N-acetylglucosamine: more than a silent partner in insulin resistance

Abstract

Pedersen et al. (Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, Forslund K, Hildebrand F, Prifti E, Falony G, et al. 2016. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 535: 376-381.) report that human serum levels of branched-chain amino acids (BCAA) and N-acetylglucosamine (GlcNAc) increase in proportion to insulin resistance. They focus on the microbiome and the contributing subset of microbe species, thereby demonstrating disease causality in mice. As either oral GlcNAc or BCAA in mice are known to increase insulin resistance and weight gain, we note that recently published molecular data argues for a cooperative interaction.

Keywords: N-acetylglucosamine; branched-chain amino acids; insulin resistance; mTOR; microbiome.

Fig. 1.

Possible synergy of GlcNAc and BCAA leading to IR: de novo nucleotide-sugar biosynthesis in yellow. Nucleotide-hexoses (brackets) contribute to glycoconjugate biosynthesis, and upon turnover the hexoses are available to host energy harvest, whereas fucose and GlcNAc are phosphorylated and returned to the nucleotide-sugar pools. The Golgi N-acetylglucosyltransferases (MGAT1, 2, 4 and 5) form a linear pathway displaying an increasing dependence on UDP-GlcNAc concentrations (Km increasing), whereas galectins bind to with affinities proportional to N-glycan branching, and stabilizing receptors and transporters against loss to endocytosis (Lau et al. 2007). These kinetics combine for ultrasensitive responses to changes in UDP-GlcNAc. SLC1A5 and SLC2A1-4 import glutamine and glucose, respectively. SLC7A5/SLC3A2 is an antiporter for BCAA/glutamine (Nicklin et al. 2009).