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Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series



Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies. Patients with IAS usually complain of hypoglycemia without any previous insulin received. Glucocorticoids and immunosuppressants are used to treat IAS.

Case presentation

We report four patients with diabetes who were diagnosed with non-classical IAS and describe the treatment of these patients. Moreover, the differential diagnosis with hyperinsulinism is discussed.


High levels of insulin autoantibodies, as well as hyperinsulinemic hypoglycemia, are found in patients with diabetes mellitus and prior exogenous insulin exposure. This situation that we classified as non-classical IAS should be attached importance to.

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Classical insulin autoimmune syndrome (IAS) is characterized by extremely high serum insulin concentrations, as well as spontaneous hypoglycemia [1]. In IAS, there are also high titers of autoantibodies against endogenous insulin, which occur without any prior exposure to exogenous insulin [2, 3]. Hypoglycemia that results from exogenous insulin administration can also manifest with symptoms resembling those of IAS. Patients usually present with postprandial hypoglycemia, marked neuroglycopenic symptoms of confusion, and an altered state of consciousness in these two conditions [1]. In this case series, we introduce a new concept of non-classical IAS and elaborate on insulin-resistant syndrome, as well as relationships with other hyperinsulinemic diseases.

Research methods

All the measurements of hormone were made in the Laboratory of The Second Affiliated Hospital of Zhejiang University. Serum insulin concentrations were measured by automated microparticle enzyme immunoassays (Abbott AxSYM MEIA; Abbott Laboratories, Abbott Park, IL, USA). C-peptide concentrations were measured by a specific immunoradiometric assay (Immunotech, Prague, Czech Republic). The qualitatively assessment of circulating immune complexes were precipitation with polyethylene glycol followed by an insulin assay of the supernatant [2]. The reduced accuracy of insulin measurement is not clinically relevant in patients with IAS because of the high serum insulin values. Moreover, there is no cross-reactivity of the insulin assay with synthetic insulin in this detection method.

Case presentations

Case 1

This patient was a 79-year-old man who had a 10-year history of hyperglycemia in addition to fluctuating glucose concentrations for more than 1 year. This was accompanied by diabetic nephropathy as well as a history of gout for more than 30 years. His glucose concentrations were initially well controlled with metformin after diagnosis of type 2 diabetes mellitus. A subcutaneous insulin pump (lispro) was recently added to his treatment regimen for renal insufficiency, and metformin was gradually changed to Humulin R (6–4-4 units, three times a day) combined with glargine 12 units a day. Thereafter, he had recurrent midnight hypoglycemia and daytime hyperglycemia, with blood glucose concentrations up to 20 mmol/L. Therefore, he was treated with acarbose (50 mg three times a day) instead of insulin injections. At this time, his C-peptide values were 5.45/6.94/6.94/7.89/7.17 nmol/L at 0/0.5/1/2/3 h, respectively (normal range: 0.27–1.28 nmol/L). His insulin concentrations were > 1000.00/> 1000.00 pmol/L at 0/2 h, respectively (normal range: 13–161 pmol/L), during an oral glucose tolerance test (OGTT), his HbA1c concentration was 10.2%, and an anti-insulin antibody test was positive (reference level: < 0.4). His glucose concentrations still fluctuated between 11 mmol/L and 22 mmol/L in the daytime, while hypoglycemia occurred at night. Subsequently, acarbose (100–100-50 mg three times a day) and sitagliptin (50 mg per day) were prescribed for symptom management, and his glucose concentrations returned to the normal range. Laboratory findings at a 1-year follow-up showed an HbA1c concentration of 7.0%, insulin concentrations of 138.53/733.40 pmol/L at 0/2 h, and C-peptide concentrations of 1.35/2.21 nmol/L at 0/2 h, respectively.

Case 2

This patient was a 71-year-old man who was admitted because of polydipsia and polyuria that had persisted for 8 years, as well as recurrent episodes of unconsciousness throughout this period. He was diagnosed with type 2 diabetes mellitus 8 years before admission. Acarbose was initially prescribed, but was switched to insulin aspart 30 (8–12 units twice a day) because of poor glucose control 5 years previously. Three months previously, the dose of insulin aspart 30 was gradually reduced to 4–10 units because of hypoglycemia. However, he had unexpected episodes of unconsciousness due to hypoglycemia 12 days before admission. Moreover, his symptoms were obviously relieved after food intake. He was subsequently treated with voglibose instead of insulin injections. However, the hypoglycemic symptoms continued to appear between 02:00 am and 03:00 am, despite the absence of other treatments. A laboratory examination showed the following: C-peptide values were 15.22/17.59/19.73/15.22 nmol/L at 0/1/2/3 h, and insulin concentrations were > 2089.5/> 2089.5/> 2089.5/> 2089.5 pmol/L at 0/1/2/3 h during the OGTT, respectively. The anti-insulin antibody test was also positive. His treatment regimen was changed to prednisone (5 mg three times a day), acarbose (50 mg three times a day), metformin (0.5 g twice a day), and glargine (12–18 units twice a day) for glucose control. Insulin injections were also gradually discontinued. Following this treatment, he showed improved glucose control. Laboratory tests during a recent follow-up showed the following: C-peptide levels of 0.77/2.40 nmol/L at 0/2 h and insulin levels of 430.13/1350.21 pmol/L at 0/2 h during the OGTT, respectively.

Case 3

This patient was a 79-year-old man who presented with a 3-year history of hyperglycemia and a 1-year history of polydipsia. At the time of presentation, he had been in a hypodynamic state for 15 days. Three years previously, he was diagnosed with impaired glucose tolerance without any symptoms, but no treatment was provided. One year earlier, he developed polydipsia, hyperuresis, and cutaneous pruritus, and lost weight. His random plasma glucose concentrations increased to as high as 20 mmol/L. Consequently, he was started on aspart 30 (21 units before breakfast and 8 units before dinner) and metformin (0.5 g twice a day). One month previously, he visited our hospital because of complaints of recurrent midnight hypoglycemia, particularly at approximately 02:00 am. During that period, although an insulin injection was gradually reduced and subsequently discontinued, his glucose concentration still dropped to 3 mmol/L. Laboratory tests showed that C-peptide and insulin concentrations were above the normal range, and the insulin autoantibody test was positive. At that time, non-classical IAS was considered as the probable cause of repeated hypoglycemia, and treatment was changed to acarbose (50 mg three times a day). After 15 days, blood tests showed the following: fasting plasma glucose level, 3.71 mmol/L; anti-insulin antibody, > 45.4 U/mL; and insulin concentrations were 1567.44/1493.06/1370.20/1616.43/1812.01 pmol/L at 0/30/60/120/180 min and C-peptide concentrations were 3.41/3.68/3.95/4.56/4.51 nmol/L at 0/30/60/120/180 min during the OGTT, respectively. For treatment of IAS, prednisone therapy was started at 12 mg daily (4 mg per dose three time daily) then reduced to 8 mg daily after 2 weeks and to 4 mg per night 1 week later. The diabetes treatment plan was changed to human biosynthetic insulin injection (16 units per day), sitagliptin (50 mg per day), and voglibose (0.3–0.2 mg twice a day). Repeated laboratory tests showed the following: C-peptide concentrations were 0.73/1.67 nmol/L at 0/2 h, respectively, and the insulin concentration was 728.14 pmol/L at 0 h during the OGTT. The glucose concentration fluctuated between 7 and 12.9 mmol/L.

Case 4

This patient was a 52-year-old man diagnosed with type 2 diabetes mellitus at the local hospital according to a fasting glucose test that showed a concentration of 16 mmol/L. His postprandial glucose concentration was 27 mmol/L. However, the patient was asymptomatic. He was then treated with a 50/50 Mixture Recombinant Human Insulin Injection (Gansulin 50R) of 12–16 units twice a day, and the dose had been adjusted to 6–10 units 2 months previously. During this period, his glucose was well controlled. One month previously, he developed dizziness and was flustered again. He also started sweating excessively, and at that time, his fasting plasma glucose concentration was 2.8 mmol/L. One week previously, the treatment was changed to acarbose 0.1 mg three times a day because of repeated occurrence of hypoglycemic symptoms. His insulin concentrations were 1294.01/1303.77/1456.7/2057.11/2032.41 pmol/L at 0/30/60/120/180 min and C-peptide concentrations were 1.30/1.80/2.21/2.87/2.55 nmol/L at 0/30/60/120/180 min during the OGTT, respectively. The anti-insulin antibody test was positive. He was prescribed metformin (0.5 g twice a day), acarbose (0.05 g three times a day), aspart (6–5-5 units three times a day), and methylprednisolone (4 mg three times a day) for glucose control. After these changes, hypoglycemia syndrome did not recur (Table 1).

Table 1 The related information about the patient

Discussion and conclusions

We experienced four cases of IAS that all shared the following characteristics: [1] recurrent episodes of symptomatic hypoglycemia [2]; prior exposure to exogenous insulin; and [3] high concentrations of plasma insulin immunoreactive antibodies and hyperinsulinemia after discontinuing insulin injection. All four cases manifested symptoms, such as classical IAS. Therefore, we temporarily identified these cases as non-classical IAS. We review hyperinsulinemia-related diseases and discuss their distinct features compared with other cases below.

Many endocrine diseases can present with endogenous hyperinsulinemic hypoglycemia (EHH). EHH is diagnosed with the presence of inappropriately high serum insulin concentrations while plasma concentrations of glucose are < 55 mg/dL and ≤ 70 mg/dL in individuals with and without diabetes, respectively [4, 5]. IAS is a rare cause of EHH, characterized by spontaneous hypoglycemia, extremely high serum insulin levels (> 1000 pmol/L), and high titers of insulin autoantibodies against endogenous insulin [1]. After a meal or oral glucose load, increased glucose levels can stimulate insulin secretion, but autoantibodies bind to these insulin molecules, rendering them unavailable to exert their effects. The resulting hyperglycemia further promotes insulin release. The inappropriately increased concentrations of free insulin eventually cause hypoglycemia. Most patients with IAS achieve remission with nutritional management [6], and small frequent meals with low carbohydrates are preferred [7]. Additionally, glucocorticoids and immunosuppressants are prescribed to ameliorate immune dysregulation as well as avoid hypoglycemic attacks in IAS [8,9,10,11,12]. Other therapeutic options have also been shown to be successful in the management of IAS (e.g., acarbose for decreasing endogenous insulin secretion) [13]. In addition, plasmapheresis and rituximab can be used to eliminate insulin autoantibody titers in the circulation [1, 8, 12].

Aside from IAS, another type of autoimmune hyperinsulinemia is type B insulin resistance [2, 14]. The diagnosis of type B insulin resistance syndrome is based on the presence of antibodies directed against the cell surface insulin receptor [14,15,16]. These autoantibodies prevent endogenous insulin from binding to insulin receptors and decrease transduction of the insulin signal [17, 18]. Hyperinsulinemia in these patients has been attributed to increased secretion of insulin to compensate for peripheral insulin resistance and concomitant reduction in insulin clearance [17, 18]. Type B insulin resistance syndrome is characterized by severe hyperglycemia and is less common hypoglycemia compared with IAS [17, 18]. Treatment strategies for type B insulin resistance syndrome should be based on the specific requirements and individualized. Many of these patients undergo spontaneous remission of autoantibodies after 11–48 months of treatment with insulin and an insulin sensitizer. In severe cases, intravenous methylprednisolone and cyclophosphamide are recommended [14, 17].

Apart from autoimmune-induced EHH, insulinoma and nesidioblastosis should also be considered. Insulinoma is a small (< 2 cm) and benign tumor that is the most common neuroendocrine tumor of the pancreas [19, 20]. Secretion of endogenous insulin cannot be suppressed by hypoglycemia in insulinoma [21]. The common diagnostic criteria for insulinoma include increased concentration of insulin (≥43.05 pmol/L), C-peptide (≥0.2 nmol/L), and proinsulin (≥5 pmol/L). Surgical resection is the first-line treatment for insulinoma [22]. Nesidioblastosis is a condition involving diffuse hyperplasia of the pancreatic islets [23]. Formation of nesidioblastosis is attributed to congenital or acquired excessive function of abnormal pancreatic β-cells [24]. Additionally, subtotal pancreatectomy is a good option because of the diffuse nature of the disease [25] (Table 2). Furthermore, insulin receptor-negative insulin resistance also leads to hyperinsulinemia. Activation of the protein kinase Cu and phosphorylated insulin receptor substrate-1 Ser-307 by intramyocellular lipids can lead to muscle insulin resistance [26]. Moreover, activation of IκB kinase affects insulin signaling by phosphorylating and switching off the function of insulin receptor substrate, leading to increased insulin concentrations [27]. Hyperinsulinemia is also present in overtreatment with exogenous insulin. The difference between exogenous insulin-and endogenous insulin-induced hyperinsulinemia is the lowering of plasma glucose, lipoproteins, and inflammatory markers [28].

Table 2 Differential diagnosis of hyperinsulinemia

In the current case series, each of the four patients was found to have non-classical IAS with high concentrations of anti-insulin antibodies that were caused by exogenous insulin injection. These antibodies can cause hypoglycemia, even after insulin injection is discontinued. In patients with classical IAS, hypoglycemia is typically postprandial. As glucose concentrations eventually fall, insulin secretion also subsides, and the total insulin level decreases. This leads to an increase of released free insulin concentration that is inappropriate for the glucose concentration, resulting in postabsorptive hypoglycemia [1]. However, most of our cases had fasting hypoglycemia, which were attributed to dissociation of insulin and insulin antibodies while the internal environment changed at night (which may be related to decreased affinity of the insulin antibody). Insulin antibodies bind with sufficient insulin in the daytime, accounting for less antibodies to be attached in the middle of the night. Therefore, increased free insulin concentrations could induce fasting hypoglycemia.

In the treatment of non-classical IAS, a suitable dose and disposition of insulin are required for better glycemic control. However, while case 3 was in a hypoglycemic status, the patient was treated with the same insulin and it was gradually discontinued, and in case 4, the type of insulin was changed. On the basis of our experience, we prefer to switch to another type of insulin if islet function appears to be poor. This is because changing to another insulin type can make the insulin antibodies disappear and glycemic concentrations more stable. However, if islet function is good, we prefer to gradually reduce the same insulin dose and add oral drugs. Although steroids can aggravate hyperglycemia, they are always used to treat IAS and non-classical IAS in clinical practice due to the following reasons. First, steroids reduce the hypoglycemia phenomenon that occurs in the middle of the night in non-classical IAS. Second, steroids decrease insulin antibodies and have advantages for glycemic control in the daytime. Therefore, we justify the treatment effectiveness in our patients through stability of glycemic concentrations.

However, discontinuing previous insulin treatment and switching to steroid treatment may worsen glucose control in patients with diabetes mellitus. Therefore, further studies are required to determine whether a smaller dose of prednisone in combination with a suitable dose of insulin can specifically treat non-classical IAS (Table 3).

Table 3 The relationship between classic and non-classic insulin resistance

Availability of data and materials

Not applicable



Endogenous hyperinsulinemic hypoglycemia


Insulin autoimmune syndrome


Oral glucose tolerance test


  1. 1.

    Wong SL, Priestman A, Holmes DT. Recurrent hypoglycemia from insulin autoimmune syndrome. J Gen Intern Med. 2014;29(1):250–4.

    Article  Google Scholar 

  2. 2.

    Gullo D, Evans JL, Sortino G, Goldfine ID, Vigneri R. Insulin autoimmune syndrome (Hirata disease) in European Caucasians taking alpha-lipoic acid. Clin Endocrinol. 2014;81(2):204–9.

    CAS  Article  Google Scholar 

  3. 3.

    Su CT, Lin YC. Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog. Endocrinol Diabetes Metab Case Rep. 2016;2016.

  4. 4.

    Woo CY, Jeong JY, Jang JE, Leem J, Jung CH, Koh EH, et al. Clinical features and causes of endogenous hyperinsulinemic hypoglycemia in Korea. Diabetes Metab J. 2015;39(2):126–31.

    Article  Google Scholar 

  5. 5.

    Matej A, Bujwid H, Wronski J. Glycemic control in patients with insulinoma. Horm (Athens). 2016;15(4):489–99.

    Article  Google Scholar 

  6. 6.

    Sahni P, Trivedi N, Omer A. Insulin autoimmune syndrome: a rare cause of postprandial hypoglycemia. Endocrinol Diabetes Metab Case Rep. 2016;2016.

  7. 7.

    Roh E, Kim YA, Ku EJ, Bae JH, Kim HM, Cho YM, et al. Two cases of methimazole-induced insulin autoimmune syndrome in graves' disease. Endocrinol Metab (Seoul). 2013;28(1):55–60.

    Article  Google Scholar 

  8. 8.

    Chu JP, Zheng XW, Lu J, Zhong JY, Li JL, Xu M, et al. Insulin-induced autoimmune syndrome: a case report. Exp Ther Med. 2016;12(5):3359–62.

    Article  Google Scholar 

  9. 9.

    Saxon DR, McDermott MT, Michels AW. Novel Management of Insulin Autoimmune Syndrome with rituximab and continuous glucose monitoring. J Clin Endocrinol Metab. 2016;101(5):1931–4.

    CAS  Article  Google Scholar 

  10. 10.

    Ohtsuka Y, Kondo T, Shimada M, Murakami K, Ide H, Kawakami Y. Erythrocyte insulin receptor in insulin autoimmune syndrome: effects of corticosteroid therapy. Tohoku J Exp Med. 1987;151(2):181–90.

    CAS  Article  Google Scholar 

  11. 11.

    Sharwood EF, Hughes IP, Pretorius CJ, Trnka P, Peake J, Huynh T. Therapeutic plasma exchange normalizes insulin-mediated response in a child with type 1 diabetes and insulin autoimmune syndrome. Pediatr Diabetes. 2017.

  12. 12.

    Kroemer TM, Erler A, Tsourdi E, Gruber M, Tselmin S, Julius U, et al. Immunoadsorption followed by rituximab as a definitive treatment for insulin autoimmune syndrome (Hirata syndrome): a case report. Diabetes Care. 2017.

  13. 13.

    Jain N, Savani M, Agarwal M, Kadaria D. Methimazole-induced insulin autoimmune syndrome. Ther Adv Endocrinol Metab. 2016;7(4):178–81.

    CAS  Article  Google Scholar 

  14. 14.

    Joung KH, Kim HJ, Ku BJ. Type B insulin resistance syndrome with diabetic ketoacidosis. Acta Diabetol. 2012;49(1):81–2.

    CAS  Article  Google Scholar 

  15. 15.

    Arzamendi AE, Rajamani U, Jialal I. Pseudoinsulinoma in a white man with autoimmune hypoglycemia due to anti-insulin antibodies: value of the free C-peptide assay. Am J Clin Pathol. 2014;142(5):689–93.

    Article  Google Scholar 

  16. 16.

    Rajpal A, Kassem LS, Moscoso-Cordero M, Arafah BM. Clopidogrel-induced insulin autoimmune syndrome: a newly recognized cause of hypoglycemia in a patient without diabetes. J Endocr Soc. 2017;1(9):1217–23.

    CAS  Article  Google Scholar 

  17. 17.

    Zhang S, Wang G, Wang J. Type B insulin resistance syndrome induced by systemic lupus erythematosus and successfully treated with intravenous immunoglobulin: case report and systematic review. Clin Rheumatol. 2013;32(2):181–8.

    CAS  Article  Google Scholar 

  18. 18.

    Ismail AA. The insulin autoimmune syndrome (IAS) as a cause of hypoglycaemia: an update on the pathophysiology, biochemical investigations and diagnosis. Clin Chem Lab Med. 2016;54(11):1715–24.

    CAS  Article  Google Scholar 

  19. 19.

    Shin JJ, Gorden P, Libutti SK. Insulinoma: pathophysiology, localization and management. Future Oncol. 2010;6(2):229–37.

    CAS  Article  Google Scholar 

  20. 20.

    Kittah NE, Vella A. MANAGEMENT OF ENDOCRINE DISEASE: pathogenesis and management of hypoglycemia. Eur J Endocrinol. 2017;177(1):R37–47.

    CAS  Article  Google Scholar 

  21. 21.

    Tuzcu SA, Pekkolay Z, Kilinc F, Tuzcu AK. (68) Ga-DOTATATE PET/CT can be an alternative imaging method in Insulinoma patients. J Nucl Med Technol. 2017;45(3):198–200.

    Article  Google Scholar 

  22. 22.

    Morera J, Guillaume A, Courtheoux P, Palazzo L, Rod A, Joubert M, et al. Preoperative localization of an insulinoma: selective arterial calcium stimulation test performance. J Endocrinol Investig. 2016;39(4):455–63.

    CAS  Article  Google Scholar 

  23. 23.

    Schwetz V, Horvath K, Kump P, Lackner C, Perren A, Forrer F, et al. Successful medical treatment of adult Nesidioblastosis with Pasireotide over 3 years: a case report. Medicine (Baltimore). 2016;95(14):e3272.

    Article  Google Scholar 

  24. 24.

    Kowalewski AM, Szylberg L, Kasperska A, Marszalek A. The diagnosis and management of congenital and adult-onset hyperinsulinism (nesidioblastosis) - literature review. Pol J Pathol. 2017;68(2):97–101.

    Article  Google Scholar 

  25. 25.

    Garcia-Santos EP, Manzanares-Campillo Mdel C, Padilla-Valverde D, Villarejo-Campos P, Gil-Rendo A, Munoz-Atienza V, et al. Nesidioblastosis. A case of hyperplasia of the islets of Langerhans in the adult. Pancreatol. 2013;13(5):544–8.

    Article  Google Scholar 

  26. 26.

    Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1).

    Article  Google Scholar 

  27. 27.

    Stafeev IS, Vorotnikov AV, Ratner EI, Menshikov MY, Parfyonova YV. Latent inflammation and insulin resistance in adipose tissue. Int J Endocrinol. 2017;2017:5076732.

    CAS  Article  Google Scholar 

  28. 28.

    Park K, Li Q, Evcimen ND, Rask-Madsen C, Maeda Y, Maddaloni E, et al. Exogenous insulin infusion can decrease atherosclerosis in diabetic rodents by improving lipids, inflammation, and endothelial function. Arterioscler Thromb Vasc Biol. 2018;38(1):92–101.

    CAS  Article  Google Scholar 

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Thanks for the support of the Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Endocrinology and the assistance of all interviewers and subjects who participated in our study.



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XXS attended the patient and reviewed the manuscript. YMS wrote the manuscript. YZR reviewed the literature. All authors read and approved the final manuscript.

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Correspondence to Yuezhong Ren.

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Shen, Y., Song, X. & Ren, Y. Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series. BMC Endocr Disord 19, 148 (2019).

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  • Insulin autoimmune syndrome
  • Hyperinsulinism
  • Hypoglycemia
  • Glucose
  • Diabetes
  • Acarbose
  • Steroid