Glutamate Supplementation and Its Effects on Skeletal Muscle Glucose Metabolism During an Oral Glucose Challenge in Healthy Young Men

Glutamate is involved in several aspects of glucose metabolism in both muscle and liver, however its role has not been fully defined. It is the primary amino acid taken up by resting and exercising skeletal muscle, where it interacts with pyruvate (derived from glycolysis) to produce the TCA cycle intermediate 2-oxoglutarate and the gluconeogenic precursor alanine. Glutamate is also required for the production of glutamine, another gluconeogenic precursor, via intramuscular reactions with ammonia. Given that skeletal muscle is responsible for 85% of whole body glucose disposal, investigating the interplay between glutamate, its related amino acids, and glucose homeostasis is of particular relevance. However, despite its many links to energy provision, the role of glutamate in skeletal muscle glucose metabolism remains poorly understood.

Few studies have manipulated circulating concentrations of both glutamate and glucose in humans, and none have evaluated the effect of this unique manipulation in skeletal muscle tissue. In healthy young adults, a dose of roughly 10 g monosodium glutamate (MSG) transiently elevates plasma (700-800%) and intramuscular (30%) glutamate concentrations. Acute MSG supplementation also stimulates modest increases in plasma concentrations of aspartate, alanine, and glutamine (which are produced from glutamate within the muscle and subsequently released into circulation). Intriguingly, insulin is secreted in response to MSG supplementation, an effect that appears to be mediated by glutamate binding to an excitatory amino acid receptor on the pancreas. In addition to its action on the pancreas, there is some evidence to suggest that glutamate may function as a secondary messenger by enhancing glucose-stimulated insulin secretion during periods of increased carbohydrate (CHO) availability. However this secondary effect of glutamate on insulin is poorly understood.

The ability of glutamate to independently stimulate insulin secretion provides further support for an association between glutamate and glucose metabolism, yet only two studies to date have administered MSG during an oral glucose challenge to directly examine this relationship. One study observed no effect of MSG on glucose tolerance, however peak plasma glutamate was dramatically blunted in this study compared to previous reports (~ 80 vs. 400-500 µM), likely due to glutamate being retained in the gut as a result of co-ingestion with CHO. In a separate study, the authors developed a methodological approach to circumvent this issue: by staggering the administration of MSG and CHO by 30 min, plasma glutamate and glucose were both significantly and simultaneously elevated. Furthermore, MSG administration improved glucose tolerance. In support of these findings, improvements in glucose clearance following a high-fat meal combined with MSG has also been reported. Interestingly, not all studies have observed enhanced insulin secretion with higher glutamate availability. This suggests that the ability of carbohydrate to stimulate insulin secretion may overpower any effect of glutamate on this hormone, but the specific mechanisms remain to be fully elucidated.

Recently, investigators have developed a cell culture model to show that glutamate stimulates glucose uptake in rat L6 myotubes in the absence of insulin. This suggests that glutamate is capable of acting directly on skeletal muscle, and supports previous findings of improved glucose tolerance with acute MSG supplementation despite no further increase in insulin secretion. Additionally, cell data demonstrates that glutamate-stimulated glucose uptake results from increased glucose transporter 4 (GLUT4) translocation to the sarcolemma, via the activation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK). It is possible that these mechanisms underpin glutamate-mediated improvements in glucose tolerance in humans. However, this - as well as the fate of glucose upon being taken up by the muscle cell - has yet to be investigated.

There is a high degree of interplay between glutamate and glucose metabolism, but it remains unclear whether elevated plasma concentrations of glutamate and glucose influence one another's uptake into human skeletal muscle, as well as their subsequent respective intramuscular metabolic reactions. Therefore, the overarching goal of this study is to uncover the effects of acute MSG+CHO supplementation on plasma and intramuscular amino acid concentrations, as well as aspects of skeletal muscle glucose metabolism, in healthy young men in comparison to the ingestion of MSG and CHO alone.