Stress, a pervasive aspect of modern life, has significant implications for health at both individual and family levels. Insulin autoimmune syndrome (IAS), or Hirata’s disease, is a rare hypoglycemic disorder first described in 1970 by Hirata and cols. (1). Most cases have been found in Japanese and Koreans (2,3). It is characterized by spontaneous postprandial hypoglycemia, high levels of immunoreactive insulin, and anti-insulin antibodies. Anti-insulin antibodies triggered by viruses and drugs bind to insulin and proinsulin, resulting in initial hyperglycemia and further stimulation of insulin secretion. Eventually, antibody-binding capacity is exceeded, and unbound free insulin causes hypoglycemia. Dissociation of antibodies also contributes to hypoglycemia (4). In a Japanese cohort of 197 patients with IAS, 43% were exposed to drugs with sulfhydryl radicals (5), including captopril, methimazole (4,6). The mechanism by which these radicals lead to the development of IAS is unknown.This paper describes a case of IAS in a Sub Himalyan region patient after use of alpha lipoic acid, the most prescribed mulitivitamin in our practice

hours after breakfast manifesting as confusion, irritability, sweating, and tremors, which resolved with carbohydrate intake. Glucometer readings during these episodes ranged from 35-45 mg/dl.There was no personal or family history of diabetes mellitus or other endocrinopathies, such as insulinoma,or previous use of oral hypoglycemic drugs such as sulfonylureas or exogenous insulin. Dietary recall revealed high consumption of foods rich in simple carbohydrates and fats, with low fiber intake. She had a sedentary lifestyle, BMI of 32.2 kg/m2, abdominal circumference of 107 cm, and absence of acanthosis nigricans.

During hypoglycemic episodes, plasma glucose was 32 mg/dl, with C-peptide levels elevated at 29.70 ng/ml (normal: 1.1-4.4 ng/ml). Fasting insulin levels were markedly elevated (>1000 uIU/ml, normal: 2.4-24.9 uU/ml). Insulin to C-peptide molar ratio could not be calculated due to assay limitations. Further investigations revealed IAA titers >100 U/ml (normal range <10 U/ml), confirming the diagnosis of IAS. Ultrasonography and abdominal magnetic resonance imaging showed no pancreatic or extra-pancreatic lesions. Anamnesis and detailed clinical investigation ruled out oral hypoglycemic use. Screening for anti-nuclear factor, serum protein electrophoresis, serology for viral hepatitis, and other autoimmune diseases were negative. Upon history review, it was discovered that the patient had been regularly consuming ALA supplements for four months. ALA is known to induce insulin autoantibodies, especially in individuals with genetic predisposition (HLA-DRB1*0406). ALA was discontinued, and the patient was advised frequent low-carbohydrate meals. Symptoms of hypoglycemia gradually resolved over three months, with a subsequent decrease in IAA titers to 3.6 U/ml.

Insulin autoimmune syndrome (IAS) is a rare condition characterized by the production of insulin autoantibodies (IAA), leading to hyperinsulinemic hypoglycemia. It is primarily observed in Japansese individuals, but in India , only 28 cases have been reported. It affects men and women indiscriminately but is more frequent in patients aged > 40 years (7).

The pathogenic mechanisms that lead to the development of IAS are not fully understood. They seem to be associated with the formation of insulin-antibody complexes, which hinder the physiological mechanism of insulin action. After a meal, anti-insulin antibodies bind to secreted insulin in response to increased glycemia. This binding reduces the availability of insulin to its receptors in the liver and peripheral tissues causing hyperglycemia and additional secretion of insulin. The hyperglycemic effect is dose-dependent according to anti-insulin levels. Parallel to the decrease in blood glucose, the insulin bound to the antibodies is released, which results in free insulin concentrations disproportionately high for glycemia. Thus, late postprandial hypoglycemia occurs (4,8). Consistent with the kinetics of the insulin-antibody complex in IAS, we could infer that our patient presented with hyperglycemia at the beginning of the postprandial period, explained by the antibodies that bound to the endogenous insulin, with subsequent late occurrence of hypoglycemia when the antibodies dissociated from the insulin, increasing availability. Another possible mechanism behind IAS is the presence of a high-capacity, low-affinity paraprotein, capable of causing hypoglycemia associated with high plasma insulin levels and relatively low C-peptide levels. A plausible mechanism is delayed clearance of insulin, which is still available to bind its receptor due to the relatively weak affinity of the IgA anti-insulin for insulin (4,9).

Initially, we performed magnetic resonance imaging and ultrasonography of the pancreas to rule out insulinoma or other extrapancreatic tumors, which would not justify the high levels of anti-insulin antibodies observed in our case. We did not measure plasma sulfonylureas because it was an unlikely diagnosis for our patient. Autoimmune insulin receptor disease (insulin resistance type B) is also part of the differential diagnosis. It is caused by the agonistic effect of antibodies against the insulin receptor resulting in significant insulin resistance and paradoxical hypoglycemia. In these cases, anti-receptor insulin antibodies are usually positive whereas anti-insulin antibodies are negative (4,10). Therefore in our case, absence of acanthosis nigricans with markedly elevated fasting insulin levels and high IAA titers, supported the diagnosis of IAS. The presence of anti-thyroid peroxidase antibodies suggested a possible underlying autoimmune predisposition.

Insulin-immunoglobulin complexes (macro-complexes) may pose a significant challenge to the measurement of hormones by immunoassay and may also interfere with bioactivity of the hormones to cause clinical disorders. Church and cols. demonstrated that immunoprecipitation with polyethylene glycol (PEG) must be used with caution in screening for insulin-antibody complexes as gel filtration chromatography (GFC) with addition of exogenous insulin enhances sensitivity for the identification of insulin immune complexes (11). It is noteworthy that we did not consider the possibility of laboratory analytical interference, and we did not test heterophile antibodies.

The association with alpha-lipoic acid (ALA) in our patient is noteworthy.

Recent studies have shown a direct association between the appearance of IAS and LA intake in genetically predisposed people. A recent epidemiological analysis reported 18 cases of LA-related IAS in Japan (12).  ALA, a potent antioxidant and widely used supplement for various medical conditions including diabetic neuropathy and metabolic syndrome, has been implicated in inducing IAS. ALA enhances insulin immunogenicity by forming complexes with insulin, triggering an autoimmune response in genetically susceptible individuals, particularly those with HLA-DRB1*0406 haplotype. This interaction leads to the production of high-affinity IAA, which bind to insulin and prolong its half-life, contributing to persistent hypoglycemia even after discontinuation of exogenous insulin therapy.

Regarding clinical manifestations, reported cases of IAS have varied from mild, transient, to very severe presentations (13). Most patients with drug-induced IAS can achieve remission of the disease soon after stopping use of the medication (6).

The management of IAS revolves around the withdrawal of the offending agent, supportive care with frequent low-carbohydrate meals to prevent postprandial hyperinsulinemia, and close monitoring of blood glucose levels. Nutritional management is recommended with small, frequent meals and reduction of rapidly-absorbed carbohydrates to avoid rapid elevation of blood glucose levels (13).In our case, cessation of ALA supplementation resulted in gradual resolution of hypoglycemic episodes over three months, accompanied by a decline in IAA titers, highlighting the importance of identifying and removing triggering factors in the management of IAS.

In more severe or prolonged cases, glucocorticoids, immunosuppressants, and even plasmapheresis may be useful as adjuvant therapy (3,10). Other reported alternatives include pancreatectomy, diazoxide, and octreotide (10). Immunoadsorption using a reusable adsorber system loaded with sheep antigens directed against human immunoglobulin followed by two doses of 1 g of rituximab has been reported effective in a patient with IAS refractory to prednisolone and azathioprine therapy (14). Finally, in the medical literature, meals containing reduced amounts of carbohydrates and corticosteroids were described as the most effective (7, 8).

Because our patient had a mild condition with infrequent hypoglycemia and without severe hemodynamic repercussions, we opted for lifestyle-changes with nutritional dietary management, and suspension of the medication Alpha lipoic acid, a known trigger.

In conclusion, IAS should be considered in patients presenting with recurrent hypoglycemia and a history of supplement use, particularly ALA. Prompt diagnosis and management are essential to prevent complications associated with severe hypoglycemia. Further research is needed to elucidate the mechanisms underlying the development of IAS and to optimize therapeutic strategies for this rare autoimmune disorder.

1. Hirata Y, Ishizu H, Ouchi N, Motomura M, Abe M, Hara Y, et al. Insulin autoimmunity in a case of spontaneous hypoglycemia. J Jpn Diabetes Soc. 1970;13:312-20. 

2. Uchigata Y, Tokunaga K, Nepom G, Bannai M, Kuwata S, Dozio N, et al. Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata’s disease) and monoclonal insulin autoimmune syndrome. Diabetes. 1995;44(10):1227-32. 

3. 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. 

4. Censi S, Albergoni MP, Gallo N, Plebani M, Boscaro M, Betterle C. Insulin autoimmune syndrome (Hirata’s disease) in an Italian patient: a case report and review of the literature. Clin Chem Lab Med. 2018;56(6):889-95. 

5. Uchigata Y, Eguchi Y, Takayama-Hasumi S, Omori Y. Insulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan. Diabetes Res Clin Pract. 1994;22(2-3):89-94. 

6. Uchigata Y, Hirata Y, Iwamoto Y. Drug-induced insulin autoimmune syndrome. Diabetes Res Clin Pract. 2009;83(1):e19-20. 

7. Savas-Erdeve S, Yılmaz Agladioglu S, Onder A, Peltek Kendirci HN, Bas VN, Sagsak E, et al. An uncommon cause of hypoglycemia: insulin autoimmune syndrome. Horm Res Paediatr. 2014;82(4):278-82.8. 

8. Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am. 1999;28(3):603-18. 

9. Halsall DJ, Mangi M, Soos M, Fahie-Wilson MN, Wark G, Mainwaring-Burton R, et al. Hypoglycemia due to an insulin binding antibody in a patient with an IgA-kappa myeloma. J Clin Endocrinol Metab. 2007;92(6):2013-6. 

10. 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;12:3359-62. 

11. Church D, Cardoso L, Bradbury S, Clarke C, Stears A, Dover A, et al. Diagnosis of insulin autoimmune syndrome using polyethylene glycol precipitation and gel filtration chromatography with ex vivo insulin exchange. Clin Endocrinol (Oxf). 2017;86(3):347-53. 
12. Bae SM, Bae MN, Kim EY, Kim IK, Seo MW, Shin JK, Cho SR, Jeong GH. Recurrent insulin autoimmune syndrome caused by alpha-lipoic acid in type 2 diabetes. Endocrinology and Metabolism 2013. 28 326–330. 
13. 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. 

14. 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. 2018;41(3):e23-4.