Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], −1.04[−1.19, −0.89]%) and BBR-alone group (−0.99[−1.16, −0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (−0.59[−0.75, −0.44]%, −0.53[−0.68, −0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).

Accumulating evidence has indicated the significant roles of long noncoding RNAs (lncRNAs) in the pathophysiology of diabetic nephropathy (DN). LncRNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to exert a key role in the progression of several diseases including diabetes. However, the role of NEAT1 in the regulation of DP progression remains barely known. Therefore, our study aimed to investigate the role of NEAT1 in a streptozotocin‐induced diabetes model (DM) of rats and glucose‐induced mouse mesangial cell models. Currently, we found that NEAT1 was greatly upregulated in DM rats and glucose‐induced mice mesangial cells, in which a high activation of Akt/mTOR signaling was also observed. Then, it was shown that knockdown of NETA1 was able to reduce renal injury in DM rats obviously. In addition, cell counting kit‐8 assay and 5‐ethynyl‐2′‐deoxyuridine assay were carried out and we observed downregulation of NEAT1 significantly inhibited mesangial cell proliferation. Meanwhile, extracellular matrix proteins and messenger RNA (transforming growth factor β1, fibronectin, and collagen IV) expression was dramatically restrained by silencing of NEAT1 in the high glucose‐induced mesangial cells. Finally, knockdown of NEAT1 greatly reduced the expression of the phosphorylation of Akt and mammalian target of rapamycin (mTOR) in vitro. These findings revealed that the decrease of NEAT1 repressed the proliferation and fibrosis in DN via activating the Akt/mTOR signaling pathway, which might represent a novel pathological mechanism of DN progression.

Diabetic nephropathy (DN) is one of the leading causes of end-stage renal diseases worldwide. This study is designed to investigate the underlying function and mechanism of a novel lncRNA GAS5 in the progression of DN. We found that lncRNA GAS5 expression level was decreased in type 2 diabetes (T2D) with DN compared with that in patients without DN. Moreover, lncRNA GAS5 expression level was negatively associated with the severity of DN-related complications. lncRNA GAS5 inhibited MCs proliferation and caused G0/1 phase arrest. lncRNA GAS5 overexpression alleviated the expression of fibrosis-related protein in mesangial cells (MCs). The dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay results revealed that lncRNA GAS5 functions as an endogenous sponge for miR-221 via both the directly targeting way and Ago2-dependent manner. Furthermore, SIRT1 was confirmed as a target gene of miR-221. lncRNA GAS5 upregulated SIRT1 expression and inhibited MCs proliferation and fibrosis by acting as an miR-221 sponge. Finally, we found that lncRNA GSA5 suppressed the development of DN in vivo. Thus, lncRNA GAS5 was involved in the progression of DN by sponging miR-221 and contributed to lncRNA-directed diagnostics and therapeutics in DN.