Jiangtangjing ameliorates type 2 diabetes through effects on the gut microbiota and cAMP/PKA pathway

Background:During the clinical use of Jiangtangjing granules,we have found that they improve glucose metabolism and relieve symptoms in patients with type 2 diabetes mellitus.We aimed to further investigate the hypoglycemic effects of Jiangtangjing granules and the mechanisms involved.Methods:Type 2 diabetes mellitus was induced in rats by high-fat diet feeding and streptozotocin injection.The rats were then orally administered Linagliptin(3 mg/kg)or Jiangtangjing granules(13 g crude preparation/kg)for 4 weeks.The therapeutic effects of Jiangtangjing granules on glucose metabolism were then investigated.The serum glucagon-like peptide-1,insulin and glycosylated hemoglobin concentrations were measured using enzyme linked immunosorbent assay.Immunohistochemistry and quantificational real-time polymerase chain reaction were performed to quantify glucagon-like peptide-1 protein expression and cAMP,protein kinase A,and Epac1 mRNA expression,respectively.In addition,amplicon sequencing of bacterial 16s rDNA genes in rat feces was also performed to analyze the richness and diversity of the intestinal microbiota and to determine the relative abundances of the dominant bacterial phyla in the intestinal contents of the rats.Results:Jiangtangjing reduced fasting blood glucose concentration(P<0.05)and blood glucose concentrations during oral glucose tolerance testing(P<0.01),increased serum glucagon-like peptide-1 concentration after glucose administration(P<0.05)and improved glucose tolerance(P<0.05).It also increased glucagon-like peptide-1 protein expression(P<0.05)and the mRNA expression of cAMP(P<0.05),PKA(P<0.05),and Epac1(P<0.05)in the jejunum.Jiangtangjing also affected the composition of the intestinal microbiota in rats with type 2 diabetes mellitus.Specifically,it increased the relative abundance of Bacteroides and reduced that of Actinobacteria.Conclusion:Jiangtangjing granules have anti-diabetic effects,increasing circulating insulin concentration and glucose tolerance.These effects may be mediated by increases in glucagon-like peptide-1 secretion via upregulation of the cAMP/PKA signaling pathway in the jejunum and alterations in the composition of the intestinal microbiota.