Spontaneously Diabetic Torii Research Articles

Diabetic Nephropathy in Spontaneously Diabetic Torii (SDT) Rats

Diabetic nephropathy is a serious complication of diabetes mellitus, making it essential to develop animal models of diabetic complications to simulate the pathogenesis in humans. We monitored pathobiochemical parameters and histopathological findings of kidneys in male Spontaneously Diabetic Torii (SDT) rats. Renal-related parameters in SDT rats have deteriorated with the progress of diabetes mellitus, and histopathological changes in the renal tubules and the glomeruli were observed with aging. Glycemic control in SDT rats prevented the development of renal lesions. The features of SDT rat indicate its usefulness as an animal model for investigating diabetic nephropathy.

Aldose Reductase Inhibitor Fidarestat Prevents Diabetic Ocular Complications in Spontaneously Diabetic Torii Rats

We evaluated the effect of an aldose reductase inhibitor, fidarestat, on diabetic retinopathy (DR) and cataract in spontaneously diabetic Torii (SDT) rats. Four rat groups were included: untreated, low- and high-dose (8 and 32 mg/kg/day) fidarestat-treated SDT rats, and nondiabetic control Sprague-Dawley rats. DR and cataract were evaluated and retinal and lens sorbitol, reduced glutathione (GSH), ocular fluid vascular endothelial growth factor (VEGF), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured. The incidence rates of DR and cataract were significantly lower in the low- and high-dose fidarestat groups vs the untreated group (p<0.001/p<0.001). Retinal and lens sorbitol levels were lower in the control (1.1±0.1/3.1±0.2 nmol/mg protein) (p<0.05/p<0.01) and low- (2.7±1.1/30.0±3.3 nmol/mg protein) (p<0.01/p<0.01) and high-dose groups (0.7±0.2/5.9±0.6 nmol/mg protein) (p<0.001/p<0.001) vs the untreated group (23.2±4.7/123.9±29.6 nmol/mg protein). Retinal and lens GSH levels were higher in the nondiabetic control (52.2±5.8/29.0±2.7 � mol/mg protein) (p<0.01/p<0.001) and the low- (46.8±8.2/24.7±2.8 � mol/mg protein) (not significant (NS)/p<0.001) and high-dose groups (63.3±14.6/26.9±3.6 � mol/mg protein) (p<0.05/p<0.001) vs the untreated group (30.3±2.0/1.6±0.4 � mol/mg protein). VEGF levels were lower in the nondiabetic control (40.4±10.0 pg/ml) (p<0.01) and low- (65.3±4.5 pg/ml) (p<0.05) and high-dose groups (47.7±10 pg/ml) (p<0.001) vs the untreated group (324.7±76.4 pg/ml). 8-OHdG levels were lower in the nondiabetic control (0.73±0.11 ng/mg creatinine) (p<0.01) and low- (4.57±0.42 ng/mg creatinine) (NS) and high-dose groups (3.58±0.70 ng/mg creatinine) (NS) vs the untreated group (6.04±1.28 ng/ml). Fidarestat inhibited activation of the polyol pathway, reduced oxidative stress and VEGF, and prevented DR and cataract in SDT rats.

Glucose and Lipid Metabolism in Spontaneously Diabetic Torii Rat

The impairment of glucose metabolism may lead to type 2 diabetes and the malfunction of lipid metabolism contributing to metabolic syndrome, which increases risk of heart disease, vascular disease, and type 2 diabetes. Our previous study provided evidence for involvement of hepatic glucose metabolic disorder in onset and progress of diabetes in Spontaneously Diabetic Torii (SDT) rats. As it is increasingly important to elucidate the mechanism of onset of diabetes and to develop drugs to prevent diabetic pathological progress, SDT rat should offer a highly useful model of spontaneous diabetic onset for such studies. In addition, abnormality in triglyceride (TG) absorption and impaired lipid catabolism antecedent to hypoinsulinemia/hyperglycemia seem to cause postprandial hypertriglyceridemia in SDT rat; hence, the characteristics of lipid metabolism in SDT rat can be useful in studies of diabetic hypertriglyceridemia and TG metabolism.

Characteristics of Diabetes in the SDT Rat

The Spontaneously Diabetic Torii (SDT) rat is a useful animal model of type 2 diabetes mellitus without obesity. The diabetes in this model manifests as severe hyperglycemia and hypoinsulinemia. However, insulin treatment is not required for survival despite marked hyperglycemia. Pancreatic islets display unique pathologic changes such as hemorrhage and fibrosis before the onset of hyperglycemia as well as marked atrophy. Islet injury is associated with macrophage infiltration of the islets and excess production of nitric oxide. Impaired glucose tolerance results from impaired insulin secretion following by decrease in beta cell mass and glucose-stimulated insulin release from beta cells. Beta cells in these animals have low insulin-secreting capacity in response to glucose stimulation, but retain normal responses to sulfonylurea and incretin. Although insulin resistance is less presented by body composition without obesity, the SDT rat has the potential contributions of hepatic insulin resistance and low energy expenditure to the development of diabetes. This article provides an overview of the pathologic features of pancreatic islets such as beta cell function and possible insulin resistance in SDT rats.

Gene Therapy for Diabetic Retinopathy in Animal Models and Humans

Gene therapy is considered as one of the innovative treatment modalities for diabetic retinopathy (DR). Since genuine animal models of DR are limited, only a few studies have reported the efficacy of gene therapy. For preclinical study of DR, spontaneously diabetic Torii (SDT) rat is a valuable model. Fortunately, we could evaluate the efficacy of adeno-associated virus (AAV)-mediated gene therapy in SDT rats and proved that sFlt-1 expression prevented DR progression. Because of a limited number of large-animal models of DR, it is uncertain whether gene therapy experiments using dogs or monkeys allow reliable conclusions. On the other hand, owing to the recent progress in AAV-mediated gene therapy for retinal diseases in monkeys and humans, gene therapy for DR using AAV vectors may become a reality in the near future.

Diabetic Ocular Complications in the SDT Rat

The purpose of the current article was to describe the diabetic ocular complications in a new animal model of diabetes, the Spontaneously Diabetic Torii (SDT) rat. Three major diabetic ocular complications, cataract, diabetic retinopathy (DR), and neovascular glaucoma develop in the SDT rat. The cataract develops to maturity, and DR develops to the advanced stage. Large retinal folds mimicking a tractional retinal detachment with extensive fluorescein leakage around the optic disc are the most characteristic finding of DR in this rat. In some rats, neovascular glaucoma develops with a massive hemorrhage in the anterior chamber associated with neovascular fibrous membranes around the iris. Although there are some differences in the diabetic ocular complications between SDT rats and human patients with diabetes, the SDT rat model is useful for studying diabetic ocular complications.

Effects of Topical Nipradilol on Early Diabetic Retinopathy in SDT Rats

We tested the effect of topical nipradilol, an antiglaucoma drug with α- and β-blocker and nitric oxide (NO) donor activities, on the early retinal changes using electron microscopy in Spontaneously Diabetic Torii (SDT) rats. In seven young male SDT rats (17 to 18 weeks old), nipradilol solution was instilled in the right eyes and nipradilol-free base solution in the left eyes three times daily for 3 months. All rats were sacrificed and both eyes were enucleated for electron microscopy at the end of the experiments. All rats had blood glucose levels exceeding 350 mg/dl within 2 weeks after the beginning of the experiment (mean final blood glucose level, 558±100.2 mg/dl). In untreated eyes of young SDT rats, the overall pathological features were almost comparable to those in older SDT rats, although the pinocytotic vesicles and free ribosomes were not as remarkable in the latter. In contrast, in nipradilol-treated eyes of SDT rats, although the basement membrane was thickened, microvilli were seen, and a larger number of electron-dense mitochondria were in the wide cytoplasm. Lipofuscin-like electron-dense granules and lamellated myelin figures also were identified. Nipradilol reduced the early morphologic changes in the endothelial cells, which reflects the metabolically active state of diabetic retinopathy in SDT rats through its action as a NO donor.

Prevention of Proliferative Diabetic Retinopathy and Cataract in SDT Rats with Aminoguanidine, an Anti-Advanced Glycation End Product Agent

Advanced glycation end products (AGEs) play important roles in the development of ocular complications in diabetes mellitus. Spontaneously Diabetic Torii (SDT) rats have marked hyperglycemia and severe ocular complications. We evaluated the effect of anti-AGE agents, aminoguanidine and pyridoxamine, and an antioxidant, probucol, on the development of diabetic retinopathy (DR) and cataract in SDT rats. Experiment 1 included five SDT rats treated with aminoguanidine, four SDT rats treated with probucol, and four untreated control SDT rats. After age 55 weeks, we evaluated DR by fluorescein angiomicroscopy and pathological study and cataract by biomicroscopy. Experiment 2 included six SDT rats treated with pyridoxamine, and six SDT rats and 10 non-diabetic normal Sprague-Dawley (SD) rats not treated with pyridoxamine. Retinopathy and cataract were evaluated as in experiment 1. Urinary pentosidine and Maillard reaction product X (MRX) levels were measured for 40 weeks in each group. Experiment 1: Mature cataracts and DR developed in all untreated SDT rats; aminoguanidine prevented cataracts and DR (p<0.05, vs untreated SDT rats). Probucol had no effect. Experiment 2: Mature cataracts developed in all untreated SDT rats (p<0.001 vs normal SD rats [0/10]) and DR developed in 67% (p<0.01, vs normal SD rats [0/10, 0%]). Pyridoxamine did not prevent cataracts (6/6, 100􀀃) or DR (4/6, 37%) (nonsignificant vs untreated SDT rats) in SDT rats. Urinary pentosidine levels were higher in untreated (0.12±0.07 μg/mg􀀂Cre) and pyridoxamine-treated (0.12±0.05 μg/mg􀀂Cre) SDT rats than normal SD rats (0.069±0.019 μg/mg􀀂Cre), but not significantly so. Urinary MRX levels were significantly (p<0.01) lower in normal SD rats (17.5±9.6 μg/mg􀀂Cre) compared with untreated SDT rats (163.0±107.0 μg/mg􀀂Cre); pyridoxamine had no effect (149.0±66.5 μg/mg􀀂Cre) (nonsignificant vs untreated SDT rats). Aminoguanidine but not pyridoxamine and probucol prevents DR and cataracts in SDT rats.

Establishment and Clinical Features in Spontaneously Diabetic Torii Rat

The Spontaneously Diabetic Torii (SDT) rat is a spontaneous animal model of non-obese Type 2 diabetes (T2D) resembling those of humans, established in 1997. I investigated the clinical features of the SDT rats. The time of onset of glucosuria was different between male and female SDT rats; glucosuria appeared at approximately 20 weeks of age in male rats and at approximately 45 weeks of age in female rats. A cumulative incidence of diabetes of 100% was noted by 40 weeks of age in male rats, while it was only 33.3% even by 65 weeks of age in female rats. The survival rate up to 65 weeks of age was 92.9% in male rats and 97.4% in female rats. The male SDT rats were (1) hyperglycemia and hypoinsulinemia (from 25 weeks of age); (2) a significant increase in urea nitrogen levels, urinary protein excretion and HbA1c levels (from 35 weeks of age); (3) long-term survival without insulin treatment after onset of diabetes; additionally, no obesity was noted in any of the male and female rats. These results indicated that the SDT rat strain described here would serve as useful animal model for studies of non-obese T2D.

Diabetic Neuropathy in Spontaneously Diabetic Torii Rat

To aid in the study of diabetes and its complications, many diabetic animal models have been reported. Although most diabetic patients suffer type 2 diabetes, studies using type 2 diabetic animal models have been carried out less frequently. Spontaneously Diabetic Torii (SDT) rat, a non-obese type 2 diabetes model, shows neuropathies and severe ocular complications. Decreased nerve conduction velocity and thermal hypoalgesia were improved by insulin treatment, indicating that the peripheral neuropathies in SDT rats are caused by sustained hyperglycemia. Autonomic nerve dysfunctions such as decreased coefficients of variance of R-R intervals (CVR-R) in electrocardiogram, functional gastrointestinal disorders, and voiding dysfunction are also observed in SDT rats. Therefore, SDT rat is a useful diabetic animal model for studies of diabetic neuropathies in type 2 diabetes and development of new drugs and therapies for diabetic neuropathies.

Diabetes induces expression of aquaporin-0 in the retinal nerve fibers of spontaneously diabetic Torii rats

Diabetes redistributes the expression of glial aquaporin (AQP) water channels in the retina. However, it is not known whether diabetes also affects retinal AQP-0 expression. This study examined the effects of the development of diabetes on the expression of retinal AQP-0 in spontaneously diabetic Torii (SDT) rats. Male SDT rats at 10 and 40 weeks of age and age-matched male Sprague-Dawley (SD) rats were used. The localization of AQP-0 was assessed immunohistochemically using sagittal cryosections of the rats’ retinas and optic nerves. Fold changes in AQP-0 gene expression relative to controls were assessed by real-time RT-PCR. All SDT rats spontaneously developed diabetes by 40 weeks of age (the mean hemoglobin (Hb) A1c levels were 2.8 ± 0.2% and 11.2 ± 1.0% at 10 and 40 weeks, respectively). SD rats did not develop diabetes (the HbA1c levels were 2.7 ± 0.2% and 2.6 ± 0.3% at 10 and 40 weeks, respectively). In the retinas of SD rats and in those of SDT rats at 10 weeks of age, immunoreactivity for AQP-0 was confined predominantly to the inner nuclear layer and to the border between the inner plexiform layer and the ganglion cell layer (GCL), where AQP-0 colocalized with protein kinase C-α. AQP-0 immunoreactivity was also observed in the GCL to a lesser degree, which colocalized with the neuronal nuclei. In the 40-week-old SDT rat retinas, additional AQP-0 immunoreactivity was observed in the GCL and colocalized with neurofilaments, indicating expression of AQP-0 in ganglion cell axons. However, the axonal AQP-0 immunoreactivity was restricted to the retinal nerve fibers, whereas the optic nerve axons were devoid of AQP-0. Retinal blood vessels did not express AQP-0. AQP-0 gene expression was 3.4-fold higher in SDT rat retinas than in SD rat retinas at 40 weeks of age. AQP-0 was predominantly expressed in the bipolar cells of the non-diabetic rat retinas, whereas it was also expressed in the retinal nerve fibers of diabetic rat retinas. The disrupted water transport between astrocytes and retinal nerve fibers may be associated with the known accelerated apoptosis of retinal ganglion cells induced by diabetes.

Changes in Glycolipid Metabolism During A High-Sucrose Feeding in Spontaneously Diabetic Torii (SDT) Rats, A Genetic Model of Nonobese Type 2 Diabetes

Changes in Glycolipid Metabolism During A High-Sucrose Feeding in Spontaneously Diabetic Torii (SDT) Rats, A Genetic Model of Nonobese Type 2 Diabetes

Effects of Food Restriction on Pancreatic Islets in Spontaneously Diabetic Torii Fatty Rats

The Spontaneously Diabetic Torii (SDT) fatty rat, established by introducing the fa allele of the Zucker fatty rat into the SDT rat genome, is a new model of obesity/type 2 diabetes. The present study investigated effects of food restriction on metabolic and endocrinological function in SDT fatty rats. SDT fatty rats were pair-fed with SDT rats from 7 to 21 weeks of age. The SDT fatty rats were already hyperinsulinemic and hyperlipidemic at 7 weeks of age. After 7 weeks of age, SDT fatty rats showed age-dependently increasing serum glucose levels associated with decreasing serum insulin levels. However, in pair-fed SDT fatty rats, hyperglycemia and hyperinsulinemia were attenuated at 9 weeks of age. After 9 weeks of age, the serum insulin levels unexpectedly increased in the pair-fed SDT fatty rats. Glucose tolerance was also improved, and the pancreatic insulin contents were increased in these rats. Pancreatic islets were hypertrophied in pair-fed SDT fatty rats compared with ad lib-fed SDT fatty rats, which were comparable to SDT rats. This study showed that, in SDT fatty rats, calorie restriction by paired-feeding with SDT rats attenuated hyperglycemia and hyperinsulinemia for the first 2 weeks. Thereafter, the serum insulin levels and pancreatic insulin contents were increased, though the restriction was continued. Hypertrophic pancreatic islets were also remarkable, indicating increased beta cell proliferation. The activated pancreatic beta cell functions might be due to rapid food ingestion, a change of feeding behavior resulting form increasing the fasting period, which was indispensable for calorie restriction.

A high-fat diet inhibits the progression of diabetes mellitus in type 2 diabetic rats

It is well known that rats and mice, when fed a high-fat diet, develop obesity associated with abnormal glycolipid metabolism. In this study, we investigated the effects of a high-fat diet on a diabetic rat model, Spontaneously Diabetic Torii (SDT), which develops diabetes due to decreased insulin production and secretion with age. We hypothesized that a high-fat diet would accelerate the induction of diabetes in this model. The SDT rats were divided into 2 groups, which were fed a high-fat diet or standard diet for 16 weeks. The group fed a high-fat diet developed obesity, hyperinsulinemia, and hyperlipidemia until 16 weeks of age. Before 16 weeks of age, hyperglycemia accompanied by hypoinsulinemia developed in the group on a standard diet, but serum glucose levels were comparable in both groups. After 16 weeks of age, the group on a standard diet showed an increase in serum glucose levels and a decrease in serum insulin levels. Unexpectedly, in the group on the high-fat diet, we observed a suppressed of the progression of hyperglycemia/hypoinsulinemia. Histopathological observation revealed more pancreatic beta cells in the group on the high-fat diet. This study suggests that feeding SDT rats a high-fat diet induces obesity, hyperinsulinemia, and hyperlipidemia, but not hyperglycemia, until 16 weeks of age. Thereafter, age-dependent progress of hyperglycemia and hypoinsulinemia was delayed by a high-fat diet. The hyperfunction of pancreatic beta cells induced by a high-fat diet before the onset of hyperglycemia appears to suppress development of hyperglycemia/hypoinsulinemia.

Oxidative and Nitrosative Stress and Progression of Diabetic Nephropathy in Type 2 Diabetes

Background: The role of nitric oxide (NO) is controversial in diabetes nephropathy progression and the mechanisms remain unknown, especially in non-obese type 2 diabetes. To examine mechanisms of nephropathy progression in non-obese type 2 diabetes, we used spontaneously diabetic Torii (SDT) rats, a newly established model of non-obese type 2 diabetes. Methods: Fourteen male Sprague-Dawley rats were used as a control (20 weeks, n = 6; 30 weeks, n = 8), and 20-week-old male SDT rats were divided into 2 groups: diabetic (DM, n = 8) and DM + insulin (n = 8) groups. Twenty- and 36-week-old rats were sacrificed, and blood, urine, and histomorphometric analyses, mRNA expression analysis of endothelial NO synthase (eNOS) and NADPH oxidase, and blood pressure measurement were performed. Results: At 36 weeks, NO metabolites, and 8-hydroxydeoxyguanosine (8-OHdG) were significantly higher in the diabetic group than in the other 2 groups. Further renal studies showed increased glomerular volume and mesangial area, and intensified eNOS, 8-OHdG, and nitrotyrosine immunostaining in the diabetic group. Oxidative and nitrosative stress were positively associated with increased glomerular volume and mesangial area, which were mostly recovered by insulin therapy. Conclusions: NO and oxidative stress increased in SDT rats, suggesting that these play key roles in nephropathy progression in non-obese type 2 diabetes.

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.

Protein kinase C beta inhibitor prevents diabetic peripheral neuropathy, but not histopathological abnormalities of retina in Spontaneously Diabetic Torii rat

Spontaneously Diabetic Torii (SDT) rat shows severe ocular complications such as tractional retinal detachment. In the present study, effect of protein kinase C beta (PKCbeta) inhibitor JTT-010 was evaluated to clarify the involvement of PKCbeta in complications of SDT rat. SDT rats were administered JTT-010 (10 or 50 mg/kg/day) for 48 weeks. SDT rats showed delayed oscillatory potentials in electroretinogram. Delayed motor nerve conduction velocity, decreased coefficients of variation of R-R intervals in electrocardiogram and thermal hypoalgesia were also observed. These functional disorders were prevented by administration of JTT-010. Abnormal retinal vascular was formed and the optic disc was protruded in SDT rat; however, JTT-010 did not prevent these hyperglycaemia-induced retinal abnormalities. These findings indicate that PKCbeta is intimately involved in diabetic complications; however, it seems that other factor(s) are primary contributors to histopathological abnormalities in retina. Therefore, PKCbeta inhibitors require concurrent administration of antihyperglycaemic drugs to achieve maximum effect on diabetic complications.

Altered expression of aquaporins 1 and 4 coincides with neurodegenerative events in retinas of spontaneously diabetic Torii rats

Evidence is mounting that not only microangiopathy, but also neurodegenerative events occur in the retinas of humans and rodents with early diabetes. Diverse pathologies are known to alter the amount and/or location of glial expression of the water-selective channels aquaporins (AQPs) 1 and 4. However, the temporal relationships among glial activation, the altered expression of the AQP proteins and neuronal death in the retinas of diabetic animals remains to be investigated. Male spontaneously diabetic Torii (SDT) rats reportedly develop diabetes by 40 weeks of age at the latest and manifest proliferative diabetic retinopathy at 50 weeks or later. This study compared temporal changes in neuroretinal apoptosis, glial fibrillary acidic protein (GFAP) expression and the expression of AQPs 1 and 4 between SDT rat retinas and age-matched Sprague–Dawley (SD) rat retinas. Cell death was detected by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling on retinal flatmounts and activated caspase 3 immunofluorescence of retinal cryosections. The expression of GFAP and AQPs 1 and 4 was assessed by immunohistochemistry of cryosections and retinal flatmounts. Diabetes started to develop around 15 weeks in SDT rats. Apoptotic cells in the ganglion cell layer and the inner nuclear layer were significantly more numerous in 40-week-old SDT rat retinas than in either age-matched SD rat retinas or 10-week-old SDT rats. GFAP immunoreactivity was confined to the nerve fiber layer both in SD and SDT rats at 10 weeks, whereas it spanned the whole retina in SDT rats, but not in SD rats, at 40 weeks. AQP1 was expressed in the outer retina, whereas AQP4 was expressed in the perivascular and end feet of Müller cells and astrocytes in the inner retina in the control SD rats and the SDT rats at 10 weeks. The perivascular AQPs shifted from AQP4 to AQP1 in 40-week-old SDT rats that exhibited marked hyperglycemia. Thus, the development of diabetes increases neuroretinal apoptosis, and this coincides with an altered expression pattern of GFAP and water-selective channels AQPs 1 and 4 in SDT rats.

P21: Unique histopathological characteristics of diabetic ocular lesions in both sexes of the Spontaneously Diabetic Torii (SDT) rat

The Spontaneously Diabetic Torii (SDT) rat is a novel rat model recently established for type 2 diabetes mellitus. The rats develop hyperglycemia (non-fasting plasma glucose level in males at 25 weeks: about 700 mg/dL) but can survive for long period of time without insulin therapy. The onset of diabetes is as early as 15 weeks of age in males and 40 weeks in females. The cumulative incidence of diabetes reaches 100% by 40 weeks of age in males, however, only 33% of female SDT rats develop diabetes by 65 weeks of age. To elucidate the histopathologic characteristics of the diabetic ocular lesions and the gender difference of the lesions, eyes of various ages from 23 SDT rats (twelve males of 39–70 weeks, mean, 63 weeks; eleven females 60–82 weeks, mean, 67 weeks) kept without any treatment were examined. Histopathologically, severe diabetic ocular lesions including cataracts (total incidence, 23/23:100%), rapture of the lens (57%), posterior vitreous detachment (83%), proliferative retinopathy (57%), tractional retinal detachment (74%) and iris neovascularization (83%) were observed in both sexes. In one case of 64-week-old male, a massive anterior chamber hemorrhage was observed. The onset of diabetes is about 6 months later in females, however, the diabetic ocular lesions were similar in females and males at ages over 60 weeks. Female SDT rats suffered from impaired glucose tolerance (IGT) as early as 25 weeks of age and over a long period of time of IGT in females may relate to the progressive development of the lesions. In conclusion, SDT rats of both sexes can develop similar ocular complications, which closely mimic morphologically those reported in diabetic patients. The SDT rats represent the first animal model for diabetic ocular complications.

Telmisartan, an angiotensin II type 1 receptor blocker, prevents the development of diabetes in male Spontaneously Diabetic Torii rats

To assess the beneficial effects of the angiotensin II type 1 receptor blocker telmisartan on a non-obese animal model of reduced function and mass of islet β-cells prior to the development of diabetes, Spontaneously Diabetic Torii (SDT) rats were treated with telmisartan at 8 weeks of age. At 24 weeks of age, the treatment with telmisartan dose-dependently ameliorated hyperglycemia and hypoinsulinemia, and high-dose (5 mg/kg/day) treated SDT rats did not developed diabetes. Real-time RT-PCR analysis revealed that treatment with high-dose telmisartan reduced mRNA expression of local renin–angiotensin system (RAS) components, components of NAD(P)H oxidase, transforming growth factor-β1 and vascular endothelial growth factor in the pancreas of male SDT rats. Immunohistochemical and Western blot analyses revealed that treatment with telmisartan also reduced expression of p47 phox. These results suggest that treatment with telmisartan reduces oxidative stress by local RAS activation and protects against islet β-cell damage and dysfunction. These findings provide at least a partial explanation for the reduced incidence of new-onset diabetes that has been observed in several clinical trials involving angiotensin II type 1 receptor blockers and ACE inhibitors.