Pathophysiological Characteristics of Diabetic Ocular Complications in Spontaneously Diabetic Torii Rat

The Spontaneously Diabetic Torii (SDT) rat, a nonobese type 2 diabetes model, develops severe diabetic retinopathy as result of chronic severe hyperglycemia. Although existing diabetes animal models also develop ocular complications, severe retinal lesions frequently observed in human diabetes patients such as preretinal neovascularization or retinal detachment are not found. Distinctive features in SDT rat are hypermature cataract, tractional retinal detachment with fibrous proliferation, and massive hemorrhaging in the anterior chamber. These pathophysiological changes are caused by sustained hyperglycemic condition and subsequent increased expression of vascular endothelial growth factor (VEGF) in retina, iris, and ciliary body. Although some differences in diabetic retinopathy exist between SDT rats and humans (e.g., a low incidence of neovascular formation and poor development of nonperfused area are found in this animal), SDT rat will be a useful model in studies of the pathogenesis and treatment of diabetic retinopathy

Transient Receptor Potential Vanilloid (TRPV) channels: Basal Properties and physiological potential

Transient receptor potential vanilloid (TRPV) channels are TRP homologs and have been classified into six subfamilies. They are unique mediators of sensory signals with multiple physiological effects and are potential targets for developing new therapies targeting human diseases. TRPV channels play crucial roles in normal physiological processes, and their dysfunction has been implicated in various disease states. Several small-molecule compounds, such as TRPV1 and TRPV3 antagonists, have been developed as novel analgesic agents. A better understanding of the physiological functions of TRPV channels would lead to progress in life science. In this review, we focus on various functions of TRPV channels, including pain sensing, temperature sensing, and metabolic control, as well as summarize the basal properties and pathophysiological contributions of six TRPV channels. Moreover, we discuss the pharmacological effects of endogenous and exogenous ligands on TRPV channels and related diseases

Morphological analysis of the retina in salt-loaded KK-Ay mice, obese and type 2 diabetic model

Retinopathy, one of the microvascular complications in diabetes, can cause blindness. Salt-loading is known to exacerbate microvascular damage and may affect retinopathy. In this study, we investigated the effect of salt loading on early lesions of diabetic retinopathy. Male C57BL/6 and KK-Ay mice were salt-loaded with 1% sodium chloride (NaCl)-containing drinking water for 12 weeks. In addition, to determine the effects of high fat and high sucrose, a high fat/high sucrose diet was also fed to the 1% NaCl-loaded group of mice of both strains. Retinal thickness was measured at an arbitrary location from the optic nerve disc, and thinning of the retina was observed in KK-Ay mice compared to C57BL/6 mice. Salt-loading caused retinal thinning in C57BL/6 mice, but not in KK-Ay mice. In KK-Ay mice, the effect of salt-loading may have been masked by the effects of obesity and diabetic status during this experimental period. There was also a small effect of QF on the retina, suggesting that dietary components other than salt loading may affect retinopathy

Analysis of haemodynamics and angiogenic response to ischaemia in the obese type 2 diabetic model Spontaneously Diabetic Torii <i>Lepr^fa</i> (SDT fatty) rats

Peripheral artery disease (PAD) is defined as peripheral blood flow impairment, especially in the legs, caused by atherosclerotic stenosis. The disease decreases quality of life because of intermittent claudication or necrosis of the leg. The hindlimb ischaemia model, in which ischaemia is induced by femoral artery ligation, is often utilized as a PAD model. In the hindlimb ischaemia model, nonmetabolic syndrome animals are mainly used. In this study, we investigated the usefulness of Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a new model for obese type 2 diabetes, as a new PAD animal model. We found that hindlimb blood flow in SDT fatty rats was significantly lower than that in Sprague–Dawley (SD) rats under nonischaemic conditions. Furthermore, SDT fatty rats showed a significantly higher plasma nitrogen oxide level, shorter prothrombin time, and shorter activated partial thromboplastin time than SD rats. In addition, we found that the change in blood flow 7 days after induction of hindlimb ischaemia and the number of Von Willebrand factor‐positive vessels in gastrocnemius muscles were significantly lower in SDT fatty rats than in SD rats. These results suggest that excess production of reactive oxygen species and coagulation activation could be involved in lower blood flow in non‐ischaemic rats and that decreased angiogenesis could be involved in the poor recovery of blood flow in SDT fatty rats with hindlimb ischaemia. Taken together, our results suggest that SDT fatty rats might be useful as a new model for PAD with metabolic syndrome

The sphingosine-1-phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats

The sphingosine-1-phosphate (S1P) receptor modulator regulates lymphocyte trafficking, resulting in its depletion from circulation, which ultimately causes immunosuppression. In this study, we investigated the preventive effect of fingolimod (FTY720) in the non-obese type 2 diabetic model, Spontaneously Diabetic Torii (SDT) rats. The S1P receptor modulator, FTY720 (0.3 mg/kg p.o.), was administered for 12 weeks to SDT rats from 5 to 17 weeks of age. Based on our findings, FTY720 could suppress the incidence of diabetes in SDT rats. Further, glucose intolerance was improved in FTY720-treated SDT rats at 14 weeks of age. Based on the haematological and histological analyses performed at 17 to 18 weeks of age, a decrease in lymphocytes and monocytes in the peripheral blood and a decrease in lymphocyte and atrophy in spleen occurred in the FTY720-treated SDT rats. Furthermore, the pancreatic changes, such as inflammation, atrophy, and fibrosis in islets observed in SDT rats were improved by FTY720 treatment. These findings suggest that the immunomodulatory effects of FTY720 reduced the pancreatic lesion in SDT rats, thereby demonstrating its preventive effect against diabetes. The development of diabetes in SDT rats is related to disorders of the immune system. However, the S1P receptor modulator may be useful for treating type 2 diabetes

JTP-109192, a novel G protein-coupled receptor 119 agonist, prevents atherosclerosis by improving hypercholesterolemia in congenic spontaneously hyperlipidaemic mice

G protein‐coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L‐cells is a potential therapeutic target for the treatment of type 2 diabetes. Previously, we have reported that the GPR119 agonist JTP‐109192 improves glucose metabolism with single and repeated administration. Conversely, overexpression of the Gpr119 gene reportedly regulates cholesterol transporter expression in animal models, and a natural GPR119 agonist, oleoylethanolamide (OEA), improves atherosclerosis. Therefore, improving dyslipidaemia is considered a possible feature of GPR119 agonists. In the present study, the lipid‐lowering effect of JTP‐109192 was examined in BALB/c background spontaneously hyperlipidaemic (SHL) mice with repeated administration, once daily for 12 weeks. On repeated administration, JTP‐109192 revealed a cholesterol‐lowering effect and improved atherosclerosis following histopathological examination. With further investigation, the cholesterol‐lowering effect and subsequent antiatherosclerotic effect of JTP‐109192 was attributed to changes in intestinal cholesterol metabolism gene expression. Based on these results, JTP‐109192 represents a new potential antihypercholesterolaemic agent for the treatment of dyslipidaemia

Ocular Changes --Cataract And Retinal Lesion-- In Spontaneously Diabetic Torii (SDT) Fatty Rats, An Obese Type 2 Diabetic Model

Cataract and retinopathy remain the preventable cause of blindness worldwide, and many pharmacological strategies have been proposed for the treatment of these eye diseases. Animal models play an important role in understanding the pathophysiological features of eye disease and developing for a new therapy. In this study, we investigated the development of cataract and retinal lesion with diabetes using an obese type 2 diabetic models SDT fatty rat. Macroscopic analysis in eyes was performed from 16 to 24 weeks of age and histological analysis was performed at 24 weeks of age. As a result, the lens cloudiness was observed from 19 weeks of age and the degree of the cloudiness was more progressed until 24 weeks of age. Histopathological findings, such as degeneration of lens fiber and shortening and irregular arrangement of cone and rod in retinal tissue, were observed at 24 weeks of age. In conclusion, SDT fatty rats may be useful to understand the pathological features in diabetic cataract and retinopathy develop a new therapy for the disease