Objective:To observe the relationship between the different stages of type 2 diabetes mellitus(T2DM)and the intestinal flora and verify its underlying mechanism.Methods:T2DM rats were generated by high-fat diet(HFD)combined with intraperitoneal streptozo-tocin(STZ)injection.The rats were divided into four groups:the control group(fed with normal feed for 1 month),the HFD group(fed with HFD for 1 month),the T2DM group(HFD combined with STZ and blood glucose＞11.1 mM),and the unformed T2DM model(Un-mod)group(HFD combined with STZ and blood glucose＜11.1 mM).Feces were collected,and bacterial communities in the fecal samples were analyzed by 16S rRNA gene sequencing.The content of short-chain fatty acids(SCFAs)in feces was measured by gas chromatography.Western blot and quantitative real-time polymerase chain reaction were used to detect the expression of G protein-coupled receptor 41(GPR41)and GPR43.Results:At different stages of T2DM,the intestinal flora and SCFAs content of rats were significantly decreased(all P＜.05).Our results indicated that g_Prevotella had a significant negative correlation,and g_Ruminococcus_torques_group and g_lachnoclastic had a significant positive correlation with blood glucose.The content of SCFAs,in particular acetate and butyrate,in rat feces of different stages of T2DM were significantly reduced,as well as GPR41 and GPR43 expression.The results in the Un-mod group were similar to the T2DM group,and the expression of GPR41 and GPR43 proteins were significantly higher than those in the T2DM group(both P＜.001).Conclusion:The intestinal flora-SCFAs-GPR41/GPR43 network may be important in the development of T2DM.Decreasing blood glucose levels by regulating the intestinal flora may become a new therapeutic strategy for T2DM,which has very important clinical and social values.

Mulberry (Morus alba L.) leaf is a well-established traditional Chinese botanical and culinary resource. It has found widespread application in the management of diabetes. The bioactive constituents of mulberry leaf, specifically mulberry leaf flavonoids (MLFs), exhibit pronounced potential in the amelioration of type 2 diabetes (T2D). This potential is attributed to their ability to safeguard pancreatic β cells, enhance insulin resistance, and inhibit α-glucosidase activity. Our antecedent research findings underscore the substantial therapeutic efficacy of MLFs in treating T2D. However, the precise mechanistic underpinnings of MLF's anti-T2D effects remain the subject of inquiry. Activation of brown/beige adipocytes is a novel and promising strategy for T2D treatment. In the present study, our primary objective was to elucidate the impact of MLFs on adipose tissue browning in db/db mice and 3T3-L1 cells and elucidate its underlying mechanism. The results manifested that MLFs reduced body weight and food intake, alleviated hepatic steatosis, improved insulin sensitivity, and increased lipolysis and thermogenesis in db/db mice. Moreover, MLFs activated brown adipose tissue (BAT) and induced the browning of inguinal white adipose tissue (IWAT) and 3T3-L1 adipocytes by increasing the expressions of brown adipocyte marker genes and proteins such as uncoupling protein 1 (UCP1) and beige adipocyte marker genes such as transmembrane protein 26 (Tmem26), thereby promoting mitochondrial biogenesis. Mechanistically, MLFs facilitated the activation of BAT and the induction of WAT browning to ameliorate T2D primarily through the activation of AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway. These findings highlight the unique capacity of MLF to counteract T2D by enhancing BAT activation and inducing browning of IWAT, thereby ameliorating glucose and lipid metabolism disorders. As such, MLFs emerge as a prospective and innovative browning agent for the treatment of T2D.
Mice ; Animals ; Adipose Tissue, Brown ; Sirtuin 1/pharmacology* ; Diabetes Mellitus, Type 2/metabolism* ; AMP-Activated Protein Kinases/metabolism* ; Morus/metabolism* ; Flavonoids/metabolism* ; Prospective Studies ; Signal Transduction ; Adipose Tissue, White ; Plant Leaves ; Uncoupling Protein 1/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism*