CASE STUDIES

Autoantibodies to and Dysglycemia in People With and Without : An Underdiagnosed Association Praveen Valiyaparambil Pavithran, Nisha Bhavani, Rohinivilasam Vasukutty Jayakumar, Arun Somasekharan Menon, Harish Kumar, Vadayath Usha Menon, Vasantha Nair, and Nithya Abraham

he potential effects of inhibito- In this article, we describe our ry immunoglobulins to insulin experience with patients who pre- Twere first described in insulin- sented with glycemic excursions treated patients many decades ago resulting from insulin autoantibodies (1). This antibody response is thought from a single university referral teach- to occur in at least 40% of patients ing center in South India. on insulin therapy (2). Subsequent Spontaneous Hyperinsulinemic case reports documented glycemic excursions in the form of markedly increased insulin requirements and Case Presentation unpredictable hypoglycemic episodes, At the Department of Endocrinology both of which were attributable to in- of Amrita Institute of Medical sulin autoantibodies (3). Sciences in Kochi, Kerala, India, a Autoantibodies to insulin also can large tertiary care center, between occur occasionally in patients who 2008 and 2014, we diagnosed eight have not been previously exposed to cases in which insulin autoantibodies insulin. Autoimmune hypoglycemia could be implicated as the etiological resulting from high titers of insulin factor responsible for spontaneous autoantibodies have been reported, hyperinsulinemic hypoglycemia. One patient presented exclusively with mostly from Japan, as a rare cause of postprandial hypoglycemia–related hyperinsulinemic hypoglycemia (4). symptoms, whereas the others pre- There has only been one confirmed sented with a combination of fasting case of autoimmune hypoglycemia and postprandial symptoms. During reported from India (5). The esti- the same time period, there were mation of insulin autoantibodies is only seven cases of histopathological- an integral part of the diagnosis in ly proven diagnosed in such cases. our center. Apart from insulin, other inciting All the patients underwent a agents implicated include sulfahydryl mixed-meal challenge test, fol- group–containing drugs and alpha- lowed by a supervised fast. Samples Department of Endocrinology, Amrita lipoic acid (ALA). Autoimmune Institute of Medical Sciences, Kochi, India were collected to measure insulin hypoglycemia also has been reported Corresponding author: Praveen and C-peptide when the patients Valiyaparambil Pavithran, pravvp@gmail. to be associated with autoimmune were symptomatic, with blood glu- com disorders and plasma cell dyscrasias cose levels of <55 mg/dL. Insulin DOI: 10.2337/diaclin.34.3.164 (6). Spontaneous resolution has been autoantibodies were estimated by reported in a few cases of autoim- radiobinding assay. A postprandial ©2016 by the American Diabetes Association. Readers may use this article as long as the work mune hypoglycemia, and a dramatic rise of after the mixed meal is properly cited, the use is educational and not response to steroids was seen in some was demonstrable in all patients. for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0 other cases that manifested both Imaging of the pancreas by a for details. hypoglycemia and . multi-detector computed tomography

164 CLINICAL.DIABETESJOURNALS.ORG pav i t h r a n e t a l .

TABLE 1. Clinical and Biochemical Details of Eight Patients With Autoimmune Hypoglycemia Case Case Case Case Case Case Case Case 1 2 3 4 5 6 7 8 Age (years)/sex (F/M) 69/F 28/F 60/M 62/F 65/M 42/F 66/M 41/M Symptoms: postprandial (P), P F C P C P F C fasting (F), or combined (C) Duration of symptoms 2 2 2 3 3 1 3 3 (months) Inciting agent ALA Carbimazole None None None None None None Insulin (µIU/mL) 68.5 1,410 163 113 >300 73 >300 10,080 C-peptide (ng/mL) 5.6 2.9 2.3 5.2 9.3 7. 2 6.2 20 Insulin autoantibodies >50 >300 >50 >50 >50 >50 >50 >50 (normal <0.4 U/mL) (ELISA) Other relevant results Serum electrophoresis No M No M No M No M No M band band band band band Antinuclear antibody Negative testing Remission characteristics: S S S P P S P P spontaneous (S) or after (20 mg) (20 mg) (40 mg) (40 mg) oral prednisolone for 3 months (P [dosage]) M band, monoclonal protein band, a serum electrophoresis finding suggestive of multiple myeloma. pancreatic protocol was also per- Table 1 provides patients’ clinical and agents, presented with diabetic ke- formed. Other relevant investigations biochemical details. toacidosis (DKA) precipitated by a such as serum protein electrophoresis Onset was abrupt in all eight urinary tract infection, for which she were done to exclude myeloma and patients. In one patient, the inciting was started on insulin. One month af- benign gammaglobinopathy in older agent was carbimazole prescribed for ter starting insulin, she had recurrent patients. Endoscopic ultrasound Graves’ disease. In another patient, nocturnal hypoglycemic episodes with was performed in three patients. ALA, which was used as a health postprandial hyperglycemia. The basal Interestingly, urine ketones were supplement, could be implicated. component of her basal-bolus insulin positive in two patients during the Patients with less severe presenta- regimen was then stopped, but even 72-hour fasting. tions had spontaneous remission while only using an ultra-short-acting Insulin was estimated by che- within 3 months. All of the severe analog insulin at dinner, she had miluminescent microparticle cases responded to steroid therapy at documented early-morning hypogly- immunoassay with an analytic sen- doses of 0.5–0.75 mg/kg/day, which cemia. Despite discontinuing insulin sitivity of <1 µIU/mL. C-peptide were tapered and stopped within 3 for 72 hours, she continued to expe- was estimated by electrochemilu- months. None of the patients had a rience nocturnal hypoglycemia with minescence immunoassay on the recurrence. Three patients had other random venous plasma glucose of 54 Elecsys system (Roche Diagnostics, autoimmune comorbid diseases mg/dL. A critical sample showed an Mannheim, Germany) with an ana- (patient 2: Graves’ disease, patient 3: insulin level of 1,901 µIU/mL and lytical sensitivity of 0.01 ng/mL. pernicious anemia and autoimmune C-peptide level of 11 ng/mL, which Insulin autoantibodies were esti- hypothyroidism, and patient 7: auto- ruled out exogenous insulin–related mated by radiobinding assay in Quest immune hypothyroidism). hypoglycemia. Several postprandial > Diagnostics (Nichols Institute, San Glycemic Fluctuations in People glucose levels were 400 mg/dL. She Juan Capistrano, CA). Less than 0.4 With Diabetes Taking Insulin was then suspected to have autoim- U/mL was considered an undetectable mune hypoglycemia. Insulin antibod- titer. In one patient, insulin autoan- Case 1 Presentation ies were elevated >50 U/mL. She was tibody estimation was carried out A 67-year-old woman with type 2 di- started on prednisolone 0.5 mg/kg by enzyme-linked immunosorbent abetes for the past 10 years, previously and two doses of short-acting insu- assay (ELISA; positive: >15 U/mL). well controlled on oral hypoglycemic lin before breakfast and lunch. She

VOLUME 34, NUMBER 3, SUMMER 2016 165 CASE STUDIES had a partial remission at the end of Questions Insulin autoantibodies are mostly 2 weeks; 6 weeks after initiation of 1. In what clinical circumstances polyclonal in origin and are mostly treatment, she had a full remission, should insulin autoantibody syn- of the immunoglobulin G class. They and the steroids were tapered. drome be suspected? can be of high affinity/low binding 2. What are the biochemical and capacity or low affinity/high binding Case 2 Presentation hormonal indicators of autoim- capacity (8). The latter is often asso- A 75-year-old man with type 2 dia- mune hypoglycemia? ciated with clinical manifestations. betes for 6 years who was on insu- 3. What are the available These antibodies are virtually indis- lin therapy for the past 4 years was management strategies for dys- tinguishable from the antibodies seen detected to have carcinoma of the glycemia resulting from insulin in up to 70% of children with type 1 colon 1 year before presentation. He autoantibodies? diabetes. When the antibody titers are underwent a hemicolectomy and was very high, there may be clinical mani- Commentary later diagnosed with liver metastasis festations resulting from the ability of and cirrhosis of the liver. He was on We described above two scenarios in these antibodies to act as temporary bavacizumab and chemotherapy for which we believe insulin autoantibod- storehouses of insulin, which prevents the disease, which was staged as T4 ies played a pathogenic role—patients its action, and then the subsequent M1. His glycemic control was erratic without diabetes who have hyperin- release of the stored insulin, which 1 month before presentation, and he sulinemic hypoglycemia and those causes hypoglycemia. This explains was admitted with DKA five times with diabetes who have wide glyce- the characteristic increase in blood during this period and once had lactic mic excursions on insulin. These cases glucose in the immediate postpran- acidosis requiring dialysis. His blood offer insights that may be useful in dial period and the hypoglycemia glucose was controlled only with in- the management of similar cases in observed later. Possible alternative travenous insulin infusion; when he resource-limited settings. explanations include direct stimu- was shifted back to subcutaneous in- Autoimmune responses and their latory effects of the antibodies on sulin, he slipped back into DKA. propensity for leading to disease the pancreas and the crosslinking of At presentation, he was on deglu- states are well known. It is, however, insulin-insulin receptor complexes dec and three-times-daily short-acting very rare for a protein hormone to by the insulin antibodies, resulting insulin. His random blood glucose elicit an antibody response and still in potentiation or prolongation of was 520 mg/dL, and his DKA was rarer for that response to manifest insulin action (6). severe, with a pH of 6.9 and bicarbon- as clinically important states beyond Patients with exclusive postpran- ate of 3 mEq/L. He was managed with assay interferences. Some HLA class dial symptoms might be mislabeled routine care, but for the unremitting II subtypes, especially DRB10406, as having if acidosis, he required hemodialysis. DQA10301, and DQB10302, are antibodies are not checked. This is His glucose was not controlled even known to be associated with insulin especially relevant in that current with 100 units/hour of intravenous autoantibody responses (7). Drugs Endocrine Society guidelines cau- insulin, and his blood glucose values containing sulfahydryl groups are tion against testing for insulin and ranged from 600 to 700 mg/dL. thought to interact with the disul- C-peptide, even in cases involving Considering the possibility of fide bond in insulin and make it symptoms in the course of a mixed- antibody-mediated insulin resis- immunogenic. Methimazole ther- meal test (9). An individualized tance, steroids were started after apy and ALA use, both of which approach is probably the answer. sending a serum sample for insulin contain sulfahydryl groups, were In symptomatic patients with doc- antibody testing. Within 4 hours probable inciting agents in our case umented hypoglycemia, testing for of the first hydrocortisone dose, his series. Autoimmune diseases are also insulin and C-peptide is of value. glucose decreased to <500 mg/dL, known to be associated with insulin Classically, insulin autoantibody syn- and within 24 hours of starting ste- autoantibodies (6). In the majority of drome is associated with insulin levels roids, his DKA resolved. He was cases, however, these antibodies do >100 µIU/mL, which was true in all switched to prednisolone 1 mg/kg/day not cause any clinical effects. Patients but one of our patients. and was on multiple subcutaneous with autoimmune diseases such as The use of exogenous insulin itself doses of short-acting analog and pernicious anemia and autoimmune elicits antibodies, and the detection degludec insulin. With this regimen, thyroid disease were present in our of antibodies alone does not suggest his glycemic control was satisfactory. series. We screened all patients >50 that they are pathogenic. However, Subsequently, he was on tapering years of age for monoclonal gammop- in the first case we presented of an doses of steroids with reasonable gly- athies because hypoglycemia may insulin-using person with diabetes, cemic control. He has been restarted precede the clinical manifestation of the very high insulin and C-peptide on chemotherapy with panitumab. myeloma by many years. levels and subsequent response to ste-

166 CLINICAL.DIABETESJOURNALS.ORG pav i t h r a n e t a l . roids suggest that the autoantibodies • Postprandial increase in glucose with the insulin analog lispro: a case report. Diabetes Care 1997;20;71–73 were pathogenic. In the second case during a mixed-meal test can point 3. Matsuyoshi A, Shimoda S, Tsuruzoe K, et presentation of a person with diabetes toward an autoimmune etiology, al. A case of slowly progressive type 1 diabe- using insulin, the patient had cirrho- especially in resource-limited set- tes with unstable glycemic control caused by sis of the liver and was treated with tings where there are limitations unusual insulin antibody and successfully treated with steroid therapy. Diabetes Res insulin, both of which can be asso- on imaging and Clin Pract 2006;72:238–243 ciated with autoantibodies (6). The estimation. 4. Uchigata Y, Eguchi Y, Takayama-Hasumi patient’s extreme insulin resistance • Recent onset of extreme insulin S, Omori Y. Insulin autoimmune syndrome and dramatic response to steroids resistance with a very high insu- (Hirata disease): clinical features and epide- point to the antibodies as the culprit lin requirement, especially with miology in Japan. Diabetes Res Clin Pract 1994;22;89–94 in this case. unpredictable hypoglycemia, can 5. Gopal K, Priya G, Gupta N, Praveen In summary, we share our expe- be a feature of insulin autoimmu- EP, Khadgawat R. A case of autoimmune rience with insulin autoantibody nity syndrome. hypoglycemia outside Japan: rare, but in syndrome, which can manifest as • In most cases of autoimmune- the era of expanding drug-list, important to suspect. Indian J Endocrinol Metab hypoglycemia, hyperglycemia, or related glycemic excursions, the 2013;17:1117–1119 both. Autoantibodies probably need response to steroid treatment is 6. Redmon JB, Nuttall FQ. Autoimmune to be ruled out in all cases of doc- dramatic. hypoglycemia. Endocrinol Metab Clin umented symptomatic postprandial North Am 1999;28:603–618 hypoglycemia to avoid misdiagnosing Duality of Interest 7. Uchigata Y, Kuwata S, Tokunaga K, et this syndrome as reactive hypogly- al. Strong association of insulin autoim- No potential conflicts of interest relevant to mune syndrome with HLA DR 4. Lancet cemia. In our center’s experience, this article were reported. 1992;339:393–394 this entity appears to be more com- 8. Goldman J, Baldwin D, Rubenstein mon than as a cause of References AH, et al. Characterization of circulating noniatrogenic hyperinsulinemic 1. Berson SA, Yalow RS, Bauman A, insulin and proinsulin-binding antibodies hypoglycemia. Rothschild MA, Newerly K. Insulin I131 in autoimmune hypoglycemia. J Clin Invest metabolism in human subjects: demon- 1979;63:1050–1059 Clinical Pearls stration of insulin binding globulin in the 9. Cryer PE, Axelrod L, Grossman AB, • Autoimmune hypoglycemia is a circulation of insulin treated subjects. J Clin et al.; Endocrine Society. Evaluation Invest 1956;35;170–190 and management of adult hypoglycemic differential for patients with doc- 2. Lahtela JT, Knip M, Paul R, Antonen disorders: an Endocrine Society clinical umented reactive hypoglycemia J, Salmi J. Severe antibody-mediated practice guideline. J Clin Endocrinol Metab and very high insulin levels. insulin resistance: successful treatment 2009;94:709–728

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