Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, Ohio; Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Surg Obes Relat Dis. 2020 Sep;16(9):1242-1248. doi: 10.1016/j.soard.2020.04.017. Epub 2020 Apr 24.
Diabetic nephropathy is the leading cause of chronic kidney disease. Observational studies suggest Roux-en-Y gastric bypass (RYGB) reduces progression of diabetic nephropathy.
To unravel the mechanisms by which RYGB is beneficial and protective for diabetic nephropathy.
Academic laboratories.
Forty-eight Zucker diabetic fatty rats were randomized to RYGB, sham surgery (SHAM), or pair-fed (PF) groups. An oral glucose tolerance test was performed at 25 days post intervention and kidneys were harvested at 30 days. Primary outcome measures included expression of key genes and proteins in the glucose transport, oxidative stress, inflammation, and fibrosis pathways.
Thirty days post intervention, RYGB rats weighed 349 ± 8 g, which was lower than SHAM (436 ± 14 g, P < .001), but not PF (374 ± 18 g) rats. RYGB rats had lower fasting glucose than PF animals and improved homeostatic model assessment of insulin resistance compared with PF and SHAM groups. These enhanced metabolic outcomes were accompanied by reduced sodium-glucose co-transporter 1 (Sglt1) gene expression (-23% versus PF, P = .01) in the kidney of RYGB rats. Expression of Sglt2, Glut1, or Glut2 mRNA, or oxidative stress and inflammation markers did not differ significantly. However, RYGB surgery induced a 19% lower expression of transforming growth factor (Tgfβ) mRNA (P = .004) compared with SHAM treated animals. Notably, adenosine monophosphate-activated protein kinase phosphorylation was increased (P = .04) in kidneys of the RYGB surgery animals.
Improvement of hyperglycemia after RYGB may reduce the glucose load on the kidney leading to a downregulation of specific glucose transporters. RYGB surgery may also attenuate kidney fibrosis through the adenosine monophosphate-activated protein kinase/TGFβ pathway.
糖尿病肾病是慢性肾脏病的主要病因。观察性研究表明，Roux-en-Y 胃旁路（RYGB）可减缓糖尿病肾病的进展。
阐明 RYGB 对糖尿病肾病有益和保护作用的机制。
学术实验室。
48 只 Zucker 糖尿病肥胖大鼠随机分为 RYGB 组、假手术（SHAM）组和等热量喂养（PF）组。干预后 25 天进行口服葡萄糖耐量试验，30 天采集肾脏。主要观察指标包括葡萄糖转运、氧化应激、炎症和纤维化途径中的关键基因和蛋白的表达。
干预 30 天后，RYGB 组大鼠体重为 349 ± 8 g，低于 SHAM 组（436 ± 14 g，P <.001），但与 PF 组（374 ± 18 g）大鼠无差异。RYGB 组大鼠的空腹血糖低于 PF 组动物，且与 PF 和 SHAM 组相比，其稳态模型评估的胰岛素抵抗得到改善。这些代谢改善的结果伴随着肾脏中钠-葡萄糖共转运蛋白 1（Sglt1）基因表达降低（与 PF 组相比降低 23%，P =.01）。Sglt2、Glut1 和 Glut2mRNA 的表达或氧化应激和炎症标志物无显著差异。然而，RYGB 手术诱导转化生长因子（Tgfβ）mRNA 表达降低 19%（与 SHAM 组相比，P =.004）。值得注意的是，RYGB 手术组肾脏中腺苷一磷酸激活蛋白激酶磷酸化增加（P =.04）。
RYGB 后高血糖的改善可能会降低肾脏的葡萄糖负荷，导致特定葡萄糖转运体的下调。RYGB 手术还可能通过腺苷一磷酸激活蛋白激酶/TGFβ 途径减轻肾脏纤维化。
