Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide and is impacted by an unhealthy diet with excessive calories, although the role of sugars in NAFLD etiology remains largely unexplored. Rare sugars are natural sugars with alternative monomers and glycosidic bonds, which have attracted attention as sugar replacers due to developments in enzyme engineering and hence an increased availability. We studied the impact of (rare) sugars on energy production, liver cell physiology and gene expression in human intestinal colorectal adenocarcinoma (Caco-2) cells, hepatoma G2 (HepG2) liver cells and a coculture model with these cells. Fat accumulation was investigated in the presence of an oleic/palmitic acid mixture. Glucose, fructose and galactose, but not mannose, l-arabinose, xylose and ribose enhanced hepatic fat accumulation in a HepG2 monoculture. In the coculture model, there was a non-significant trend (p = 0.08) towards higher (20–55% increased) median fat accumulation with maltose, kojibiose and nigerose. In this coculture model, cellular energy production was increased by glucose, maltose, kojibiose and nigerose, but not by trehalose. Furthermore, glucose, fructose and l-arabinose affected gene expression in a sugar-specific way in coculture HepG2 cells. These findings indicate that sugars provide structure-specific effects on cellular energy production, hepatic fat accumulation and gene expression, suggesting a health potential for trehalose and l-arabinose, as well as a differential impact of sugars beyond the distinction of conventional and rare sugars.

In view of the global pandemic of obesity and related metabolic diseases, there is an increased interest in alternative carbohydrates with promising physiochemical and health-related properties as a potential replacement for traditional sugars. However, our current knowledge is limited to only a small selection of carbohydrates, whereas the majority of alternative rare carbohydrates and especially their properties remain to be investigated. Unraveling their potential properties, like digestibility and glycemic content, could unlock their use in industrial applications. Here, we describe the enzymatic production and in vitro digestibility of three novel glycosides, namely, two kojibiose analogues (i.e., D-Glc p -α-1,2-D-Gal and D-Glc p -α-1,2-D-Rib) and one nigerose analogue (i.e., D-Glc p -α-1,3-L-Ara). These novel sugars were discovered after an intensive acceptor screening with a sucrose phosphorylase originating from Bifidobacterium adolescentis (BaSP). Optimization and upscaling of this process led to roughly 100 g of these disaccharides. Digestibility, absorption, and caloric potential were assessed using brush border enzymes of rat origin and human intestinal Caco-2 cells. The rare disaccharides showed a reduced digestibility and a limited impact on energy metabolism, which was structure-dependent and even more pronounced for the three novel disaccharides in comparison to their respective glucobioses, translating to a low-caloric potential for these novel rare disaccharides.

Rare sugars have recently attracted attention as potential sugar replacers. Understanding the biochemical and biological behavior of these sugars is of importance in (novel) food formulations and prevention of type 2 diabetes. In this study, we investigated whether rare sugars may positively affect intestinal and liver metabolism, as well as muscle insulin sensitivity, compared to conventional sugars. Rare disaccharide digestibility, hepatic metabolism of monosaccharides (respirometry) and the effects of sugars on skeletal muscle insulin sensitivity (impaired glucose uptake) were investigated in, respectively, Caco-2, HepG2 and L6 cells or a triple coculture model with these cells. Glucose and fructose, but not l-arabinose, acutely increased extracellular acidification rate (ECAR) responses in HepG2 cells and impaired glucose uptake in L6 cells following a 24 h exposure at 28 mM. Cellular bioenergetics and digestion experiments with Caco-2 cells indicate that especially trehalose (α1-1α), D-Glc-α1,2-D-Gal, D-Glc-α1,2-D-Rib and D-Glc-α1,3-L-Ara experience delayed digestion and reduced cellular impact compared to maltose (α1-4), without differences on insulin-stimulated glucose uptake in a short-term setup with a Caco-2/HepG2/L6 triple coculture. These results suggest a potential for l-arabinose and specific rare disaccharides to improve metabolic health; however, additional in vivo research with longer sugar exposures should confirm their beneficial impact on insulin sensitivity in humans.