseau PJ. Insulin autoimmune syndrome: a rare cause of hypoglycaemia not to be overlooked. Diabetes Metab
88. Vogeser M, Parhofer KG, Furst H, Jacob K, Brodl UC, Seidel D. Autoimmune hypoglycemia presenting as seizure one week after surgery. Clin Chem
89. Walters EG, Tavare JM, Denton RM, Walters G. Hypoglycaemia due to an insulin-receptor antibody in Hodgkin's disease. Lancet
90. Yamasaki H, Yamaguchi Y, Fujita N, Kato C, Kuwahara H, Yamauchi MD, Yamakawa K, Abe T, Ozaki M, Sera Y, Uotani S, Kawasaki E, Takino H, Eguchi K. Anti-insulin receptor autoantibodies in a patient with type B insulin resistance and fasting hypoglycemia. Acta Diabetol
91. Yaturu S, DePrisco C, Lurie A. Severe autoimmune hypoglycemia with insulin antibodies necessitating plasmapheresis. Endocr Pract
92. Zhang B, Roth RA. A region of the insulin receptor important for ligand binding (residues 450-601) is recognized by patients' autoimmune antibodies and inhibitory monoclonal antibodies. Proc Natl Acad Sci U S A
© 2009 by Lippincott Williams & Wilkins, Inc.
93. Zick Y, Rees-Jones RW, Taylor SI, Gorden P, Roth J. The role of antireceptor antibodies in stimulating phosphorylation of the insulin receptor. J Biol Chem