Duodenal long noncoding RNAs are associated with glycemic control after bariatric surgery in high-fat diet-induced diabetic mice.

The duodenum plays a role in the mechanism of type 2 diabetes remission after bariatric surgery. Roux-en-Y gastric bypass (RYGB) may change gene expression in the duodenum and metabolism. Long noncoding RNAs (lncRNAs) constitute a novel class of RNAs that regulate gene expression. Little is known about how duodenal lncRNAs respond to RYGB. Logically, studies on the changes of duodenal lncRNAs potentially can lead to an understanding of the mechanisms of bariatric surgery, as well as discovery of antidiabetic drug targets and biomarkers predicting postoperative outcome. To investigate the expression signature of duodenal lncRNAs associated with glycemic improvement by duodenal-jejunal bypass (DJB), a component of RYGB, on a genome-wide scale in high-fat diet-induced diabetic mice. University medical center. High fat diet-induced diabetic mice were randomized into 2 groups receiving either the DJB or a sham procedure. Microarray was applied to screen the differentially expressed lncRNAs and messenger RNAs (mRNAs) in the duodenum between the DJB and sham groups, and the result was validated by quantitative real-time polymerase chain reaction in another cohort of animals. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the potential lncRNA functions. Based on Pearson correlation analysis, the lncRNA-mRNA and lncRNA-transcription factor (TF) interaction networks were constructed to identify and rank core regulatory lncRNAs and transcription factors. A total of 301 lncRNAs, including 232 that were upregulated and 69 downregulated (fold change≥2.0), were differentially expressed in the duodenum between the DJB and sham groups. GO enrichment indicated that these lncRNA-coexpressed mRNAs were correlated with biological processes including cell proliferation, digestion, and catabolic and biosynthetic processes. KEGG pathway analysis revealed that in addition to the digestion and absorption signaling pathways, pancreatic secretion- and inflammatory process-related signaling pathways were mostly enriched in the DJB group. In addition, the lncRNA-mRNA interaction network combined with GO and KEGG pathway analysis suggested that as a top-ranked gene, NONMMUG021726 may play an important role in the mechanism of type 2 diabetes remission after DJB. DJB leads to drastic changes in lncRNA and mRNA expressions in the duodenum. The majority of top-ranked lncRNAs and mRNAs have roles in pancreatic secretion and inflammatory processes, implying that bypass of the duodenum may initiate insulin secretion and attenuate inflammation. In addition, modulators of such lncRNAs, most likely NONMMUG021726, have potential to become therapeutic targets or biomarkers for prediction of the outcomes of bariatric surgery.

Liang Y ，Yu B ，Wang Y ，Qiao Z ，Cao T ，Zhang P ... -  《-》

Jejunal long noncoding RNAs are associated with glycemic control via gut-brain axis after bariatric surgery in diabetic mice.

Metabolic and bariatric surgery is effective in ameliorating type 2 diabetes, although its underlying mechanisms are largely unknown. Our previous study indicated that the distinctly expressed duodenal long noncoding RNAs (lncRNAs) induced by the duodenal-jejunal bypass (DJB) might play a role in improving glycemic control via the enteropancreatic axis. Therefore, the physiologic role of the jejunum in metabolic regulation after DJB requires investigation. To investigate the alterations in the jejunal Roux limb lncRNA expression signatures after DJB and analyze the functional pathways associated with metabolic improvement on a genome-wide scale in high-fat diet-induced diabetic mice. University medical center. Diabetic mice induced by high-fat diet were randomly assigned into 2 groups undergoing either DJB or sham surgery. The lncRNA and messenger (m)RNA expression profiles of the Roux limb segment of the jejunum in both groups were investigated using microarray. To identify the functional characteristics of the distinctly expressed lncRNAs, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted. The lncRNA-mRNA and lncRNA-transcription factor interaction networks were constructed based on Pearson correlation analysis. Compared with the sham group, 827 dysregulated (fold change ≥2.0) jejunal lncRNAs were identified in the DJB group. Both Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology enrichment analysis revealed that 601 lncRNA-co-expressed mRNAs (fold change ≥2.0) were associated with neuromodulation-related pathways or biological processes, including serotonergic, glutamatergic, and dopaminergic synapses. In addition, hormonal regulation-related pathways, especially steroid biosynthesis, were also enriched. The results were further confirmed by bioinformatic analysis of target genes or transcription factors predicted on the basis of dysregulated jejunal lncRNAs. Furthermore, the NONMMUT023781 lncRNA may simultaneously target the Adcy8 mRNA both in cis and in trans and participate in neuromodulation and hormonal regulation. Alterations of jejunal Roux limb lncRNA and mRNA expression profiles trigger both neuromodulation and endocrine-related pathways, which play a critical role in type 2 diabetes remission after metabolic and bariatric surgery via the gut-brain axis. NONMMTU023781 and Adcy8 were identified as potential targets, which warrant further research.

Liang Y ，Yu B ，Wang Y ，Qiao Z ，Cao T ，Zhang P ... -  《-》

Duodenal-jejunal bypass attenuates progressive failure of pancreatic islets in streptozotocin-induced diabetic rats.

Preservation of pancreatic beta cell function has been increasingly appealing in the treatment of type 2 diabetes. Evidence is still limited on how bariatric surgery affects pancreatic beta cell apoptosis. University medical center. The study aimed to investigate the effect of a major component of Roux-en-Y gastric bypass, duodenal-jejunal bypass, on protecting pancreatic beta cells from progressive loss. Forty-five normal Sprague-Dawley rats were randomly assigned into 3 groups: duodenal-jejunal bypass (DJB) group (n = 16) and sham (S) group (n = 17), based upon the procedure received, and a control (C) group (n = 12) without any procedure performed, to eliminate potential traumatic effects from surgery. Ten days after surgery, streptozotocin (STZ, 45 mg/kg weight) was injected intraperitoneally into each animal, including the control animals, to selectively induce pancreatic beta cell apoptosis. Weight, food intake, plasma glucose level, and the results of an oral glucose tolerance test were measured before surgery, pre-STZ injection, and up to 4 weeks after STZ injection. Plasma insulin and glucagon-like peptide-1 levels were also assayed during oral glucose tolerance test. At the end, pancreatic tissues were sliced and stained for beta cell analysis. There were no significant differences in weight among all groups at any time points measured, despite rats in the S and C groups consuming more food than those in the DJB group as measured on day 10 (P<.05) and day 20 (P<.01) after STZ injection. Animals undergoing DJB did not experience symptoms typical of uncompensated diabetes, including hyperphagia and progressive weight loss. After STZ injection, fasting plasma glucose levels in the DJB group were significantly lower than those in the C and S groups (P<.001). When challenged by glucose load, DJB rats also had a better glycemic excursion (P<.01) and incretin response compared with C and S rats (P<.05). In addition, pancreatic beta cell size and mass was better preserved in DJB rats (P< .001). DJB is able to protect pancreatic beta cells from apoptosis, which leads to better glycemic control and delayed onset of diabetes. These results imply the necessity of including a DJB component when designing bariatric procedure to achieve a better long-term outcome.

Wang T ，Zhang P ，Zhang X ，Cao T ，Zheng C ，Yu B ... -  《-》

Aberrant expression of long noncoding RNAs in early diabetic retinopathy.

Yan B ，Tao ZF ，Li XM ，Zhang H ，Yao J ，Jiang Q ... -  《-》

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats.

The mechanisms underlying diabetes remission after duodenal-jejunal bypass (DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids (BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB. To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1. Twenty diabetic rats were randomly allocated to the sham (n = 10) and DJB (n = 10) groups. Body weight, food intake, fasting blood glucose (FBG), serum and intraduodenal total BA (TBA) levels were measured accordingly. Oral glucose tolerance test (OGTT) and intraperitoneal pyruvate tolerance test (ipPTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor (FXR), small heterodimer partner (SHP), and Takeda G-protein-coupled receptor 5 (TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK (p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes. The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ipPTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated mRNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the mRNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells. DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.

Han HF ，Liu SZ ，Zhang X ，Wei M ，Huang X ，Yu WB ... -  《-》