IntractableKanika Shanker, MD,​a Tanicia Daley, MD,Hypoglycemia MPH,​a Robert Semple, MD,​b Kelly Rouster-Stevens, in the MD,c​ J. Nina Setting Ham, MDa of Autoimmune Overlap Syndromeabstract

Evaluation of hypoglycemia in a patient with known diabetes mellitus, although usually straightforward, can at times be challenging. We present the case of an 8 year-old Latina girl initially diagnosed with type 1 diabetes mellitus in the setting of multiple autoimmune disorders, including dermatomyositis and lupus nephritis. She subsequently developed signs of insulin resistance and severe hypoglycemia, which aDivision of Pediatric Endocrinology and bMetabolic was found to be due to insulin-receptor autoantibodies. This condition, Research Laboratories, Institute of Metabolic Science, known as type B insulin resistance, is a rare, heterogeneous metabolic University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and cDivision of Pediatric disease that may feature hypoglycemia in the setting of extreme insulin Rheumatology, Department of Pediatrics, Emory University, resistance and hyperinsulinemia and, in this case, masqueraded as type 1 Atlanta, Georgia diabetes mellitus. The presence of hypoglycemia in the setting of multiple Dr Ham conceptualized and designed the study and autoimmune disorders should prompt consideration of autoimmune- reviewed the manuscript; Dr Shanker designed, coordinated, and drafted the manuscript; Drs Daley mediated hypoglycemia. In addition to immunologic modifying therapies, and Rouster-Stevens reviewed the manuscript; advances in diabetes care in the form of continuous glucose monitoring have Dr Semple provided laboratory assistance and provided an additional tool to manage recurrent hypoglycemia. reviewed the manuscript; and all authors approved the manuscript as submitted. DOI: 10.1542/peds.2016-0866 Autoimmune hypoglycemia and polydipsia, a random blood Accepted for publication Nov 29, 2016 syndromes are rare causes glucose (BG) level of >200 mg/dL, and Address correspondence to Kanika Shanker, MD, of hypoglycemia in children, elevated hemoglobin A1C of 7.3%. 2015 Uppergate Dr NE, Atlanta, GA 30322. E-mail: characterized by elevated levels She had been on a prednisone dose [email protected] of insulin and antibody-mediated of 15 mg (0.8 mg/kg) daily, however, PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, hypoglycemia. The predominance she was diagnosed with type 1 DM 1098-4275). of signs of insulin resistance and based on a highly elevated GAD-65 Copyright © 2017 by the American Academy of hyperandrogenism, concomitant autoantibody level (Table 1) and was Pediatrics presence of rheumatologic disease, started on 1.1 U/kg per day of insulin. FINANCIAL DISCLOSURE: Dr Semple is supported and poor response to therapy suggest After her DM diagnosis, she developed by a Senior Research Fellowship from the Wellcome 1,2​ Trust grant WT098498. The other authors have type B insulin resistance. ‍ In this systemic lupus erythematosus (SLE) indicated they have no financial relationships case report, we describe a case of an along with glomerulonephritis. relevant to this article to disclose. 8-year old girl with type B insulin Three months later, the patient FUNDING: Dr Semple is funded by the Wellcome resistance, which was initially thought was admitted to the hospital with Trust (grant WT098498), the UK Medical Research to be type 1 diabetes mellitus (DM). Council (MRC_MC_UU_12012/5) and the United refractory hypoglycemia despite This case report illustrates the utility Kingdom National Institute for Health Research, cessation of insulin therapy. Her of advanced technology, such as Cambridge Biomedical Research Centre. hemoglobin A1C decreased from 7.3% continuous glucose monitoring (CGM) POTENTIAL CONFLICT OF INTEREST: The authors to 5.6%. During the course of her and novel immunotherapy, in the have indicated they have no potential conflicts 3 admission, she had wide excursions in of interest to disclose. management of hypoglycemia. BG, with postprandial hyperglycemia Case Report > 300 mg/dL and early morning hypoglycemia <50 mg/dL (Fig 1). Her To cite: Shanker K, Daley T, Semple R, et al. Intrac­table Hypoglycemia in the Setting of Auto­ autoimmune disease–related medical immune Overlap Syndrome. Pediatrics. 2017; history is shown in Table 1. An 8 year-old Latina girl with a 139(6):e20160866 history of dermatomyositis managed On examination, her weight was on steroids presented with polyuria 20.7 kg (7th percentile), her height Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139, number 6, June 2017:e20160866 CASE REPORT TABLE 1 Autoimmune Profile of the Patient Disease Abnormal Biochemical Markers (Normal Range) Additional Findings was 116.5 cm (2nd percentile),2 and her BMI was 15.2 kg/m (36th Dermatomyositis Aldolase: 11 U/L (3.3–9.7) Bilateral heliotrope rash LDH: 866 U/L (420–750) Gottron’s papules percentile). She had a heart rate of von Willebrand factor Ag: 249% (44–144) Proximal muscle weakness 113 beats per minute, respiratory and tenderness rate of 20/minute, and her blood SLE ANA: 1:640 (<1:40) Facial swelling pressure was 110/73 mm Hg. She Anti-double stranded DNA Ab: 1:40 (<1:10) had a thin body habitus, acanthosis Proteinuria:​100 mg/dL (<10) C4: <2 mg/dL (13–37) nigricans in multiple body folds (Fig C3: 19 mg/dL (90–200) 2A), hypertrichosis on the face and CH50: 0 shoulders, and swelling of the finger Renal biopsy, membranous lupus nephritis, class tips (Raynauds phenomenon). She V lupus nephritis Type 1 DM GAD-65 Ab: 184.3 U/mL (<5.0) Presented with polyuria and was prepubertal, without evidence of IA-2 Ab: <0.8 U/mL (0–0.8) polydipsia adrenarche; otherwise, her physical Urine glucose: 1000 mg/dL (<10) examination was unremarkable. Blood glucose: 510 mg/dL Autoimmune Anti-thyroid peroxidase Ab: 37.8 IU/mL (<9.0) Normal thyroid function, A fasting study to understand the thyroiditis Thyroglobulin Ab: 57.5 IU/mL (<4) no symptoms and signs etiology of her hypoglycemia was suggestive of thyroid performed in a supervised clinical dysregulation Type B insulin Insulin receptor Ab positive by Western blot Hypoglycemia, acanthosis environment (Table 2). She became resistance nigricans, ovarian hypoglycemic 5 hours after start of enlargement the fast, with suppressed ketones, ANA, antinuclear antibody; CH50, total complement level; GAD-65, glutamic acid decarboxylase-65; IA-2, islet antigen 2; LDH, suppressed free fatty acids, and lactate dehydrogenase. a positive response to glucagon stimulation at the time of low blood Disease Course glucose, all of which are indicative of insulin-mediated hypoglycemia. insufficiency, however, she was In addition to elevated insulin and receiving supraphysiologic steroids Given the patient’s diagnosis C-peptide, laboratory studies revealed for her SLE. With signs of insulin of DM, insulin overtreatment paradoxical hyperadiponectinemia resistance, fasting hypoglycemia, of 24.4 mg/L and normal triglyceride was considered the cause of her and postprandial hyperglycemia, levels of 109 mg/dL. An ultrasound hypoglycemia. Despite insulin we postulated the presence of showed increased bilateral ovarian withdrawal, she continued to have autoantibodies against the insulin enlargement with multiple cysts hypoglycemia. The differential receptor. Laboratory evaluation (Fig 2B). diagnosis included adrenal confirmed the presence of insulin

FIGURE 2 FIGURE 1 Clinical features of insulin resistance. A, Axillary Blood glucose profile during hospital stay. Arrow indicates glucagon administration at the time of acanthosis nigricans. B, Enlarged ovaries with hypoglycemia, with resultant increase in blood glucose from 49 mg/dL to 109 mg/dL, suggestive of multiple ovarian cysts; left ovary, 21.6 cm3, insulin-mediated hypoglycemia. right ovary, 25.3 cm3

Downloaded from www.aappublications.org/news by guest on September 30, 2021 e2 Shanker et al FIGURE 3 Immunoprecipitation semiquantitative assay for insulin receptor antibodies. The positive control was from a previous patient with a classic presentation and a strongly positive antibody result, and the negative control is healthy control serum.

Pathophysiology receptor autoantibodies in high titers autoimmune syndrome, or insulin (Fig 3). receptor antibodies in type B 1 The presence of polyclonal insulin resistance. However, the For the treatment of hypoglycemia, antibodies against the insulin predominance of signs of insulin the patient was managed initially receptor is the hallmark of type B resistance and hyperandrogenism, by frequent oral and enteral insulin resistance syndrome and is the concomitant presence of feeding, along with oral high-dose responsible for the abnormalities in rheumatologic disease, and the poor corticosteroids, mycophenolate glucose homeostasis. Physiologically, response to therapy suggest type B mofetil, rituximab, intravenous hypoglycemia tends to be associated insulin resistance. Although it can affect immunoglobulin (IVIG), and with low titers of insulin receptor males and younger patients, it usually plasmapheresis. The episodes autoantibody, whereas high titers presents in middle-aged women. 6 of hypoglycemia decreased are associated with hyperglycemia. but continued, highlighting These antibodies, when acting her poor response to B-cell Our pediatric patient had glucose agonistically, can lead to activation immunomodulation. A novel immune abnormalities preceded by other of the downstream insulin signaling therapy, bortezomib (Velcade), was autoimmune disorders. The pathway and result in hypoglycemia. initiated to control antibody-mediated presence of multiple autoimmune Hypoglycemia can then be followed hypoglycemia. Over the intervening disorders places her in the category by increased receptor degradation, months, the intensity of hypoglycemia of autoimmune overlap syndrome a decreased number of cell-surface (Table 1). Autoimmune overlap decreased but has not completely ≥ insulin receptors, with subsequent resolved (Fig 4). The addition of CGM syndrome is defined as the presence insulin resistance (antagonistic has provided the ability to monitor of 2 autoimmune diseases in effect), and development of glucose trends and avert severe a patient, and this classification hyperglycemia. episodes of hypoglycemia. helps in defining management and Discussion understanding4 the prognosis of Abnormalities in glucose homeostasis the patient. Autoimmune diseases range from extreme insulin usually precede the metabolic resistance and clinical diabetes The antibodies in autoimmune problems of type B insulin resistance, to fasting hypoglycemia. In some hypoglycemia can be against the with the most frequent5 underlying cases, there can be a change from insulin peptide, known as insulin condition being SLE. hyperglycemia to intractable Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139, number 6, June 2017 e3 TABLE 2 Diagnostic Fasting Study During Hospital Admission Parameter Patient Value Normal Values and/or Interpretation Baseline blood glucose 153 mg/dL 90–160 mg/dL Blood glucose at 5 h fasting duration 49 mg/dL Fasting hypoglycemia defined as blood glucose <50 mg/dL β hydroxybutyrate 0.2 mmol/L Suppressed serum ketones Free fatty acid 0.35 mmol/L Suppressed free fatty acid Insulin 937.6 uIU/mL Elevated insulin level C-peptide 7.1 ng/mL Elevated C-peptide Insulin/C-peptide molar ratio 2.8 <1 Blood glucose after administration of 109 mg/dL, blood glucose Positive glucagon stimulation intravenous glucagon increased by 60 mg/dL test indicating insulin from baseline mediated hypoglycemia FIGURE 4 Continuous glucose monitoring shows blood glucose variability with hyper- and hypoglycemia. hypoglycemia. In a 6long-standing thyroid antibody positivity in the face series, Arioglu et al reported that of normal thyroid function, is likely 24% of patients manifested some secondary to her overwhelming due to the11 loss of insulin receptor form of hypoglycemia during autoimmune state. Therefore, her function. Also, in contrast to other the course of their illness. The initial misdiagnosis of type 1 DM hyperglycemia and insulin-resistant hypoglycemia may occur in the had clouded her presentation of states, patients with type B insulin fasting or the postprandial state. type B insulin resistance. Our case resistance have surprisingly normal is complementary to a previously (relatively low compared with Acanthosis nigricans and reported case of an obese 55-year-old their insulin-resistant state) fasting hyperandrogenism, although 1 male presenting with type 2 diabetes, Managementtriglyceride levels. commonly seen in these patients without physical signs of insulin as a part of the insulin resistance resistance, who was later found to picture, are not pathognomonic for 7 have severe insulin resistance due this syndrome. Ultrasonography 8 Therapeutic interventions are to insulin-receptor antibodies. Our may show ovarian cysts as a divided into 2 categories: (1) therapy pediatric patient was thought to have manifestation of insulin-mediated to achieve euglycemia, and (2) 6 what was typical type 1 DM, with her hyperandrogensism. Our patient therapy to4 modulate the autoimmune diagnosis later evolving into classic exhibited both of these features response. The hyperglycemic phase type B insulin resistance syndrome, (Fig 2), although she did not can usually be managed by high- with alternating severe hyper- and have premature adrenarche. 9 dose insulin and/or oral agents. hypoglycemia. Hyperandrogenism and ovarian Treatment of hypoglycemia involves enlargement can remit with a Nonketotic hypoglycemia with a rise immunomodulatory therapies, such as a high dose of glucocorticoids, decrease6 in insulin receptor antibody in BG level on glucagon challenge levelsEvaluation. is the hallmark of insulin-mediated employed to control autoantibody hypoglycemia. Insulin is produced production, and is usually guided and cosecreted in equimolar by the protocols used to treat the amounts with C-peptide; therefore, underlying6 condition, such as lupus Diagnosis can be challenging. under normal circumstances, nephritis. Our patient fulfilled the clinical the molar ratio should be close definition of type 1 DM with classic Frequently, a combination of to 1. Our patient had an elevated symptoms of polyuria and polydipsia, steroids and immunomodulators, molar ratio, consistent with type B hyperglycemia, and high titers of such as azathioprine, rituximab, insulin resistance (Table 2). This 2 GAD-65 antibodies. Accordingly, and cyclophosphamide, are used. phenomenon is related to impaired she received treatment with Alternative strategies include IVIG insulin degradation and poor insulin subcutaneous insulin. However, and plasma exchange. Our patient clearance due to a functional lack of her elevated insulin level of 937.6 continued to have low blood sugar insulin receptor. uIU/mL (range: 1.7–55.9) and despite pulse steroids, cycles of IVIG, C-peptide level of 7.1 ng/mL (range: β Other laboratory findings rituximab, and plasma exchange. She 0.8–3.5) were not consistent with the include a paradoxical10 elevation was then treated with bortezomib, destruction of pancreatic cells as of adiponectin. This finding is a newer drug used in the treatment seen in true type 1 DM. The presence postulated to be the result of loss of multiple myeloma, which acts by of GAD-65 antibodies, similar to her of insulin action in adipocytes proteasome inhibition and increased Downloaded from www.aappublications.org/news by guest on September 30, 2021 e4 Shanker et al and other autoimmune features in patients with diabetes mellitus due apoptosis3 of antibody-producing presentation with a classic picture of to autoantibody to insulin receptors. cells. type 1 DM added a layer of diagnostic Ann Intern Med. 1985;102(2): 176–181 New technologies, such as CGM, add dilemma before her final diagnosis of a dynamic facet to the management type B insulin resistance. The use of 6. Arioglu E, Andewelt A, Diabo C, Bell M, of type B insulin resistance. The adjunct glucose monitoring devices Taylor SI, Gorden P. Clinical course ability to monitor glucose in real and an enteral feeding regimen have of the syndrome of autoantibodies to the insulin receptor (type B time provides a tool to avert provided additional tools to prevent insulin resistance): a 28-year severe hypoglycemia, especially in severe hypoglycemic episodes. Abbreviations perspective. Medicine (Baltimore). children who are not cognizant of 2002;81(2):87–100 neuroglycopenic symptoms or those 7. Dons RF, Havlik R, Taylor SI, with hypoglycemia unawareness. Baird KL, Chernick SS, Gorden P. Upcoming advances in diabetes BG: blood glucose DM: diabetes mellitus Clinical disorders associated with care, such as integrated insulin autoantibodies to the insulin receptor. CGM: continuous glucose delivery systems (CGM combined Simulation by passive transfer of with subcutaneous pump delivery of monitoring immunoglobulins to rats. J Clin Invest. insulin and glucagon), may provide IVIG: intravenous 1983;72(3):1072–1080 immunoglobulin the capability to respond to12 both 8. Bourron O, Vigouroux C, Halbron M, SLE: systemic lupus hyper-Prognosis and hypoglycemia. et al. Association of type B insulin erythematosus resistance and type 1 diabetes resulting in ketoacidosis. Diabetes Although autoantibodies remit References Care. 2012;35(2):e4 spontaneously in one-third of 1. Lupsa BC, Chong AY, Cochran EK, Soos 9. American Diabetes Association. patients, the mortality rate of the MA, Semple RK, Gorden P. Autoimmune Classification and diagnosis of disease continues to be high and forms of hypoglycemia. Medicine diabetes [published correction appears to be primarily driven (Baltimore). 2009;88(3):141–153 appears in Diabetes Care. by the severity of the underlying 2016;39(9):1653]. Diabetes Care. 2. Malek R, Chong AY, Lupsa BC, disease. Both fasting hypoglycemia 2016;39(suppl 1):S13–S22 et al. Treatment of type B insulin 10. Semple RK, Cochran EK, Soos MA, et al. and a switch from hyperglycemia to resistance: a novel approach to reduce Plasma adiponectin as a marker of hypoglycemia are indicators of poor insulin receptor autoantibodies. insulin receptor dysfunction: clinical prognosis and may lead to mortality6 J Clin Endocrinol Metab. utility in severe insulin resistance. due to intractable hypoglycemia. 2010;95(8):3641–3647 Conclusions Diabetes Care. 2008;31(5):977–979 3. Khandelwal P, Davies SM, Grimley 11. Semple RK, Halberg NH, Burling K, MS, et al. Bortezomib for refractory et al. Paradoxical elevation of high- autoimmunity in pediatrics. molecular weight adiponectin in DM is a common pediatric disease Biol Blood Marrow Transplant. acquired extreme insulin resistance seen both by general pediatricians 2014;20(10):1654–1659 due to insulin receptor antibodies. and subspecialists. Hypoglycemia, 4. Jury EC, D’Cruz D, Morrow WJW. Diabetes. 2007;56(6):1712–1717 although common with insulin Autoantibodies and overlap syndromes 12. Russell SJ, El-Khatib FH, Sinha M, et therapy, if severe, recurrent, or in autoimmune rheumatic disease. al Outpatient glycemic control with a unexplained may indicate a more J Clin Pathol. 2001;54(5):340–347 bionic pancreas in type 1 diabetes. complex pathophysiology. Careful 5. Tsokos GC, Gorden P, Antonovych T, N Engl J Med. 2014;371(4): history and physical examination Wilson CB, Balow JE. Lupus nephritis 313–325 may promote timely diagnosis and treatment. This patient’s

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139, number 6, June 2017 e5 Intractable Hypoglycemia in the Setting of Autoimmune Overlap Syndrome Kanika Shanker, Tanicia Daley, Robert Semple, Kelly Rouster-Stevens and J. Nina Ham Pediatrics originally published online May 10, 2017;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2017/05/08/peds.2 016-0866 References This article cites 12 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2017/05/08/peds.2 016-0866#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Endocrinology http://www.aappublications.org/cgi/collection/endocrinology_sub Diabetes Mellitus http://www.aappublications.org/cgi/collection/diabetes_mellitus_sub Metabolic Disorders http://www.aappublications.org/cgi/collection/metabolic_disorders_s ub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Intractable Hypoglycemia in the Setting of Autoimmune Overlap Syndrome Kanika Shanker, Tanicia Daley, Robert Semple, Kelly Rouster-Stevens and J. Nina Ham Pediatrics originally published online May 10, 2017;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2017/05/08/peds.2016-0866

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 30, 2021