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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.

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.

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.

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.

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.

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.

Tumor necrosis factor-α (TNF-α) converting enzyme/a disintegrin and metalloproteinase domain-containing protein 17 (TACE/ADAM17) is a key sheddase that releases TNF-α from its inactive precursor and is thought as a new drug target to inhibit TNF-α production. In the present study, pharmacological effects of a novel TACE selective inhibitor, JTP-96193, on type 2 diabetes and diabetic peripheral neuropathy (DPN) as its major complication was examined. Enzyme inhibitory activity of JTP-96193 on TACE and other ADAMs was measured in in vitro. High fat-induced obese mice and type 2 diabetic KK-Ay mice were used to evaluate the effect of JTP-96193 on insulin resistance. Finally, streptozotocin (STZ)-induced diabetic mice were treated with JTP-96193 to evaluate the sciatic motor nerve conduction velocities (MNCV). JTP-96193 selectively inhibited human TACE activity with IC50 value of 5.4 nM and showed more than 1800-fold selectivity against other matrix metalloproteinases. In mouse models of obesity and diabetes, JTP-96193 reduced the TNF-α release from the fat tissue and prevented development of diabetes and improved insulin resistance, respectively. Furthermore, JTP-96193 prevented delay of sciatic MNCV without any effects on blood glucose or insulin levels in STZ-induced diabetic mice. TACE inhibitor is effective on insulin resistance and DPN independent from glucose-lowering effect. These pharmacological properties of JTP-96193 may be helpful to treat type 2 diabetes accompanied by its microvascular complications.

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.

Glomerular hyperfiltration is observed in an early stage of kidney diseases including diabetic nephropathy. A better understanding of pathophysiological changes in glomerular hyperfiltration is essential for development of new therapies to prevent kidney disease progression. In this study, we investigated glomerular changes including glomerular filtration rate (GFR) and glomerular size in the Spontaneously Diabetic Torii (SDT) fatty rat, an obese type 2 diabetic model, and we also evaluated pharmacological effects of the sodium glucose cotransporter 2 inhibitor dapagliflozin on the renal lesions. Dapagliflozin was administered to SDT fatty rats from 5 to 17 weeks of age. Blood and urinary biochemical parameters were periodically measured. GFR was determined by transdermal GFR monitor at 16 weeks of age and histopathological analysis was performed at 17 weeks of age. SDT fatty rat developed severe hyperglycemia and exhibited pathophysiological abnormalities in the kidney, such as an increased GFR, glomerular hypertrophy and tissue lesions. Dapagliflozin achieved good glycemic control during the experimental period, inhibited the increase in GFR, and improved histopathological abnormalities in tubules. These results suggest that the SDT fatty rat is a useful model for analyzing the pathogenesis of diabetic nephropathy during its early stage and dapagliflozin improves not only hyperglycemia but also glomerular hyperfiltration and tubule lesions in SDT fatty 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.

Introduction To establish an animal model for diabetic peripheral neuropathy (DPN) at an earlier stage, we performed functional and pathophysiological evaluations in Spontaneously Diabetic Torii (SDT) fatty rats before 16 weeks of age. Methods Male SDT fatty rats were treated with vehicle or phlorizin (100 to 150 mg/kg/day) from 5 to 16 weeks. Sprague-Dawley (SD) rats were used as age-matched controls. Body weights and biochemical parameters were measured over time. During the treatment period, the sensory and motor nerve conduction velocity (SNCV and MNCV) of the sciatic nerve, blood pressure, pupil size, and electrocardiograms were measured. At 16 weeks, the rats were sacrificed and sural nerves and intraepidermal nerves were sampled for histological studies, electron microscopic analysis and assessments of nerve fiber density. Results Functional abnormalities, such as delays of SNCV, increase of blood pressure, reduced pupillary reactivity, and decrease of the coefficient of variance of R-R intervals were observed in SDT fatty rats. Histopathologically, decreased intraepidermal nerve fiber density, mitochondrial abnormalities of small myelinated fibers, and vacuolation and mitochondrial swelling of unmyelinated fibers were found in SDT fatty rats. These changes were prevented by well-controlled blood glucose with phlorizin treatment. Discussion Male SDT fatty rats can help future work on DPN in diabetes with obesity, since this rat exhibited functional and pathological abnormalities in somatic and autonomic nerve from an early stage of diabetes.

Diabetic macular edema (DME) is a major factor contributing to visual disabilities in diabetic patients, and the number of patients is increasing. Animal models play a key role in the development of novel therapies. In this study, pathophysiological analyses of ocular lesions in Spontaneously Diabetic Torii (SDT) fatty rats were performed. First, vascular endothelial growth factor (VEGF) concentrations in vitreous humor, retinal vascular permeability and retinal thickness were measured in SDT fatty rats (Experiment 1). Furthermore, the pharmacological effects of two anti-diabetic drugs, phlorizin and pioglitazone, on retinal lesions were evaluated (Experiment 2). As results, the SDT fatty rats exhibited VEGF increase in vitreous humor at 8 and 16 weeks of age, and both retinal vascular hyperpermeability and retinal thickening at 16 weeks of age. In particular, the layers between the retinal internal limiting membrane and the outer nuclear layer were thickened. Phlorizin treatment from 4 to 16 weeks of age improved hyperglycemia and normalized retinal thickness; however, the effect of pioglitazone on retinal thickness was not strong despite the normalization of hyperglycemia. These data demonstrate that the male SDT fatty rat is a useful model for developing new therapeutic approaches in DME.

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.

Aims Spontaneously diabetic Torii (SDT) rats exhibit vascular abnormalities in pancreatic islets as the initial changes at pre-diabetes stage (8 weeks old), which is followed by β cell deterioration. In the present study, we investigated pathophysiological interactions between β cells and intra-islet microvasculature of SDT rats at pre- and peri-onset of diabetes. Methods SDT rats were treated with Habu snake venom (HSV) to assess its hemorrhagic effects in glomeruli and pancreatic islets. SDT rats were treated with streptozotocin (STZ) to assess acute β cell fragility toward cytotoxic insult and the late-stage consequence of β cell ablation in neighboring structures. The receptor tyrosine kinase inhibitor sunitinib was administered to SDT rats to examine its therapeutic effect. Results HSV administration at 5 weeks old induced severe hemorrhage in and around islets in SDT rats. By contrast, precedent β cell depletion using STZ ameliorated hemorrhage, inflammation, and fibrosis around the islets at 13 weeks old, which is normally seen in SDT rats of this age. Blockade of vascular endothelial growth factor (VEGF)-like activity attenuated HSV-induced hemorrhage in SDT islets. VEGF release from SDT islets was increased at 13 weeks old but not at 5 weeks old, while interleukin-1β release was increased as early as 5 weeks old. Sunitinib treatment started at 5 weeks of age inhibited the onset of intra-islet hemorrhage, β cell loss, and hyperglycemia in SDT rats. Conclusions Enhanced VEGF signaling in islets contributes to β cell injury, microvascular failure, and consequential diabetes in SDT rats.

We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group.Results. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment.Conclusions. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.

The Spontaneously Diabetic ToriiLeprfa(SDT fatty) rat is a novel type 2 diabetic model wherein both male and female rats develop glucose and lipid abnormalities from a young age. In this study, we investigated gender differences in abnormalities and related complications in SDT fatty rats. Food intake was higher in males compared to female rats; however, body weight was not different between genders. Progression of diabetes, including increases in blood glucose and declines in blood insulin, was observed earlier in male rats than in females, and diabetic grade was more critical in male rats. Blood lipids tended to increase in female rats. Gonadal dysfunction was observed in both male and female rats with aging. Microangiopathies, such as nephropathy, retinopathy, neuropathy, and osteoporosis, were seen in both genders, and pathological grade and progression were more significant in males. Qualitative and quantitative changes were observed for metabolic disease gender differences in SDT fatty rats. The SDT fatty rat is a useful model for researching gender differences in metabolic disorders and related diseases in diabetes with obesity.

Spontaneously Diabetic ToriiLeprfa(SDT fatty) rat, established by introducing thefaallele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications, such as nephropathy, retinopathy, and neuropathy, in SDT fatty rats were seen at younger ages compared to those in the SDT rats. In this paper, we overview pathophysiological features in SDT fatty rats and also describe new insights regarding the hematology, blood pressure, renal complications, and sexual dysfunction. The SDT fatty rats showed an increase of leukocytes, especially the monocyte count, prominent hypertension associated with salt drinking, end-stage renal disease with aging, and hypogonadism. Unlike other diabetic models, the characteristic of SDT fatty rat is to present an incidence of diabetes in females, hypertension, and retinopathy. SDT fatty rat is a useful model for analysis of various metabolic disorders and the evaluation of drugs related to metabolic disease.

Spontaneously Diabetic Torii (SDT) rat is a hereditary model of diabetes. Although the SDT rat shows severe diabetic complications, the onset of hyperglycemia is late. SDT fatty rat, established by introducing the fa allele of the Zucker fatty rat to SDT rat, develops diabetes much faster than SDT rat. In the present study, diabetic peripheral neuropathy (DPN) was evaluated to show the further usefulness of this animal model. Motor nerve conduction velocity (MNCV) was delayed, and the number of sural nerve fibers was decreased in SDT fatty rat. Treatment of pioglitazone lowered blood glucose level and prevented delay of MNCV in SDT fatty rats. SDT fatty rat is a useful animal model for studies of DPN in type 2 diabetes.

Nutritional regulation plays a critical role to reduce the incidence or progression of diabetes mellitus. In this study, we investigated the effects of a high-fat diet on Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a novel model for obese type 2 diabetes. The SDT fatty rats were divided into two dietary groups, which were fed a high-fat diet or a standard diet for 18 weeks, from 6 to 24 weeks of age. The calorie intake in the high-fat diet (HF) group was reduced after 10 weeks of age and the group inhibited an incidence of diabetes. Interestingly, the HF induced an increase of serum glucagon-like peptide-1 (GLP-1) levels in SDT fatty rats with refeeding. Fat tissue weights in the HF group increased, but the visceral fat/subcutaneous fat (V/S) ratio decreased. Moreover, histopathological observations revealed an improvement of the pancreatic abnormalities and fatty liver in the HF group. In conclusion, a preventive effect on diabetes in rats fed a high-fat diet has a relation with an increase in incretin hormone, and it might be advantageous for prevention of incidence or progression of diabetes to develop functional foods inducing an increase in incretin hormone.

Diabetic animal models play critical roles in the elucidation of the mechanisms of diabetes mellitus and the complications, and in the development of novel drugs as treatments. Spontaneously Diabetic Torii Lepr fa (SDT fatty) rat, established by introducing the fa allele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. We have investigated the characteristics of SDT fatty rats. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications in SDT fatty rats were seen at younger ages than those in the SDT rats. Furthermore, we evaluated the pharmacological effects of anti-diabetic drugs, such as metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitor on SDT fatty rats. SDT fatty rat is a useful model for analysis of metabolic disease and the evaluation of drugs related to metabolic disease.

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.

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.

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.

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.

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.

The Spontaneously Diabetic Torii (SDT) rat is a new model for non-obese type 2 diabetes. In the present study, we investigated changes in insulin secretion from the pancreas of male SDT rats aged 8, 16, and 24 weeks in order to analyze pancreatic function. An analysis of glucose-stimulated insulin secretion (GSIS) in isolated islets showed a marked reduction in insulin secretion in pre-diabetic 16-week-old SDT rats. When the islets were treated with tolbutamide or glucagon-like peptide-1 (7-36) amide (tGLP-1) in the presence of 11.2 mM glucose, however, insulin levels were restored to levels of normal rats. In vivo study, SDT rats exhibited a marked reduction in GSIS from 16 weeks of age. However, tolbutamide or JTP-76209, which is a novel dipeptidyl peptidase IV (DPP IV) inhibitor, increased insulin release after glucose loading and improved glucose tolerance. A marked reduction in GSIS was observed in pre-diabetic SDT rats and the reduction was improved by tolbutamide, tGLP-1, and the DPP IV inhibitor. Therefore, we concluded that the SDT rat is useful, as a model of non-obese insulin secretory disorder, for the analysis of the onset of type 2 diabetes and the development of antidiabetic agents.

The Spontaneously Diabetic Torii (SDT) rat has recently been established as a new model of non-obese type 2 diabetes. In this study, we examined changes in hepatic glucose metabolism in prediabetic and diabetic SDT rats compared with age-matched control rats. The prediabetic state was confirmed at 16 weeks of age, and the diabetic state was confirmed at 24 and 32 weeks of age. Decreases in glucokinase mRNA levels and activity were observed in the prediabetic state. In this state, glycogen synthase activity and glycogen content were also decreased in the SDT rat. In addition to the above changes, glycogen phosphorylase mRNA and activity were decreased and gluconeogenetic enzyme mRNA levels were significantly increased in the diabetic state. These results indicate there is a great potential that abnormalities in hepatic glucose metabolism play a role in the progression to onset of diabetes. We suggest that the SDT rat is a valuable diabetic model for investigations into mechanisms or causes of progression to diabetes.

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 obese type 2 diabetes. The SDT-fa/fa (SDT fatty) rat shows overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with the SDT-+/+ (SDT normal) rat. However, the features of the diabetic complications in the SDT fatty rat have not been reported. In the present study, the incidence and the progression of diabetic complications in the SDT fatty rat were examined, and compared with those of the SDT normal rat. Renal function parameters, such as blood urea nitrogen, urine volume and urinary protein, increased from 4 weeks of age in the SDT fatty rat, and pathological findings in the renal tubule were observed from 8 weeks. Furthermore, cataract was observed in the SDT fatty rat from 8 weeks of age, and prolongation of peak latencies on electroretinograms was observed at 16 and 24 weeks of age. On the other hand, in the SDT normal rat, renal or ocular changes were observed from 24 weeks of age. With early incidence of diabetes mellitus, diabetes-associated complications in the SDT fatty rat were seen at younger ages than those in the SDT normal rat. In conclusion, the SDT fatty rat is expected to be a useful model for the analysis of diabetic complications and the evaluation of drugs related to metabolic diseases.

In diabetes, postprandial hyperlipidemia is recognized as a risk factor for premature atherosclerosis and following cardiovascular disease. In the present study, features of fat absorption and clearance were examined to clarify the lipid metabolism of Spontaneously Diabetic Torii (SDT) rats. Olive oil was orally administered to evaluate increase of blood triglyceride (TG) level. Mesenteric lymph chylomicron TG was also measured. mRNAs of enzymes and transfer protein related to TG metabolism and histopathological changes were evaluated. In an oil loading test, elevation of TG in plasma and lymph chylomicron was increased in SDT rats. Interestingly, SDT rats showed elevation of plasma TG after oil loading and relatively low epididymal fat lipoprotein lipase (LPL) mRNA expression even at the pre-diabetic state without increase of TG absorption from intestine. In the diabetic state, intestines of SDT rats were hypertrophic and expressed mRNAs of enzymes and transfer protein related to TG absorption highly. From these results, it seems that intestinal abnormalities related to hypoinsulinemia/hyperglycemia cause postprandial hypertriglyceridemia in SDT rats. In addition, our findings suggest that SDT rats have impaired lipid catabolism antecedent to hypoinsulinemia/hyperglycemia. These characteristics of SDT rats can be useful in studies of diabetic hypertriglyceridemia and TG metabolism.

The spontaneously diabetic Torii (SDT) rat has recently been established as an animal model of non-obese type 2 diabetes, in which ocular complications severe occur. However, the function and morphological features of the diabetic renal lesions in SDT rats have not been reported in detail. Therefore, we evaluated changes over time in renal lesions in SDT rats. In addition, SDT rats were treated with insulin to observe whether these renal complications are caused by hyperglycemia. Renal functional parameters and renal lesions were monitored in SDT rats from 8 to 68 weeks of age. Sprague-Dawley (SD) rats of similar age were used as control animals. In the insulin-treated group of SDT rats, insulin pellets were implanted at 24 weeks of age to compare the development of renal lesions. The SDT rats began to develop hyperglycemia at 20 weeks of age. In the histopathological examination of the kidney, glycogen deposition of the renal tubular epithelium and renal tubular dilation were observed from 24 weeks of age in the untreated SDT rats, and the changes in the renal tubules markedly progressed with aging. Moreover, thickening of the glomerular basement membrane was observed from 32 weeks of age. At 50 weeks of age, the glomeruli showed increase of mesangial matrix, with predominantly diffuse lesions showing by 68 weeks of age. The mesangial proliferation gradually progressed. In the SD rats, no renal lesions were present at 50 and 68 weeks of age. SDT rats with insulin treatment remained normoglycemic throughout observation and their renal functional parameters were normal. Glycemic control in SDT rats prevented the development of renal lesions. The features of SDT rats indicate their usefulness as an animal model for investigating diabetic nephropathy.

AIM: To investigate the histological features of the liver in spontaneously diabetic Torii (SDT) fatty rats compared with age-matched Sprague-Dawley (SD) rats. METHODS: Female SDT Lepr[fa](SDT fatty) rats and age-matched SD rats were fed ad libitum . Body weight and biochemical parameters, such as serum glucose, triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels as well as fatty acid and TG accumulation in the liver were evaluated at 8 wk of age in the non-fasting state and at 8-wk intervals from 8 to 40 wk of age. Histopathological examinations of the liver were performed using hematoxylin and eosin and Sirius Red staining as well as double staining for ED-1 and toluidine blue. The expression of genes involved in TG synthesis, inflammation, and fibrosis was examined in the liver. RESULTS: SDT fatty rats showed significantly increased body weight compared with SD rats. Serum glucose, TG, and TC levels were significantly higher in SDT fatty rats compared with SD rats. The serum AST and ALT levels in SDT fatty rats were significantly elevated at 8 wk of age compared with the levels in SD rats. Hepatic TG content was marked in SDT fatty rats from 8 to 32 wk of age. Histopathologically, severe hepatosteatosis accompanied by inflammation was observed at 8 wk of age, and fibrosis started to occur at 32 wk of age. Furthermore, Sirius Red and ED-1 staining were increased in the liver at 32 wk of age. Hepatic gene expression related to TG synthesis, inflammation and fibrosis tended to increase in SDT fatty rats compared with SD rats, and the gene expression related to TG secretion was decreased in SDT fatty rats compared with SD rats. CONCLUSION: Female SDT fatty rats have the potential to become an important animal model of nonalcoholic steatohepatitis with type 2 diabetes and obesity.

Metabolic diseases, including diabetes (and its complications), obesity, dyslipidemia, and hypertension, are common diseases and frequently occur in combination. To study these diseases, many hereditary animal models have been reported, such as ob/ob mouse, db/db mouse, KK-Ay mouse, Goto-Kakizaki (GK) rat, Zucker diabetic fatty (ZDF) rat, Otsuka-Long-Evans-Tokushima-fatty (OLETF) rat, Spontaneously Diabetic Torii (SDT) rat, spontaneously hypertensive rat (SHR), Watanabe Heritable hyperlipidemic (WHHL) rabbit, and Postprandial hypertriglyceridemia (PHT) rabbit. Chemical (e.g., streptozotocin (STZ), alloxan) and diet-induced (e.g., high sucrose, high fat, high cholesterol) experimental animal models have been in general use for a long time, and genetically modified animals have also been used widely in recent decades. Although molecular biological techniques have become more important for clarifying the mechanisms of the diseases, the importance of animal models has not changed. Animal models are needed to reveal the underlying pathophysiology of metabolic diseases; this approach provides information that is the key to the development of new therapies and drugs to treat and manage these diseases. In this special issue, we aim to provide information on recent beneficial experimental animal models in this field and present up-to-date information on the pathophysiology, therapeutic drugs, and diagnosis of metabolic diseases using valuable animal models. We believe that the 14 articles in this special issue satisfy these aims. Type 2 diabetes (T2D) is a complex, multifactorial disease. Both genetic and environmental factors are known to contribute to its development; however, the precise pathogenesis of T2D remains largely unclear. In the present special issue, various spontaneous T2D rodent models are summarized in “Spontaneous type 2 diabetic rodent models” by Y.W. Wang et al. Several new animal models are introduced in this special issue. Three papers introduce new diabetic animal models, SDT rat and its derivative SDT fatty rat. The SDT rat, a nonobese T2D model, shows severe hyperglycemia accompanied with hypoinsulinemia. In the review article “The Spontaneously Diabetic Torii rat: an animal model of nonobese type 2 diabetes with severe diabetic complications” by T. Sasase et al., characteristics of diabetic complications in SDT rats, such as diabetic retinopathy, diabetic peripheral neuropathy, diabetic neuropathy, and osteoporosis, are described. Among these diabetic complications, ocular complications are notably a unique characteristic of this animal model. Using this model, A. Ota et al. evaluated ranirestat, a novel aldose reductase inhibitor that is currently in phase III clinical trial, on diabetic complications, and report their findings in “Effects of long-term treatment with ranirestat, a potent aldose reductase inhibitor, on diabetic cataract and neuropathy in Spontaneously Diabetic Torii rats.” The SDT fatty rat is an obese T2D model established by introducing the fa allele of Zucker fatty rat into the SDT rat genome. In the review article “Metabolic disorders and diabetic complications in Spontaneously Diabetic Torii Leprfa rat: a new obese type 2 diabetic model,” Y. Kemmochi et al. review the pathophysiological features of this animal model. In “A novel rat model of type 2 diabetes: the Zucker fatty diabetes mellitus ZFDM rat,” N. Yokoi et al. report the establishment and characteristics of ZFDM rat. This new T2D model is derived from the ZF rat, presents with hyperglycemia, and is phenotypically distinct from normoglycemic ZF rats. Loss of islet architecture and fibrosis are also observed in the ZFDM rat. This model is useful for investigating young- to middle-aged adult-onset T2D. T. Okamura et al. report the establishment and characteristics of Long-Evans Agouti (LEA) rat derived from Long-Evans (LE) strain, in “Phenotypic characterization of LEA rat: a new rat model of nonobese type 2 diabetes.” The LEA rat displays moderate hyperglycemia and glucose intolerance along with impaired insulin secretion that is caused by progressive fibrosis in pancreatic islets. This model is useful in investigations on the progression of T2D with age. Three articles describe genetic factors of spontaneous T2D models, in detail. In “Genetic dissection of complex genetic factor involved in NIDDM of OLETF rat,” T. Yamada et al. review 14 QTLs (Nidd1–14/of) identified in OLETF rat that are responsible for noninsulin dependent diabetes mellitus (NIDDM). Their work showed that NIDDM in the OLETF rat is a highly heterogeneous and complex genetic disorder. In “Single diabetic QTL derived from OLETF rat is a sufficient agent for severe diabetic phenotype in combination with leptin-signaling deficiency,” H. Kose et al. map hyperglycemia QTLs in the OLETF rat and show that Nidd2/of is highly responsive to obesity. In addition, Nidd2/of and another hyperglycemia QTL, Nidd1/of, appear to act in combination to lead to the development of diabetes. Their new congenic strain, carrying a single QTL, may be helpful in identifying the causative gene and should aid future investigations on understanding the mechanism by which obesity interacts with QTLs to regulate diabetic traits. In the article “Dose effect and mode of inheritance of diabetogenic gene on mouse chromosome 11,” N. Babaya et al. revealed that the introgression of chromosome 11 of T2D Nagoya-Shibata-Yasuda (NSY) strain onto nondiabetic C3H caused marked changes in glucose tolerance and STZ susceptibility, even in heterozygous state. However, hyperglycemia and STZ sensitivity in heterozygous C3H-11NSY mouse was not as severe as in the homozygous mouse. The consomic strains constructed in their studies will facilitate fine mapping and identification of responsible genes for T2D-related phenotypes. Islet transplantation is an effective treatment for severe diabetes. N. Sakata et al. review three types of animal models (STZ-induced diabetes, pancreatomized diabetes, and spontaneous diabetes) used for preclinical islet transplantation research in “Animal models of diabetes mellitus for islet transplantation.” As highlighted in this review, selecting the appropriate models based on the study's objective is paramount to properly interpret a study's findings and critical to advance this area of research. Cardiovascular disorders (CVDs) are the leading cause of death in humans. In “Cardiovascular changes in animal models of metabolic syndrome” by A. M. Lehnen et al., cardiovascular findings in animal models with obesity, dyslipidemia, diabetes, or hypertension are summarized. The use of different experimental models is important in order to better understand the mechanisms involved in CVDs caused by metabolic disease. Because the mortality due to CVD is greater in type 1 diabetic (T1D) patients than in the general population, C. H. Hung et al. aimed to investigate the severity of cardiopulmonary dysfunction caused by lipopolysaccharide (LPS) in T1D rats in “Cardiopulmonary profile in streptozotocin-induced type 1 diabetic rats during systemic endotoxemia.” In this study, despite higher TNF-α level in serum and bronchoalveolar lavage fluid between nondiabetic and STZ T1D rats, there was only a modest difference of cardiopulmonary dysfunction between the two groups. T1D is an autoimmune disease that is characterized by the selective destruction of pancreatic β cells. Both environmental and genetic factors are known to contribute to the progression of this autoimmunity. In the review article “Rodent models for investigating the dysregulation of immune responses in type 1 diabetes” by F. C. Chou et al., non-obese diabetic (NOD) mouse and other spontaneous diabetes models are introduced. In addition, this review discusses genetically manipulated NOD mice that overexpress protective genes in islet, T-cell receptors, islet-specific neoantigens, or humanized MHC. Lastly, in their review article entitled “Foxp3 + regulatory T cells in mouse models of type 1 diabetes,” C. Petzold et al. focus on a murine model of T1D that expresses the Foxp3+ transcription factor in CD4+ CD25+ regulatory T (Treg) cells. In this review, spontaneous and genetically engineered NOD mice for studying the role of Foxp3+ Treg cells in β cell autoimmunity are overviewed. Tomohiko Sasase Marcus G. Pezzolesi Norihide Yokoi Takahisa Yamada Kozo Matsumoto

Aim: Spontaneously Diabetic Torii (SDT) rat is a new model of non-obese type 2 diabetes. SDT rats show severe ocular complications such as cataracts, tractional retinal detachment with fibrous proliferation and massive haemorrhaging in the anterior chamber. In the present study, blood glucose levels of SDT rats were controlled in order to examine whether these ocular complications are caused by hyperglycaemia. Methods: SDT rats were treated with an insulin implant to control blood glucose. To evaluate retinal function, we used electroretinograms (ERG) and measured vascular endothelial growth factor (VEGF) concentrations within the aqueous humour. Finally, we studied retinal flat-mounts and trypsin digestion to evaluate vascular abnormalities in SDT rats. Results: Forty-four-week-old SDT rats displayed an increase in VEGF concentrations within the aqueous humour and significant prolongation of the peak latencies in ERG (Σ(OP1–OP4); Sprague–Dawley (SD): 146.2 ± 1.06 ms; SDT: 166.3 ± 2.38 ms; SDT + insulin: 149.2 ± 1.83 ms). Retinal flat-mounts of SDT rats showed venous dilation and meandering vascular networks. Furthermore, acellular capillaries were observed in the retinal trypsin digestion. Insulin treatment prevented these ocular abnormalities in SDT rats. Conclusions: These findings indicate that ocular complications of SDT rats are caused by hyperglycaemia. The features of SDT rats indicate their usefulness for the future study of diabetic retinopathy.

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a model of obese type 2 diabetes, shows obesity, hyperglycaemia and low bone mineral density (BMD). The objective of this study is to evaluate the effects of parathyroid hormone (1-34) [PTH(1-34)] on BMD and glucose metabolism in the SDT-fa/fa rat. SDT-fa/fa rats showed obesity with hyperglycaemia and decreased serum osteocalcin levels and the tibial BMD. A 4-week treatment of PTH(1-34) (20 µg/kg/day) increased the serum osteocalcin levels and the tibial BMD, and decreased the serum glucose levels without changing the serum insulin levels. These findings indicate that PTH(1-34) improved not only BMD but also glucose metabolism in SDT-fa/fa rats. This study suggests that PTH(1-34) is a novel agent for the treatment of diabetic osteoporosis.

We overviewed the pathophysiological features of diabetes and its complications in obese type 2 diabetic rat models: Otsuka Long-Evans Tokushima fatty (OLETF) rat, Wistar fatty rat, Zucker diabetic fatty (ZDF) rat and Spontaneously diabetic Torii (SDT) fatty rat. Pancreatic changes with progression of diabetes were classified into early changes, such as islet hypertrophy and degranulation of β cells, and degenerative changes, such as islet atrophy and fibrosis of islet with infiltration of inflammatory cells. Renal lesions in tubuli and glomeruli were observed, and nodular lesions in glomeruli were notable changes in OLETF and SDT fatty rats. Among retinal changes, folding and thickening were interesting findings in SDT fatty rats. A decrease of motor nerve conduction velocity with progression of diabetes was presented in obese diabetic rats. Other diabetic complications, osteoporosis and sexual dysfunction, were also observed. Observation of bone metabolic abnormalities, including decrease of osteogenesis and bone mineral density, and sexual dysfunction, including hypotestosteronemia and erectile dysfunction, in obese type 2 diabetic rats have been reported.

We report uveitis observed in an obese type 2 diabetes rat model, Spontaneously Diabetic Torii Leprfa(SDT fatty) rats aged over 50 weeks. The eyes of SDT fatty rats (16 animals: 7 males and 9 females with 50 or 60 weeks of age) were examined histopathologically. Infiltration of inflammatory cells in the uveal tract was observed in 13 of 16 animals. One female showed severe inflammation affecting the entire uveal tract including the iris, ciliary body, and choroid with a variety of inflammatory cells (neutrophils, lymphocytes, and macrophages). Those changes clinically mimic the findings of diabetic iridocyclitis in diabetic patients. Uveitis associated with diabetes can occur in diabetic patients but the pathogenesis still remains unknown. Since increased extramedullary hematopoiesis in the spleen and abscess in the genital and lower urinary tracts were observed in some SDT fatty rats, increased susceptibility to infection, prolongation of inflammatory states, and disorders of the immune system were considered to be possible factors of the uveitis in aged SDT fatty rats. There have been few reports on how diabetes has influence on the development of uveitis associated with bacterial infection. The SDT fatty rat can be an animal model to investigate diabetes-associated uveitis.

Diabetes mellitus is classified into two categories, type 1 and type 2. Type 1 diabetes mellitus (T1D or IDDM; Insulin Dependent Diabetes Mellitus) is characterized by a loss of insulin secretion due to pancreatic β-cell degeneration, leading to autoimmune attack. Type 2 diabetes mellitus (T2D or NIDDM; Non Insulin Dependent Diabetes Mellitus) is metabolic disorder that is caused by insufficient insulin secretion and/or insulin resistance in peripheral and liver tissues. It is known that 90-95% of diabetes is diagnosed as T2D [2]. Development of T2D is usually caused by several factors, which are combined with lifestyle, genetic defects, virus infection, and drugs [3, 4]. Sustained hyperglycemia causes severe diabetic microvascular complications, such as retinopathy, peripheral neuropathy, and nephropathy. In the diabetic states, multiple mechanisms have been implicated in glucosemediated vascular damage and contribute to diabetic microvascular complications. In addition, postprandial state is also an important factor in the development of macroangiopathy. In diabetes, the postprandial phase is characterized by an exaggerated rise in blood glucose levels. It has recently been shown that postprandial hyperglycemia is relevant to onset of cardiovascular complications. From this evidence, treatment of diabetes has become a part of the strategies for the prevention of diabetic vascular complications.

The Spontaneously Diabetic Torii-Lepr(fa) (SDT- fa/fa) rat is a new model of obese type 2 diabetes. The female SDT-fa/fa rat shows obesity, hyperglycemia and hyperlipidemia from a young age. However, it is not known whether diabetes and estrogen deficiency can lead to bone abnormalities in the female SDT-fa/fa rat. The objective of the present study was to investigate the effects of ovariectomy (OVX) on bone metabolism and bone mineral density (BMD) in the female SDT-fa/fa rat. Female Sprague-Dawley rats were used as control animals. The BMDs of the whole tibia and fifth lumbar (L5) vertebral body were analyzed at 30 weeks after OVX. Serum osteocalcin, a bone formation marker, and urine deoxypyridinoline (DPD), a bone resorption marker, were sequentially analyzed before and at 5, 15 and 30 weeks after OVX. Serum osteocalcin and urine DPD levels were lower in SDT-fa/fa rats than in control rats before OVX. Both serum osteocalcin and urine DPD levels were elevated in control rats 5-30 weeks after OVX, but only the urine DPD levels were elevated in SDT-fa/fa rats 5-30 weeks after OVX. SDT-fa/fa rats showed a decrease in the BMDs of the whole tibia and L5 vertebral body compared with control rats. OVX decreased the BMDs of the whole tibia and L5 vertebral body in control rats, but not in SDT-fa/fa rats. These data suggest that estrogen deficiency is not a risk factor for bone loss in type 2 diabetes mellitus.

Blood pressure in female SDT-fa/fa rats was periodically investigated at ages 8, 16, and 24 weeks. Furthermore, an insulin therapy was performed for 5 weeks in the female rats at age 11 weeks, and the change of blood pressure was examined. In addition to obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia, hyperleptinemia and increased urinary angiotensinogen level were observed during the experimental period. Blood pressure was elevated at ages 8 and 16 weeks, but that at 24 weeks was comparable to that in Sprague-Dawley (SD) rats. Heart rate was decreased from age 8 to 24 weeks. Insulin therapy induced good glycemic control and improvement of hyperlipidemia, but the blood pressure was not reduced. Blood pressure in female SDT-fa/fa rats was elevated temporarily. The blood pressure was not decreased by insulin treatment. SDT-fa/fa rat is a useful model to investigate the relation between diabetes mellitus and hypertension.

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.

Obesity, hyperglycemia, hyperlipidemia, and diabetes-associated complications appear at younger ages (6-8 weeks) in the male Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat than in the male original SDT (SDT-+/+) rat. However, the incidence and progression of diabetes mellitus and diabetic complications in the female SDT-fa/fa rat have not been reported in detail. In the present study, the pathophysiological features of the female SDT-fa/fa rat were examined, and compared with those of the female SDT-+/+ rat. Female SDT-fa/fa rats showed hyperphagia, obesity, hyperglycemia, and hyperlipidemia from 5 or 6 weeks of age, and hyperinsulinemia was observed from 5 to 12 weeks. Pathological changes pancreatic islets were observed from 8 weeks. Renal function parameters, such as urine volume and urinary protein, increased from 16 weeks, and pathological findings in the renal tubule, and cataracts were also observed from 16 weeks. Increases of visceral and subcutaneous fats were obvious during the observation period. In pair-feeding with SDT-+/+ rats, SDT-fa/fa rats showed improved hyperglycemia and hypertriglycemia, but hypercholesterolemia was not entirely improved during the study period. Female SDT-fa/fa rats showed diabetes mellitus and diabetes-associated complications at young ages, and fat accumulation was remarkable. Suppression of hyperphagia in SDT-fa/fa rats was effective at improving hyperglycemia and hypertriglycemia. In conclusion, the female SDT-fa/fa rat has the potential to become an important animal model of type 2 diabetes mellitus with obesity, especially for women, for which few models currently exist.

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.

Aim: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-β is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-β isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined. Methods: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests. Results: JTT-010 inhibited PKC-βI and -βII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3–3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher. Conclusions: These observations suggest that PKC-β contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-β inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.

Aim: Chronic glycaemic control, in particular, the control of postprandial hyperglycaemia, is essential for preventing the development of diabetic complications. We therefore evaluated the chronic treatment effect of a new antidiabetic agent, JTT-608 [trans-4-(methylcyclohexyl)-4-oxobutyric acid], in neonatally streptozotocin-treated rats. Methods: The rats were maintained with liquid meal three times a day and treated orally with JTT-608 10 min before each meal for 12 weeks. Haemoglobin A1C (HbA1C) and fasting blood glucose levels were measured at 4-week intervals, and effects of JTT-608 on pancreatic function and diabetic complications were examined after dosing period. Results: The postprandial hyperglycaemia was suppressed by JTT-608 administration, and both HbA1C levels and fasting blood glucose levels were reduced during the experimental period. After the treatment period of 12 weeks, JTT-608 further improved the early insulin secretion and the impaired glucose tolerance after meal loading in the diabetic rats. Also, pathological examination revealed that JTT-608 reduced the incidence of the decrease in immunoreactivity of insulin. In examination of other diabetic complications, JTT-608 ameliorated the reduced motor nerve conduction velocities observed in diabetic rats and inhibited the incidence of cataracts with diabetes. Conclusions: We conclude that a newly developed antidiabetic agent, JTT-608, improves the pancreatic function and prevents the development of diabetic complications by inhibition of daily postprandial hyperglycaemia and could be useful for the treatment of diabetic subjects with impaired insulin secretion.