Katsuda Yoshiaki, Sasase Tomohiko, Tadaki Hironobu, Mera Yasuko, Motohashi Yu, Kemmochi Yusuke, Toyoda Kaoru, Kakimoto Kochi, Kume Shinichi, Ohta Takeshi
Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Exp Anim. 2015;64(2):161-9. doi: 10.1538/expanim.14-0084. Epub 2015 Jan 22.
The spontaneously diabetic torii (SDT) fatty rat is a new model of type 2 diabetes showing overt obesity, hyperglycemia and hyperlipidemia. With early onset of diabetes mellitus, diabetic microvascular complications, including nephropathy, peripheral neuropathy and retinopathy, are observed at young ages. In the present study, blood glucose levels of female SDT fatty rats were controlled with phlorizin, a non-selective SGLT inhibitor, to examine whether and how these complications are caused by hyperglycemia. Phlorizin treatment adequately controlled plasma glucose levels during the experiment. At 29 weeks of age, urinary albumin excretion considerably increased in SDT fatty rats. Glomerulosclerosis and tubular pathological findings also indicate diabetic nephropathy. These renal parameters tended to decrease with phlorizin; however, effects were partial. Sciatic nerve conduction velocities were significantly delayed in SDT fatty rats compared with Sprague-Dawley (SD) rats. Intraepidermal nerve fiber density, an indicator of subclinical small nerve fiber neuropathy, significantly decreased in SDT fatty rats. Retinal dysfunction (prolongation of peak latency for oscillatory potential in electroretinograms) and histopathological eye abnormalities, including retinal folding and mature cataracts were also observed. Both nerve and eye disorders were prevented with phlorizin. These findings indicate that severe hyperglycemia mainly causes diabetic complications in SDT fatty rats. However, other factors, such as hyperlipidemia and hypertension, may affect diabetic nephropathy. These characteristics of diabetic complications will become helpful in evaluating new drugs for diabetic complications using SDT fatty rats.
自发性糖尿病托里（SDT）肥胖大鼠是一种2型糖尿病新模型，表现为明显肥胖、高血糖和高血脂。随着糖尿病的早期发作，在幼年时即可观察到糖尿病微血管并发症，包括肾病、周围神经病变和视网膜病变。在本研究中，用非选择性钠-葡萄糖协同转运蛋白（SGLT）抑制剂根皮苷控制雌性SDT肥胖大鼠的血糖水平，以研究这些并发症是否以及如何由高血糖引起。根皮苷治疗在实验期间充分控制了血浆葡萄糖水平。在29周龄时，SDT肥胖大鼠的尿白蛋白排泄量显著增加。肾小球硬化和肾小管病理表现也提示糖尿病肾病。这些肾脏参数随根皮苷治疗有下降趋势，但效果不完全。与Sprague-Dawley（SD）大鼠相比，SDT肥胖大鼠的坐骨神经传导速度明显延迟。表皮内神经纤维密度作为亚临床小神经纤维病变的指标，在SDT肥胖大鼠中显著降低。还观察到视网膜功能障碍（视网膜电图振荡电位的峰潜伏期延长）和组织病理学眼部异常，包括视网膜折叠和成熟白内障。根皮苷可预防神经和眼部疾病。这些发现表明，严重高血糖主要导致SDT肥胖大鼠的糖尿病并发症。然而，其他因素，如高血脂和高血压，可能影响糖尿病肾病。糖尿病并发症的这些特征将有助于使用SDT肥胖大鼠评估治疗糖尿病并发症的新药。
