Monosodium glutamate added to food does not induce damage to the pancreas nor aggravate diabetes due to enhancement of oxidative stress

In the article by Gelen, et al. entitled “The investigation of the effects of monosodium glutamate on healthy rat and rats with STZ-induced diabetes,” the authors indicated that oral administration of monosodium glutamate (MSG) at a dose of 30 mg/kg bw/day by gavage for 28 days reduced antioxidative capacity and induced histological abnormalities in the pancreas of healthy rats as well as rats with STZ-induced diabetes. This was attributed to inflammation caused by increased oxidative stress and it was reported that MSG consequently disordered glucose metabolism in healthy rats and aggravated diabetes in STZ-treated rats.^[1] Finally, it was concluded that not only diabetics, but also healthy people should limit their use of the food additive, MSG. In response to this article, we would like to provide safety information on MSG used as a food additive and comment on these study results.

MSG is one of the most thoroughly studied food additives. It is well established that glutamate added to foods does not enter the blood circulation nor does the blood glutamate concentration rise when MSG is consumed as part of a normal diet, even when consumed at abnormally high levels.^[2] Glutamate ingested with food is metabolized as an energy source for enterocytes.^{[3, 4]} It has been demonstrated that dietary glutamate is intensively oxidized during the splanchnic first pass in healthy adults and preterm infants.^{[5, 6]} A study that investigated the metabolic fate of dietary glutamate (including MSG) showed that almost all dietary glutamate in the rat gut is metabolized into CO2, lactate, alanine or proline (56%, 13%, 12%, 3% of dietary input, respectively).^[7] Rodent and human studies have also shown that the major nutrients in foods, especially metabolizable carbohydrates, effectively attenuate any rise in blood glutamate levels induced by oral administration of MSG.^{[8, 9]} Further studies have shown that the circadian fluctuations in blood glutamate level are not significantly different regardless of whether a diet contains added MSG or not ^[10] and that the basal glutamate level is not affected by long-term MSG consumption.^[11] The principal conclusion from these studies is that blood glutamate concentration does not rise when MSG is ingested as part of a normal diet even in cases where intake is abnormally high. Considering the results of these studies on the safety of MSG, international scientific committees and regulatory agencies have stated that MSG is safe as a food additive. Since 1958, MSG has been classified by the US Food and Drug Administration as “generally recognized as safe.” The Joint FAO/WHO Expert Committee on Food Additives (JECFA) also evaluated the safety of MSG as a food additive in 1970, 1973, 1987 and as a flavoring agent in 2022.^{[12, 13]} Consequently, JECFA concluded that the total dietary intake of glutamate did not represent a health hazard and that it is not necessary to establish a numerically acceptable daily intake for humans, including pregnant women and infants. Until now, JECFA has maintained its safety classification for MSG as “ADI not specified.”

MSG is the sodium salt of glutamic acid, one of the most abundant naturally occurring non-essential amino acids and a component of protein. Glutamate, along with cystine and glycine, is also known as a precursor of glutathione (GSH), an antioxidant tripeptide which can prevent oxidative damage caused by reactive oxygen species.^[14] In a piglet study, dietary supplementation with glutamate was shown to alleviate herbicide-induced oxidative stress by enhancing antioxidant capacity, including increased serum superoxide dismutase activity and NO levels and inhibiting MDA generation.^[15] Another piglet study indicated that dietary supplementation with MSG increased the jejunal concentration of GSH.^[16] In a mouse study, a 1.3-fold increase in plasma glutamate levels by administration of l-theanine, a precursor of glutamate, together with cystine was reported to significantly increase the total GSH level in the liver.^[17] In a study using macrophages derived from monocytes, glutamate added to culture medium in the presence of cystine was reported to increase GSH concentration in a dose-dependent manner.^[18] A human clinical trial also showed that oral supplementation with GSH precursors, consisting of cystine, glutamate and glycine, during the intervention period could potentially increase the level of serum GSH.^[19] Thus, contrary to the findings of Gelen, et al., these results suggest that elevated Glu levels in the circulation may be able to increase GSH production and enhance antioxidant capacity. This would mean that, even when MSG is administered using a method designed to raise the blood level of glutamate, such as gavage, MSG does not lead to an increase in oxidative stress. Consequently, we find that Gelen, et al.'s assertion that oral administration of MSG increased oxidative stress in the rat pancreas is incompatible with the evidence.

It should also be noted that when MSG is used as a food additive, it is never given to humans as a bolus in the absence of food. Since MSG is always ingested as an additive with foods, it is clear that the route of administration used in this study (by gavage) is an inappropriate way to investigate the safety of MSG as a food additive. In the OECD guidelines, it is stated that the test substance should be administered by the route most relevant to human exposure. The effects of feeding an MSG-containing diet on healthy and diabetic rats have already been investigated. The study reported that addition of MSG to the diet did not induce any alteration in fasted blood glucose levels, and no significant differences were observed in other biochemical and hematological parameters, as well as liver and kidney histology between control and MSG-fed rats, irrespective of whether the rats were healthy or had diabetes.^[20] The claim in the Gelen, et al. study that MSG had a harmful effect on the pancreas of healthy and diabetic rats is not consistent with studies conducted under OECD guidelines in a manner more representative of actual exposure. Regarding the association of MSG consumption with glucose metabolism and diabetes in humans, a prospective cohort study to assess the association between MSG consumption and the change in fasting blood glucose levels, including a 5-year follow-up period, was carried out in China. The results indicated that high MSG intake is negatively associated with the incidence of hyperglycemia during the follow-up period and there was a linear inverse association between MSG intake and change in fasting blood glucose levels.^[21]

Namely, their conclusion that the prevalence of diabetes mellitus might be elevated with increased use of MSG as a seasoning and the use of MSG should be restricted not just in people with diabetes but also in healthy individuals is clearly contradicted by the scientific evidence from human epidemiological and the animal studies conducted under the realistic condition where MSG is used as a food additive. When extrapolating the results of animal studies on food safety to the human population, the difference between study design and actual dietary practice must be taken into consideration, otherwise, the study conclusion will mislead people when making choices about their diet in everyday life. And finally, we can reasonably assert that MSG does not induce any damage to pancreas nor cause poor glycemic control in diabetics when used as a food additive, and consequently there are no safety concerns associated with the use of MSG.

Shintaro Yoshida: Writing original draft; writing review and editing. Huichia Chao: Writing review and editing. Asuka Takumi: Writing review and editing. Masanori Kohmura: Writing review and editing; supervision.

Shintaro Yoshida, Huichia Chao and Asuka Takumi are the secretariat and Masanori Kohmura is the senior advisor of IGTC, a worldwide research organization having NGO status. The organization carries out or sponsors extensive research on the efficacy, application and safety of glutamic acid and its salts, especially as used in foods. The IGTC receives financial support from glutamate manufacturers and users. Shintaro Yoshida, Huichia Chao, Asuka Takumi and Masanori Kohmura are also employees of Ajinomoto Co., Inc. (Tokyo Japan).