Spontaneously Diabetic Torii Rats Research Articles

Crocodile Oil Disrupts Mitochondrial Homeostasis and Exacerbates Diabetic Kidney Injury in Spontaneously Diabetic Torii Rats.

Diabetic nephropathy is currently the leading cause of end-stage renal disease (ESRD) in type 2 diabetes. Studies have suggested that supplementation with some fatty acids might reduce the risk and delay the progression to ESRD in patient with chronic kidney disease. Crocodile oil (CO) contains a variety of fatty acids, especially omega-3, -6 and -9, that have been reported to be beneficial to human health. This study examined the impact of long-term CO supplementation on the development of diabetic nephropathy in spontaneously diabetic Torii (SDT) rats. After diabetic verification, SDT rats were assigned to receive vehicle or CO at 500 and 1000 mg/kg BW, respectively, by oral gavage. Age-matched nondiabetic Sprague–Dawley rats were given vehicle or high-dose CO. After 28 weeks of intervention, CO failed to improve hyperglycemia and pancreatic histopathological changes in SDT rats. Unexpectedly, CO dose-dependently exacerbated the impairment of kidney and mitochondrial functions caused by diabetes. CO also disturbed the expressions of proteins involved in mitochondrial biogenesis, dynamics, and mitophagy. However, no significant alterations were observed in nondiabetic rats receiving high-dose CO. The findings reveal that CO has deleterious effects that aggravate diabetic kidney injury via disrupting mitochondrial homeostasis, possibly due to its improper omega-6: omega-3 ratio.

Establishment of a new nonalcoholic steatohepatitis model; Ovariectomy exacerbates nonalcoholic steatohepatitis-like pathology in diabetic rats

An increasing number of patients worldwide are being diagnosed with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD/NASH) because of the growing prevalence of obesity and metabolic disorders. The incidence of NAFLD is higher in postmenopausal women than in premenopausal women. The decline in the level of female hormones might have an effect on the deterioration of metabolism.In the present study, we investigated the potential of Spontaneously Diabetic Torii (SDT) fatty rats as a new animal model for NAFLD. We created a menopausal model by ovariectomy (OVX) in female rats. Sprague-Dawley (SD) rats, SDT rats, and SDT-fatty rats were divided into sham and OVX groups and maintained until 40 weeks of age. The results showed that OVX-induced weight gain was observed in SD and SDT rats. In addition, OVX-induced hepatic triglyceride accumulation was increased in all strains, and there was a significant increase in hepatic triglyceride levels in OVX-SDT fatty rats compared to those in Sham-SD rats. Furthermore, liver fibrosis was worsened in the OVX-SDT fatty rats. In addition, OVX-induced increase in blood ALT level was observed in SDT-fatty rats. Gene expression analysis showed OVX-induced upregulation of Srebp1 expression and downregulation of Pemt and Mttp in OVX rats. These results indicate that OVX-SDT fatty rats exhibit NASH with more severe hepatic fibrosis than untreated animals, suggesting that OVX-induced estrogen reduction may have enhanced lipid synthesis in the liver. It is also possible, although hypothetical, that OVX may decrease VLDL secretion, which may more strongly induce NASH.

Immune disorders and sex differences in spontaneously diabetic Torii rats, type 2 diabetic model.

Type 2 diabetes (T2D) is believed to be a non-autoimmune metabolic disorder. However, there are increasing reports that some T2D patients have immune abnormalities. In addition, it is known that there are sex differences in the onset of diabetes and immune responses in humans. Spontaneously Diabetic Torii (SDT) rats, a non-obese T2D model, also have sex differences in the onset of diabetes, but the involvement of immune abnormalities in diabetes is unknown. In this study, we investigated immune abnormalities in SDT rats. Immune cell subset analysis was performed in male and female SDT rats and control Sprague-Dawley (SD) rats at 5, 11, and 17 weeks of age. Male and female SDT rats had swelling of the spleen and lymph nodes and a higher number of T cells and B cells in the blood, spleen, and lymph nodes than SD rats. Only male SDT rats developed diabetes at 17 weeks of age, and the number of classical and non-classical monocytes in the blood and spleen of male SDT rats was higher than that in male SD rats and female SDT rats that did not develop diabetes. Most of these findings were observed before the onset of diabetes (~11 weeks of age), suggesting that classical and non-classical monocytes may contribute to the development of diabetes in male SDT rats. In conclusion, SDT rats may be a useful T2D model involved in immune abnormalities, and further research will help elucidate the pathophysiology of T2D with immune abnormalities and develop new therapeutic agents.

Increased plasma drug concentration and decreased additional insulin secretion following oral administration of glimepiride in Spontaneously Diabetic Torii rats.

We aimed to evaluate the pharmacokinetics and pharmacological effects of glimepiride in the Spontaneously Diabetic Torii (SDT) rat, which is a non-obese model of type 2 diabetes. After oral administration of glimepiride (10 mg/kg), the maximum plasma concentrations and the area under the curve from 0 to 6 h of glimepiride in SDT rats were significantly higher than those in age-matched Sprague-Dawley rats. Whereas, additional insulin secretion following glimepiride treatment was markedly reduced in SDT rats. Thus, the SDT rat can be regarded as a model that reflects type 2 diabetes with reduced insulin secretory capacity. Our findings suggested that glimepiride could be ineffective in sever type 2 diabetic patients.

Pathophysiological features in the brains of female Spontaneously Diabetic Torii (SDT) fatty rats.

Diabetes mellitus (DM) and obesity are associated with neurodegenerative diseases such as Alzheimer’s disease and psychiatric disorders such as major depression. In this study, we investigated pathophysiological changes in the brains of female Spontaneously Diabetic Torii (SDT) fatty rats with diabetes and obesity. Brains of Sprague-Dawley (SD), SDT and SDT fatty rats were collected at 58 weeks of age. The parietal cortical thickness was measured and the number of pyramidal cells in the hippocampal cornu ammonis 1 and 3 (CA1 and CA3) and the number of granule cells in the dentate gyrus (DG) regions were counted. The area of glial fibrillary acidic protein (GFAP) positivity in CA1, CA3 and DG regions were measured. The parietal cortical thickness and the number of cells in CA3 and DG regions of SDT and SDT fatty rats did not show obvious changes. On the other hand, in the CA1 region, the number of cells in SDT rats and SDT fatty rats was significantly lower than that in SD rats, and that in SDT fatty rats was significantly lower than that in SDT rats. The GFAP-positive area in SDT fatty rats was significantly reduced compared to that in SD rats only in the DG region. Preliminarily result showed that the expression of S100a9, an inflammation-related gene, was increased in the brains of SDT fatty rats. These results suggest that female SDT fatty rat may exhibit central nervous system diseases due to obesity and DM.

Theaflavins prevent the onset of diabetes through ameliorating glucose tolerance mediated by promoted incretin secretion in spontaneous diabetic Torii rats

The in vivo anti-hyperglycemic effect of non-absorbable theaflavins, polyphenolic ingredients of black tea, was evaluated in spontaneously diabetic Torii (SDT) rats. A mixture of theaflavins (25 mg/kg/day) was administered to 8-week (wk)-old SDT rats for 20 weeks, showing to improve the impaired glucose tolerance of 22-wk old pre-diabetic SDT rats in both an oral glucose tolerance test and in a plasma insulin evaluation. At 28-wk diabetic SDT rats presented with increased fasting blood glucose levels (139 ± 23 mg/dL), and the intake of the theaflavins significantly (p < 0.05) reduced this effect (74 ± 11 mg/dL), demonstrating an anti-diabetic effect in vivo. The 20 week administration of theaflavins induced increased incretin secretion compared to that of the control, while there were no changes neither in dipeptidyl peptidase-IV activity nor glucose transporter expression. Collectively, these findings demonstrate that non-absorbable theaflavins exert anti-pre-diabetic and anti-diabetic effects by improving impaired insulin secretion.

Bilateral midbrain transection induced hyperphagia accelerates the development of diabetes in Spontaneously Diabetic Torii (SDT) rats

Spontaneously Diabetic Torii (SDT) rat is a model of severe type 2 diabetes and its complications. These characteristics of SDT rat are very useful to research diseases; however, the slow onset of diabetes may limit the usefulness of this animal model. To solve this problem, we performed bilateral midbrain transection on SDT rats and evaluated whether hyperphagia accelerates the onset of diabetes. By severing ascending fibers from the nucleus tractus solitarius to limbic regions through ventral and dorsal tegmental regions, food consumption was significantly increased in SDT rats and the onset of diabetes was accelerated. Cumulative incidence of diabetes in midbrain transected SDT rats was 88.9% at 7 weeks after surgery (14 weeks of age), while sham operated rats was 20.0%. Increased food consumption was correlated to body weight, plasma glucose level, plasma triglyceride level, and plasma insulin level. In conclusion, the overeating caused by blocking anorexigenic signal in brain significantly accelerates the onset of diabetes in SDT rats. The early development of type 2 diabetes may accelerate microvascular complications and is considered useful in the study of the disease in SDT rats.

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 (0.3mg/kg p.o.), was administered for 12weeks to SDT rats from 5 to 17weeks 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 14weeks of age. Based on the haematological and histological analyses performed at 17 to 18weeks 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.

Prolonged Hyperglycemia Reduces Elasticity of Type II Diabetic Rat Bone.

An increase in bone fracture risk has been reported in patients with diabetes. To evaluate an early effect of glucose intolerance on bone homeostasis, we have characterized bones from spontaneously diabetic torii (SDT) rats, an animal model of type 2 diabetes in comparison with Sprague Dawley (SD) rats as healthy control. Focusing on early effects of diabetes on bone elasticity, longitudinal wave velocities of animal bones were first determined by a micro-Brillouin scattering technique in a non-destructive way. Wave velocities in the cortical and cancellous bones in the tibias of the SDT and SD rats were compared. In a pre-diabetic stage at approximately 10weeks of age, there seems no significant difference in wave velocities in bones from age-matched SDT and SD rats. By contrast, after the onset of diabetes at approximately 20weeks of age, the mean velocities of bones from SDT rats were lower than those of SD rat. In addition, the X-ray CT showed that the bone amounts of SDT rats were smaller than those of SD rats in an early diabetic stage at 20weeks of age. The current study demonstrated that the wave velocity decreased in bones of SDT rats in the early stages of diabetes. While a decrease of bone strength in an early stage of diabetes can be partially explained from decreases in bone amount as well as bone elasticity, further studies will be needed in understanding a detailed mechanism of bone deterioration due to diabetes.

Enhancement of acetaminophen-induced chronic hepatotoxicity in spontaneously diabetic torii (SDT) rats.

Some patients encounter hepatotoxicity after repeated acetaminophen (APAP) dosing even at therapeutic doses. In the present study, we focused on the diabetic state as one of the suggested risk factors of drug-induced liver injury in humans and investigated the contribution of accelerated gluconeogenesis to the susceptibility to APAP-induced hepatotoxicity using an animal model of type 2 diabetes patients. Sprague-Dawley (SD) rats and spontaneously diabetic torii (SDT) rats were each given APAP at 0 mg/kg, 300 and 500 mg/kg for 35 days by oral gavage. Plasma and urinary glutathione-related metabolites, liver function parameters, and hepatic glutathione levels were compared between the non-APAP-treated SDT and SD rats and between the APAP-treated SDT and SD rats. Hepatic function parameters were not increased at either dose level in the APAP-treated SD rats, but were increased at both dose levels in the APAP-treated SDT rats. Increases in hepatic glutathione levels attributable to the treatment of APAP were noted only in the APAP-treated SD rats. There were differences in the profiles of plasma and urinary glutathione-related metabolites between the non-APAP-treated SD and SDT rats and the plasma/urinary endogenous metabolite profile after treatment with APAP in the SDT rats indicated that hepatic glutathione synthesis was decreased due to accelerated gluconeogenesis. In conclusion, SDT rats were more sensitive to APAP-induced chronic hepatotoxicity than SD rats and the high susceptibility of SDT rats was considered to be attributable to lowered hepatic glutathione levels induced by accelerated gluconeogenesis.

Hyperglycemia contributes to the development of Leydig cell hyperplasia in male Spontaneously Diabetic Torii rats.

Spontaneously Diabetic Torii (SDT) rats are a well-known animal model of non-obese type 2 diabetes mellitus. Although this animal model has been studied extensively over the last decade, the incidence rates of Leydig cell hyperplasia and tumors in this model have not been reported. In this study, pathophysiological analyses of the testes were performed on male SDT rats, to understand the effect of insulin treatment on the development of Leydig cell hyperplasia and tumors and the expression of integrins and extracellular matrix proteins. Testicular Leydig cell hyperplasia and tumors were observed in SDT rats at 64 weeks of age but were rarely identified in Sprague-Dawley (SD) rats of the same age. Insulin treatment decreased plasma glucose and HbA1c levels, and interestingly, decreased the number of hyperplastic Leydig cell foci and Leydig cell tumors in treated animals. A similar reduction in the expression of Ki67 in these Leydig cell foci was also observed. In addition, insulin treatment decreased the expression of integrin α5, integrin β1, integrin αvβ3, fibronectin, and vitronectin in hyperplastic Leydig cell foci. These results suggest that insulin might decrease the incidence of Leydig cell hyperplasia by reducing Leydig cell proliferation and the expression of integrins and extracellular matrix proteins through the reduction of serum glucose concentrations in these animals.

Pathological Features of Diabetic Retinopathy in Spontaneously Diabetic Torii Fatty Rats.

Objective The Spontaneously Diabetic Torii (SDT) fatty rat, established by introducing the fa allele (obesity gene) of the Zucker fatty rat into the SDT rat genome, is a new model of obese type 2 diabetes. We studied the pathologic features of diabetic retinopathy (DR) in this animal. Methods The eyes of SDT fatty, SDT (controls), and Sprague Dawley (SD) rats (normal controls) were enucleated at 8, 16, 24, 32, and 40 weeks of age (n = 5‐6 for each rat type at each age). The retinal thicknesses, numbers of retinal folds, and choroidal thicknesses were evaluated. Immunostaining for glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF) was performed. Quantitative analyses of the immunopositive regions were performed using a cell-counting algorithm. Results The retinas tended to be thicker in the SDT fatty rats and SDT rats than in the SD rats; the choroids tended to be thicker in the SDT fatty rats than in the SD rats. The retinal folds in the SDT fatty rats developed earlier and were more severe than in the SDT rats. Quantitative analyses showed that the GFAP- and VEGF-positive regions in the retinas of the SDT fatty rats were significantly larger than those of the SDT rats. Conclusions SDT fatty rats developed more severe DR earlier than the SDT rats. The SDT fatty rats might be useful as a type 2 diabetes animal model to study DR.

Ocular findings in Zucker Diabetic Fatty rats emphasize the key role of neuroglia degeneration in diabetic retinopathy pathophysiology.

Ocular findings in Zucker Diabetic Fatty rats emphasize the key role of neuroglia degeneration in diabetic retinopathy pathophysiology.

High fructose diet feeding accelerates diabetic nephropathy in Spontaneously Diabetic Torii (SDT) rats.

Diabetic nephropathy (DN) is one of the complications of diabetes and is now the most common cause of end-stage renal disease. Fructose is a simple carbohydrate that is present in fruits and honey and is used as a sweetener because of its sweet taste. Fructose has been reported to have the potential to progress diabetes and DN in humans even though fructose itself does not increase postprandial plasma glucose levels. In this study, we investigated the effects of high fructose intake on the kidney of the Spontaneously Diabetic Torii (SDT) rats which have renal lesions similar to those in DN patients and compared these with the effects in normal SD rats. This study revealed that a 4-week feeding of the high fructose diet increased urinary excretion of kidney injury makers for tubular injury and accelerated mainly renal tubular and interstitial lesions in the SDT rats but not in normal rats. The progression of the nephropathy in the SDT rats was considered to be related to increased internal uric acid and blood glucose levels due to the high fructose intake. In conclusion, high fructose intake exaggerated the renal lesions in the SDT rats probably due to effects on the tubules and interstitium through metabolic implications for uric acid and glucose.

Non-Obese Type 2 Diabetic Rat Models-GK Rat and SDT Rat

The number of diabetic patients has recently been increasing all over the world together with lifestyle changes including sedentary life and high-calorie diet intake, and as a result the increase in these suffering from diabetes mellitus has become a global issue. Diabetic animal models play a key role in bettering our understanding of the pathophysiology of diabetes and in developing new therapies for the disease. Diabetes is classified into two types, type 1 and type 2, and type 2 diabetes is chiefly caused by a depletion of insulin secretion in the pancreas and insulin resistance in peripheral tissues. The Goto-Kakizaki (GK) rat and the Spontaneously Diabetic Torii (SDT) rat are genetic non-obese type 2 diabetic models, and the both rats are considered to be suitable models for investigating the etiology of the depletion of insulin secretion and impaired glucose tolerance. In this review, we overviewed the outline of pathophysiological features in GK rats and SDT rats, including biological parameters and pharmacological responses.

Osteomeles schwerinae Extract Prevents Diabetes-Induced Renal Injury in Spontaneously Diabetic Torii Rats.

Mesangial cell proliferation contributes to the development of glomerulosclerosis in diabetic nephropathy. This study was aimed at determining whether Osteomeles schwerinae (OSSC) extract can ameliorate renal damage in Spontaneously Diabetic Torii (SDT) rats. OSSC extract (100 and 250 mg/kg/day) was administered to the SDT rats through oral gavage for 17 weeks. At the end of the experiment, glucose, HbA1c, and albuminuria were measured. In addition, the levels of mesangial proliferation-related proteins were determined by western blotting and immunohistochemistry. Our results show that albuminuria, accumulation of the extracellular matrix (ECM), and renal expansion were markedly restored by OSSC extract administration. The OSSC treatment also inhibited α-smooth muscle actin and transforming growth factor-β1 protein expression. In addition, OSSC and its bioactive compounds hyperoside and quercitrin inhibited the platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor-B receptor (PDGFR-β) ligand binding in an in vitro assay. Taken together, these results indicate that OSSC inhibits ECM accumulation and mesangial proliferation of the glomeruli in SDT rats through inhibition of the interaction between PDGF-BB and PDGFR-β. OSSC has ameliorating effects on the initiation and progression of diabetes complications and can be used for the treatment of early diabetic renal dysfunction.

Aster koraiensis extract prevents diabetes-induced retinal vascular dysfunction in spontaneously diabetic Torii rats

BackgroundAster koraiensis extract (AKE) is a standard dietary herbal supplement. The aim of this study is to investigate the inhibitory effects of AKE on diabetes-induced retinal vascular dysfunction in Spontaneously Diabetic Torii (SDT) rats.MethodsAKE (50 and 100 mg/kg body weight/day) was administered for 16 weeks. The effects of orally administered AKE on blood glucose levels, retinal vascular leakage, apoptosis, and accumulation of advanced glycation end products (AGEs) in the retina were evaluated.ResultsSDT rats exhibited hyperglycemia and retinal vascular leakage, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was clearly detected apoptosis in the retinal microvasculature. Immunofluorescence staining revealed the accumulation of AGEs in the retinal vasculature of the SDT rats. However, oral administration of AKE for 16 weeks blocked diabetes-induced blood–retinal barrier (BRB) breakdown and the loss of occludin, which is an important tight junction protein. Apoptosis of retinal vascular cells and AGE accumulation were significantly inhibited after AKE treatment.ConclusionThese results indicate that, as a dietary herbal supplement, AKE may have beneficial effects on patients with diabetic retinopathy.

Newly Developed Rat Model of Chronic Kidney Disease-Mineral Bone Disorder.

Aim: Chronic kidney disease–mineral bone disorder (CKD–MBD) is associated with all-cause and cardiovascular morbidity and mortality in patients with CKD. Thus, elucidating its pathophysiological mechanisms is essential for improving the prognosis. We evaluated characteristics of CKD–MBD in a newly developed CKD rat model.Methods: We used male Sprague–Dawley (SD) rats and spontaneously diabetic Torii (SDT) rats, which are used as models for nonobese type 2 diabetes. CKD was induced by 5/6 nephrectomy (Nx). At 10 weeks, the rats were classified into six groups and administered with a vehicle or a low- or high-dose paricalcitol thrice a week. At 20 weeks, the rats were sacrificed; blood and urinary biochemical analyses and histological analysis of the aorta were performed.Results: At 20 weeks, hemoglobin A1c (HbA1c) levels, blood pressure, and renal function were not significantly different among the six groups. Serum calcium and phosphate levels tended to be higher in SDT-Nx rats than in SD-Nx rats. The urinary excretion of calcium and phosphate was significantly greater in SDT-Nx rats than in SD-Nx rats. After administering paricalcitol, serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels were significantly higher in SDT-Nx rats than in SD-Nx rats. The degree of aortic calcification was significantly more severe and the aortic calcium content was significantly greater in SDT-Nx rats than in SD-Nx rats.Conclusions: We suggest that our new CKD rat model using SDT rats represents a useful CKD–MBD model, and this model was greatly influenced by paricalcitol administration. Further studies are needed to clarify the detailed mechanisms underlying this model.

Anti-prediabetic effect of rose hip (Rosa canina) extract in spontaneously diabetic Torii rats.

Prediabetes, a high-risk state for developing diabetes showing impaired glucose tolerance but a normal fasting blood glucose level, has an increasing prevalence worldwide. However, no study investigating the prevention of impaired glucose tolerance at the prediabetic stage by anti-diabetic functional foods has been reported. Thus, the present study aimed to evaluate the anti-prediabetic effect of rose hip in a prediabetic rat model. Spontaneously diabetic Torii (SDT) rats were supplemented with hot-water extract of rose hip at a dose of 100 mg kg-1 body weight day-1 for 12 weeks. The results obtained showed that the supplementation of rose hip extract improved impaired glucose tolerance, promoted insulin secretion, preserved pancreatic beta-cell function and suppressed plasma advanced glycation end-products formation of methylglyoxal-derived hydroimidazolone (MG-H1) residue and Nϵ -carboxymethyl-lysine residues (e.g. MG-H1, control: 465.5 ± 43.8 versus rose hip: 59.1 ± 13.0 pmol mg protein-1 , P < 0.05) in SDT rats at the prediabetic stage (12-20 weeks old). The present study provides the first evidence showing that a hot-water extract of rose hip could exert an anti-prediabetic effect in a rat model. © 2017 Society of Chemical Industry.

Diabetic Retinopathy in the Spontaneously Diabetic Torii Rat: Pathogenetic Mechanisms and Preventive Efficacy of Inhibiting the Urokinase-Type Plasminogen Activator Receptor System.

The spontaneously diabetic Torii (SDT) rat is of increasing preclinical interest because of its similarities to human type 2 diabetic retinopathy (DR). The system formed by urokinase-type plasminogen activator (uPA) and its receptor (uPAR) is a player in blood-retinal barrier (BRB) breakdown in DR. Here, we investigated whether in SDT rats, preventive administration of UPARANT, an inhibitor of the uPAR pathway, counteracts the retinal impairment in response to chronic hyperglycemia. Electroretinogram (ERG) monitoring was followed over time. Fluorescein-dextran microscopy, CD31 immunohistochemistry, quantitative PCR, ELISA, Evans blue perfusion, and Western blot were also used. UPARANT prevented ERG dysfunction, upregulation of vascular endothelial growth factor and fibroblast growth factor-2, BRB leakage, gliosis, and retinal cell death. The mechanisms underlying UPARANT benefits were studied comparing them with the acute streptozotocin (STZ) model in which UPARANT is known to inhibit DR signs. In SDT rats, but not in the STZ model, UPARANT downregulated the expression of uPAR and its membrane partners. In both models, UPARANT reduced the levels of transcription factors coupled to inflammation or inflammatory factors themselves. These findings may help to establish the uPAR system as putative target for the development of novel drugs that may prevent type 2 DR.