Scientific opinion on the relationship between intake of alpha‐lipoic acid (thioctic acid) and the risk of insulin autoimmune syndrome

Abstract

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the relationship between alpha-lipoic acid (ALA) and the risk of insulin autoimmune syndrome (IAS). The Panel was also asked to advise on the dose below which ALA added to foods is not expected to cause IAS. A review of all possible adverse effects associated with consumption of ALA was not requested. This mandate refers to the procedure under Article 8(2) of Regulation (EC) No 1925/2006 on addition of vitamins, minerals and certain other substances to foods. No pre-established rule exists for the evaluation of the safety of foods when classical toxicity tests cannot be used, e.g. for autoimmune diseases. Published scientific evidence was retrieved through comprehensive literature searches, particularly 49 case reports in which IAS developed following ALA consumption. In all cases, IAS resolved after a few weeks to months when ALA was discontinued. No publication linking the intake of ALA naturally occurring in foods to IAS was identified. The Panel concludes that the consumption of ALA added to foods, including food supplements, is likely to increase the risk of developing IAS in individuals with certain genetic polymorphisms, who cannot be readily identified without genetic testing. The plausible mechanism of such an effect has not yet been fully elucidated. The incidence of IAS in Europe is low and likely lower than in Japan where it has been estimated to be 0.017 per 100,000 inhabitants in 2017-2018. Considering the limited data available, the risk associated with the development of IAS following ALA consumption cannot be quantified precisely. An ALA dose below which IAS is not expected to occur is likely to vary between individuals and cannot be determined from the available data.

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features

“…Considering the effects of this molecule on glucose metabolism, we cannot disregard its possible interference with the immune system leading to severe hypoglycaemia. In recent years there have been many reports of ALA-induced Insulin Autoimmune Syndrome, which, however, seems to occur only in genetically predisposed individuals [ 124 ]. The exact interactions of ALA with insulin in this disease are still unclear.…”

“…In 2007, Uchigata et al published a report on the first case of ALA-induced Insulin Autoimmune Syndrome [ 123 ]. To date, 49 cases can be retrieved by a comprehensive literature search [ 124 ]. The majority of cases have been reported in Japan, while in Europe most cases have been described in Italy, two by our group in 2018 [ 15 ].The pathogenesis of ALA-induced IAS has not been fully elucidated.…”

“…In case reports, diazoxide, prednisone and other immunosuppressants were administered after ALA suspension. In all cases, hypoglycaemic events disappeared after a comparable period of time (one week to three months) [ 124 ]. Thus, the introduction of drugs is not mandatory, but based on the severity of symptoms and the patient’s general clinical condition.…”

“…Recently the European Commission has asked the European Food Safety Authority (EFSA) to review existing data on the possible link between ALA administration and IAS and provide advice on the dietary intake of foods supplemented with alpha-lipoic acid. A panel published by EFSA in April 2021 [ 124 ] concluded that the addition of ALA to foods is likely to lead to an increased risk of development of IAS in individuals with certain genetic polymorphisms. On the other hand, no link has been found between the intake of foods naturally containing ALA with IAS.…”

Safety of Antithyroid Drugs in Avoiding Hyperglycemia or Hypoglycemia in Patients With Graves’ Disease and Type 2 Diabetes Mellitus: A Literature Review

“…However, in the last decade, IAS has also been reported in adolescents [ 37 ] and elderly individuals [ 12 ]. Although the cause of IAS remains poorly understood, the most widely accepted hypothesis is that sulfhydryl group drugs, such as methimazole and carbimazole, cleave the disulfide bond of insulin and enhance its immunogenicity in patients with T2DM and GD [ 38 ]. According to a previous study, the human insulin α-chain binds with high affinity to HLA-DRB1*0406.…”