Abstract
Insulin autoimmune syndrome (IAS), also known as Hirata disease, is a rare immune-mediated cause of endogenous hyperinsulinemic hypoglycemia characterized by circulating insulin autoantibodies (IAAs). It typically develops in individuals without prior exposure to exogenous insulin. Although IAS has been associated with viral infections and, less commonly, with autoimmune and hematologic disorders, medications and dietary supplements are considered the most frequent precipitating factors. Sulfhydryl-containing compounds are the most commonly implicated triggers. Methimazole represents the classical drug-associated cause, whereas an increasing number of cases have been attributed to the widely available antioxidant supplement alpha-lipoic acid (ALA).In genetically susceptible individuals, i.e. in those carrying the HLA alleles HLA-DRB1*04:06/04:/03/04:04, sulfhydryl-containing compounds are thought to alter insulin immunogenicity and promote the formation of IAAs. The resulting insulin-antibody complexes disrupt normal insulin kinetics, leading to recurrent hypoglycemia that may alternate with episodes of postprandial hyperglycemia. Early recognition of the syndrome is of paramount importance, as withdrawal of the triggering agent together with appropriate supportive and pharmacological management is associated with a favorable prognosis in most patients. The importance of medical nutrition therapy with frequent, small meals rich in cornstarch together with the addition of acarbose or glucocorticoids should be pointed out. This narrative review provides an overview of the current evidence regarding IAS, with particular emphasis on drug- and ALA-associated disease. We further illustrate the practical application of this evidence through the presentation of a 76-year-old man who developed IAS following ALA supplementation. To our knowledge, this is the first narrative review to comprehensively address the epidemiology, pathogenesis, diagnosis, and management of ALA-associated IAS while integrating a representative clinical case to bridge current evidence with practical clinical decision-making. By highlighting this rare but increasingly recognized cause of hypoglycemia, this work aims to enhance clinical awareness and support timely diagnosis and evidence-based management.