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The Metabolite β-Hydroxybutyrate of Lactobacillus Plantarum YZX21 Improves Type 2 Diabetes By Promoting Intestinal Secretion of GLP-1
Zhe Zhang, Xi Liang, Lingjun Tong, Youyou Lv, Haiyan Lu, Maozhen Zhao, Pimin Gong, Tongjie Liu, Huaxi Yi, Lan Wei Zhang

Abstract
Background: Probiotics and their metabolites regulate type 2 diabetes mellitus (T2DM) by promoting GLP-1 secretion, but the mechanism has not yet been fully clarified.
Results: In order to reveal the effect of Lactobacillus plantarum（L. plantarum）YZX21 on the regulation of T2DM, type 2 diabetic C57BL/6 mice induced by a high-fat diet and streptozotocin (STZ) were divided into different groups and were daily treated with L. plantarum YZX21 for 8 weeks. We identified that L.plantarum YZX21 reduced blood glucose, insulin levels and HOME-IR. Histopathology was found that L.plantarum YZX21 restored the mouse islet cells morphology and increased insulin secretion. The Elisa and immumohistochemical staining revealed concentration of glucagon-like peptide-1 (GLP-1) was increased in the mice colon. UPLC-MS/MS based widely-targeted metabolomics analysis was used to identify the differential intestinal metabolites in the mice colon. It was found that the metabolite β-Hydroxybutyrate(BHB) of L.plantarum YZX21 had a negative associated with T2DM. Subsequent, type 2 diabetic C57BL/6 mice was established and used to verify hpyerglycemic effest by daily treated with BHB for 8 weeks. It was found that BHB improved pathoglycemia, insulin resistance and increased the intestinal GLP-1 levels, especially reduced free fatty acid (FFA) levels. The expression of receptors G protein-coupled receptor (GPR) was verified by RT-PCR. The GPR109a receptor was significantly stimulated which was up-regulated the expression of GLP-1, but not GPR41 and GPR43 in the mice colon.
Conclusions: We found that the hypoglycemic effect of L.plantarum YZX21 was demonstrated by increasing the intestinal GLP-1 levels in the diabetic mice. Through the widely-targeted metabolomics, we identify the close correlation between serum concentrations of BHB and T2DM. In T2DM mice model, BHB reduced the FFA levels and increased the intestinal GLP-1 levels, which is associated with the downregulated expression of GPR109a. These results demonstrated that L.plantarum YZX21 alleviated T2DM by upregulating BHB/GPR109a/GLP-1 associated pathway.

GLP-1 (GLP = glukagon like peptidi) on normaali ohutsuolesta ruokailun yhteydessä erittyvä hormoni. Se lisää verensokeria laskevan insuliinin eritystä haiman beetasoluista aterian yhteydessä ja vähentää verensokeria nostavan glukagonin eritystä haiman alfasoluista, hidastaa mahalaukun tyhjentymistä sekä lisää kylläisyyden tunnetta ja edistää laihtumista.