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In our previous study, we demonstrated that hypoglycemic agent DPP-4i changed the gut microbiota composition in diabetic patients and mice, and the DPP-4i-altered microbiome improved glucose tolerance in colonized mice. However, the mediators and their mechanisms remain to be elucidated. Comparing the intestinal metabolite profiles of HFD mice treated with or without sitagliptin (Sit) , we identified tryptophan derivative 5-methoxytryptomine (5-MT) was obviously increased after Sit treatment. In HFD and db/db mice, 5-MT treatment significantly reduced the body weight, improved glucose tolerance and insulin resistance, and ameliorated hepatic steatosis and inflammation. Drug affinity responsive target stability (DARTS) assay demonstrated the interaction between 5-MT and Aryl hydrocarbon receptor (AhR) . Specific inhibition of AhR attenuated the effects of 5-MT on improving insulin resistance. Furthermore, molecular mechanism exploration revealed that 5-MT promoted the expression and secretion of chemokine Cxcl14, which promoted macrophages maturation into alternative activation (M2-like) , subsequently inhibiting the production of inflammatory factors. These data demonstrate novel beneficial roles of 5-MT in improving obesity-related inflammation, insulin resistance and hepatic steatosis. Funding National Science Fund for Distinguished Young Scholars of China (No.81925007) , National Natural Science Foundation of China (No.81700757)

Cutaneous wound healing is a fundamental biologic and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify the pivotal role of dedicator of cytokinesis 5 (Dock5) in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration, and proliferation and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated reepithelialization and granulation tissue formation, and Dock5 overexpression–improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in reepithelialization, collagen deposition, ECM production, and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.

Background and Aims: Identification of new biomarkers and drug targets for diabetic nephropathy (DN) is required for the development of more effective therapy. In this study, we investigated the role of SIK2 in protecting against renal tubular injury. Methods: Diabetes was induced in C57BL/6 mice by streptozotocin (STZ) injection. Inhibitor ARN-3236 was administered 4 weeks after STZ injection 6 weeks, and metabolic indices and renal function were assessed. The apoptosis of HK2 cells was detected by flow cytometric analysis. The transcriptome sequencing was performed after SIK2 overexpression. Results: Salt inducible kinase 2 (SIK2) expression was obviously decreased in the diseased kidneys from humans and mice, especially in the tubules. In vivo, downregulation of SIK2 with specific inhibitor ARN3236 accelerates tubular mitochondrial dysfunction, endoplasmic reticulum (ER) stress and apoptosis in STZ mice. In tubular epithelial cells, SIK2 overexpression attenuates thapsigargin-induced ER stress and apoptosis, whereas SIK2 knockdown aggravates apoptosis. Mechanistically, SIK2 overexpression upregulates HSP70 expression by phosphorylating HSF1, and then inhibits ER stress. Conclusions: The newly identified SIK2/HSF1/HSP70 axis clarified the molecular mechanism of tubular epithelial cells apoptosis, indicating that SIK2 might be a novel target for therapeutic prevention of renal tubular injury. Disclosure X. Liao: None. B. Liu: None. H. Zheng: None.

Background and Aims: Emerging evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. While, little is known about the effect of antidiabetic agents on the gut microbiota. In the current study, we investigated the role of DPP-4i and acarbose in modulating the gut microbial community. Methods: 16S rRNA sequencing was performed to analysis the effect of DPP-4i and acarbose on the gut microbiota in HFD mice. Fecal microbiota transplantation (FMT) from DPP-4i, acarbose, or placebo- treated T2D patients to germ-free (GF) mice was performed to investigate the contribution of the altered microbiota to the antidiabetic effect. Fecal metabolomics were analyzed by untargeted and targeted GC-MS system. Results: DPP-4i and acarbose changed the gut microbial composition, and the DPP-4i- altered microbiome improved the glucose tolerance, while acarbose- altered microbiome did not. Moreover, DPP-4i primarily reduced the ratio of Firmicutes to Bacteroidetes, and changed the pattern of metabolites in HFD mice, especially the increase of succinate. Conclusions: Our findings demonstrated that the alterations of the gut microbial composition and metabolites might be a previously unsuspected hypoglycemic mechanism of DPP-4i. It might provide a potential strategy for modulating glucose homeostasis in the future. Disclosure X. Liao: None. H. Zheng: None.