α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. In the present study, the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice was examined. Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). 
It was found that α-CD forms a cloudy precipitate in the gut when administered orally. α-CD forms inclusions with small sized molecules in its hydrophobic inner cavity. When α-CD is administered intra-luminally to the gut, inclusion of lecithin by α-CD has been reported to inhibit formation of bile salt micelles, leading to inhibition of cholesterol absorption by the host . In the gut lumen, bile salts and lecithin form micelles with triglycerides and cholesterol, which are critical for absorption of dietary fat. The extracellular cholesterol concentration is sensed by absorptive epithelial cells and hepatocytes through SREBP2 signaling. Thus, blockade of the cholesterol supply to gut epithelium by α-CD may well activate SREBP2 in intestine, thus stimulating cholecystokinin (CCK) secretion that suppresses hepatic glucose production.
α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce CCK secretion to suppress hepatic glucose production via a gut/brain/liver axis.
- Lee, E.; Zhang, X.; Noda, T.; Miyamoto, J.; Kimura, I.; Tanaka, T.; Sakurai, K.; Hatano, R.; Miki, T. Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia. Int. J. Mol. Sci. 2021, 22, 10796. https://doi.org/10.3390/ijms221910796
- Furune, T.; Ikuta, N.; Ishida, Y.; Okamoto, H.; Nakata, D.; Terao, K.; Sakamoto, N. A study on the inhibitory mechanism for cholesterol absorption by α-cyclodextrin administration. Beilstein J. Org. Chem. 2014, 10, 2827–2835
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