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The renin-angiotensin system (RAS) is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and represents a potential therapeutic target for NAFLD. Glucagonlike peptide-1 (GLP-1) signaling has been shown to regulate the RAS within various local tissues. In this study, we aimed to investigate the functional relationship between GLP-1 and the local RAS in the liver during NAFLD. Wild-type and ACE2 knockout mice were used to establish a high-fat-induced NAFLD model. After the mice were treated with liraglutide (a GLP-1 analogue) for 4 weeks, the key RAS component genes were upregulated in the liver of NAFLD mice. Liraglutide treatment regulated the RAS balance, preventing a reduction in fatty acid oxidation gene expression and increasing gluconeogenesis and the expression of inflammation-related genes caused by NAFLD, which were impaired in ACE2 knockout mice. Liraglutide-treated HepG2 cells exhibited activation of the ACE2/Ang1-7/Mas axis, increased fatty acid oxidation gene expression, and decreased inflammation, which could be reversed by A779 and AngII. These results indicate that the local RAS in the liver becomes overactivated in response to NAFLD. Moreover, ACE2 knockout increases the severity of liver steatosis. Liraglutide has a negative and antagonistic effect on the ACE/AngII/AT1R axis, a positive impact on the ACE2/Ang1-7/Mas axis, and is mediated through the PI3K/AKT pathway. This may represent a potential new mechanism by which liraglutide improves NAFLD.

The angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (A1-7)/MAS axis and glutamate decarboxylase 67 (GAD67)/gamma-aminobutyric acid (GABA) signal both exist in the islet and play important roles in regulating blood glucose metabolism. It has been reported that the activation of ACE2 in the brain increases GABA expression to improve biological effects; however, it is unclear whether there is functional correlation between the ACE2/A1-7/MAS axis and GAD67/GABA signal in the islet. In this study, we showed that the ACE2/A1-7/MAS and GABA signaling systems decreased in the islet of different metabolic stress models. In ACE2-knockout mice, we found that GAD67 and GABA expression decreased significantly, which was reversed by exogenous administration of A1-7. Furthermore, A1-7 mediated PDX1 and AKT activation was inhibited by allylglycine (a specific GAD67 inhibitor) in MIN6 cells. Moreover, giving A1-7 and GABA could significantly reduce beta-cell dedifferentiation and improved glucose metabolism during metabolic stress in vivo and in vitro. In conclusion, our study reveals that the ACE2/A1-7/MAS axis improves beta-cell function through regulating GAD67/GABA signal in beta cells, and up-regulating the ACE2/A1-7/MAS axis and GABA signals delays the development of obesity-induced diabetes.

MicroRNAs (miRNAs) play a great contribution to the development of diabetic nephropathy (DN). The aim of this study was to explore potential miRNAs-genes regulatory network and biomarkers for the pathogenesis of DN using bioinformatics methods. Gene expression profiling data related to DN (GSE1009) was obtained from the Gene Expression Omnibus (GEO) database, and then differentially expressed genes (DEGs) between DN patients and normal individuals were screened using GEO2R, followed by a series of bioinformatics analyses, including identifying key genes, conducting pathway enrichment analysis, predicting and identifying key miRNAs, and establishing regulatory relationships between key miRNAs and their target genes. A total of 600 DEGs associated with DN were identified. An additional 7 key DEGs, including 6 downregulated genes, such as vascular endothelial growth factor α ( VEGFA ) and COL4A5 , and 1 upregulated gene ( CCL19 ), were identified in another dataset (GSE30528) from glomeruli samples. Pathway analysis showed that the down- and upregulated DEGs were enriched in 14 and 6 pathways, respectively, with 7 key genes mainly involved in extracellular matrix–receptor interaction, PI3K/Akt signaling, focal adhesion, and Rap1 signaling. The relationships between miRNAs and target genes were constructed, showing that miR-29 targeted COL4A and VEGFA, miR-200 targeted VEGFA, miR-25 targeted ITGAV, and miR-27 targeted EGFR. MiR-29 and miR-200 may play important roles in DN. VEGFA and COL4A5 were targeted by miR-29 and VEGFA by miR-200, which may mediate multiple signaling pathways leading to the pathogenesis and development of DN.

Objective: Angiotensin-converting enzyme 2 (ACE2) plays a vital role in regulating intestinal tryptophan (Trp) transport and maintaining Trp homeostasis. This study aimed to investigate the functional relationship between intestinal ACE2 and Trp in the regulation of glucose metabolism under metabolic stress.Methods: ACE2-knockout mice and mice with adeno-associated virus-mediated overexpression of ACE2 were fed with a high-fat diet for 12 weeks to establish a high-fat-induced metabolic stress model. They were subjected to a Trp gavage intervention for another 4 weeks.Results: Here, it is reported that ACE2 regulates intestinal Trp absorption by stabilizing neutral amino acid transporter B 0 AT1. Notably, in ACE2-knockout mice, it was found that B 0 AT1 and serum Trp levels were significantly reduced, which was not reversed by Trp supplementation. However, mice receiving adeno-associated virus-ACE2 did the opposite and showed significantly improved glycolipid metabolism. It was then confirmed that Trp potentiated glucagon-like peptide 1 production from intestinal and islet α-cells. Meanwhile, Trp-treated MIN6 cells ameliorated mitochondrial function and safely guarded MIN6 cells against reactive oxygen species exposure.Conclusions: This study highlights an essential role of ACE2 in the maintenance of systemic metabolism to optimize the function of the islets through a novel gut-islet axis mediated by Trp. These results provide proof-of-concept evidence for treating obesity and diabetes.

In vivo beta-cell neogenesis may be one way to treat diabetes. We aimed to investigate the effect of glucagon-like peptide-1 (GLP-1) on beta-cell neogenesis in type 2 diabetes mellitus (T2DM). Male C57BL/6J mice, 6 wk old, were randomly divided into three groups: Control, T2DM, and T2DM + Lira. T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin (40 mg/kg/d for 3 d). At 8 wk after streptozotocin injection, T2DM + Lira group was injected intraperitoneally with GLP-1 analog liraglutide (0.8 mg/kg/d) for 4 wk. Apparently for the first time, we report the appearance of a primitive bud connected to pancreas in all adult mice from each group. The primitive bud was characterized by scattered single monohormonal cells expressing insulin, GLP-1, somatostatin, or pancreatic polypeptide, and four-hormonal cells, but no acinar cells and ductal epithelial cells. Monohormonal cells in it were small, newborn, immature cells that rapidly proliferated and expressed cell markers indicative of immaturity. In parallel, Ngn3+ endocrine progenitors and Nestin+ cells existed in the primitive bud. Liraglutide facilitated neogenesis and rapid growth of acinar cells, pancreatic ducts, and blood vessels in the primitive bud. Meanwhile, scattered hormonal cells aggregated into cell clusters and grew into larger islets; polyhormonal cells differentiated into monohormonal cells. Extensive growth of exocrine and endocrine glands resulted in the neogenesis of immature pancreatic lobes in adult mice of T2DM + Lira group. Contrary to predominant acinar cells in mature pancreatic lobes, there were still a substantial number of mesenchymal cells around acinar cells in immature pancreatic lobes, which resulted in the loose appearance. Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud, which liraglutide facilitates in adult T2DM mice. To our knowledge, this is the first time such a phenomenon has been reported.

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