SDT Rats Research Articles

Abstract 15634: High-fat Diet Consumption Accelerates Cardiometabolic Impairment via Deteriorating Mitochondrial Function in Non-obese Spontaneously Type 2 Diabetic Rats

Introduction: Type 2 Diabetes Mellitus (T2DM) is a complex disease which is related to genetic, environmental, and lifestyle factors. In genetically-induced T2DM rats, normal diet could induce spontaneous diabetes, and induce left ventricular (LV) dysfunction over time. However, the effect of high-fat diet (HFD) in these genetically-induced T2DM rats on the cardiometabolic changes, including LV function and cardiac mitochondrial function has rarely been investigated. Hypothesis: High-fat diet (HFD) consumption accelerates the development of T2DM and LV dysfunction by inducing mitochondrial dysfunction in genetically-induced non-obese T2DM-Spontaneously Diabetic Torii (SDT) rats. Methods: Male SDT rats (n=18/group) were divided into 2 groups to receive either normal diet (ND, 19.77% fat) or HFD (57.60% fat) for 4, 8 or 12 weeks. At each time course, cardiac function determined by echocardiography and the pressure-volume loop determined by invasive intracardiac catheterization were assessed. The heart was removed to study cardiac mitochondrial function at each time-course. Results: The body weight, food intake, and visceral fat were not different between ND and HFD rats at any times. Increased blood glucose was seen earlier at week 4 in HFD rats, but later at week 12 in ND rats. The development of LV contractile dysfunction and decreased stroke volume was observed earlier at week 8 in HFD rats, compared to ND rats and HFD rats at the baseline. Increased cardiac mitochondrial ROS production and decreased mitochondrial membrane potential (i.e. mitochondrial depolarization) was observed earlier at week 8 in HFD rats, compared to ND rats (Fig). Conclusions: High-fat diet accelerates cardiometabolic impairments via impaired cardiac mitochondrial function in genetically-induced non-obese T2DM rats.

Epoetin beta pegol ameliorates flow‐mediated dilation with improving endothelial nitric oxide synthase coupling state in nonobese diabetic rats

SummaryBackground/AimsPatients with diabetic nephropathy have a high cardiovascular mortality. Epoetin beta pegol (continuous erythropoietin receptor activator, C.E.R.A.) is a drug for the treatment of renal anemia. In this study, we investigated the effect of C.E.R.A. on vascular endothelial function as evaluated by flow‐mediated dilation (FMD) and the relationship between hematopoiesis and FMD in diabetic nephropathy rats.MethodsMale Spontaneously Diabetic Torii rats (SDT, 22 weeks old) were used. C.E.R.A. (0.6, 1.2 μg/kg) was administered subcutaneously once every 2 weeks for 8 weeks. At 1 week after last administration (31 weeks old), we assessed FMD in the femoral arteries of anesthetized rats using a high‐resolution ultrasound system. FMD was also measured 1 week after single C.E.R.A. treatment (5.0 μg/kg) to examine the influence of hematopoiesis.ResultsFlow‐mediated dilation was significantly decreased in SDT rats before the start of C.E.R.A. treatment (22 weeks old). Repeated administration of C.E.R.A. dose‐dependently improved FMD in SDT rats (31 weeks old) without changing blood glucose, nitroglycerin‐induced vasodilation, or kidney function. Long‐term administration of C.E.R.A. improved the state of endothelial nitric oxide synthase uncoupling in the femoral arteries of SDT rats, which showed a positive correlation with FMD. On the other hand, there was no correlation between FMD and Hb or Hct in SDT rats. Furthermore, at 1 week after single administration of C.E.R.A., FMD was not significantly improved although hemoglobin levels were comparable with levels following long‐term C.E.R.A. treatment.ConclusionLong‐term treatment with C.E.R.A. improved FMD in SDT rats even after onset of endothelial dysfunction.

Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in spontaneously diabetic Torii rats

AimsSpontaneously 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. MethodsSDT 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. ResultsHSV 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. ConclusionsEnhanced VEGF signaling in islets contributes to β cell injury, microvascular failure, and consequential diabetes in SDT rats.

Metabolic Disorders and Diabetic Complications in Spontaneously Diabetic ToriiLeprfaRat: A New Obese Type 2 Diabetic Model

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. 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.

Modulation of AT-1R/AMPK-MAPK cascade plays crucial role for the pathogenesis of diabetic cardiomyopathy in transgenic type 2 diabetic (Spontaneous Diabetic Torii) rats

There are evidences that the activation of AMPK is playing pivotal role in the lipid and glucose metabolism. It has been reported that both the AMPK and angiotensin-II acts as a negative regulator for each protein. It has been well proven that the MAPK cascade could be modulated by the presence of angiotensin-II. Moreover, studies were shown that p38 MAPK stimulates glucose uptake through the AMPK activation. Therefore, we speculate and tried to demonstrate that the modulation of AT-R/MAPK pathway through AMPK might play crucial roles for the pathogenesis of diabetic cardiomyopathy, using the transgenic (Spontaneous Diabetic Torii – SDT) rats. We performed Western blot analysis for the measurement of myocardial AT-R, AMPK and MAPK cascades-related protein expressions, p67-phox and caspase-12. In addition, we employed dihydroethidium (DHE), Azan Mallory and hemotoxylin eosin (HE) staining methods to demonstrate the superoxide radical production, fibrosis and hypertrophy, respectively. The protein expressions, such as AT-1R, p-ERK1/2, p67-phox and caspase-12 were found to be significantly increased and conversely, the Ang-(1-7) mas R, Tak1, LKB1 and p-AMPKα1, p-p38 MAPK and p-JNK protein expressions were found to be considerably decreased in the SDT rats, in comparison to the normal rats. The DHE, Azan Mallory and HE stainings also revealed that the SDT rats have more superoxide radical production, fibrosis and hypertrophy, respectively than the normal rats. Taken together, it is suggested that the modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy.

Spontaneously Diabetic Torii Leprfa(SDT Fatty) Rat: A Novel Model of Obese Type 2 Diabetes

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.

Editorial: Novel Animal Model of Diabetic Complications: The SDT Rat

Editorial: Novel Animal Model of Diabetic Complications: The SDT Rat

Effect of Food Restriction on Adipose Tissue in Spontaneously Diabetic Torii Fatty Rats

Spontaneously Diabetic Torii-fa/fa (SDT fatty) rat is a new model of obese type 2 diabetes. SDT fatty rat exhibits obesity associated with hyperphagia. In this study, SDT fatty rats were subjected to pair-feeding with SDT-+/+ (SDT) rats from 6 to 22 weeks of age. The ratio of visceral fat weight to subcutaneous fat weight (V/S) decreased at 12 weeks of age in the pair-feeding rats. The intraperitoneal fat weight such as epididymal and retroperitoneal fat weight decreased, whereas mesenteric fat weight had no change. Cell size of the epididymal fat in the pair-feeding rats tended to decrease. Glucose oxidation level in epididymal fat in the pair-feeding rats at 12 weeks of age was recovered to a similar level with that in SDT rats. These results indicated that SDT fatty rat is a useful model to evaluate the functional or the morphological features in adipose tissue and develop a novel drug for antiobesity.

Effects of preventing hyperphagia on glycolipid metabolic abnormalities in Spontaneously Diabetic Torii fatty rats

ABSTRACTSpontaneously Diabetic Torii (SDT) fatty rats, made by introducing the fa allele of the Zucker fatty rat into the SDT rat genome, represent a new model of obese type 2 diabetes. SDT fatty fa/fa (SDT fatty) rats exhibit overt obesity, hyperglycemia, and hyperlipidemia from about six weeks of age, and this is associated with hyperphagia by an induced disorder of leptin action. The present study was conducted to elucidate whether suppression of hyperphagia can improve reduce abnormalities in SDT fatty rats. SDT fatty rats were subjected to pair‐feeding with SDT fatty +/+ (SDT) rats from 6 to 26 weeks of age, and the effects on metabolic parameters and diabetic complications were assessed. Body weights of the pair‐fed rats were similar with those of SDT rats during the experimental period. Improvement of hyperglycemia or hypertriglyceridemia was observed from 8 to 16 or 12 weeks of age in the pair‐fed rats, but hypercholesterolemia was not entirely improved during the experimental period. We also examined mRNAs expression in liver, and found that the expression associated with glyconeogenesis, such as glucose‐6‐phosphatase (G‐6‐Pase) and phosphoenolpyruvate carboxykinase (PEPCK), tended to decrease in the pair‐fed rats, and the mRNA expression of hydroxymethylglutaryl‐CoA (HMG‐CoA) was elevated. Renal parameters, such as blood urea nitrogen and urinary albumin excretion, were improved in the pair‐fed rats. The incidence or progression of diabetic complications, such as renal lesions and cataract, was reduced. In conclusion, suppression of hyperphagia in SDT fatty rats was effective in temporally improving hyperglycemia or hypertriglyceridemia, and reducing the incidence or progression of diabetic complications, but was ineffective in reducing hypercholesterolemia.

Regeneration of β Cells in the Native Pancreata After Syngeneic and Allogeneic Pancreas Transplantations in Spontaneously Type 2 Diabetic Torii Rats

Background We previously demonstrated that syngeneic pancreas transplantation has a potential to reverse diabetes even in a rat model of type 2 diabetes mellitus, namely Spontaneously Diabetic Torii (SDT; RT1 a). The onset of diabetes was significantly delayed in the pancreas transplant recipients. We speculated that perfect diabetic control achieved by pancreas transplantation showed a beneficial effect on the native pancreata & recipients. Materials and Methods Twenty-five-week-old diabetic SDT rats were divided into 3 groups: untreated controls and syngeneic and allogeneic transplant recipients. We transplanted pancreaticoduodenal grafts from nondiabetic 10-week-old SDT rats and from 10-week-old allogeneic Dark Agouti (DA; RT1 a) rats using daily administration of FK506. Results Untreated SDT rats showed disappearance of pancreatic and duodenal homeobox-1 (PDX-1) expression in the pancreas and a marked decrease in β-cell mass. Among syngeneic and allogeneic pancreas transplant recipients, islet-like cell clusters were found in the native pancreata. The β-cell mass at 40 weeks of age was significantly increased in the native pancreata of recipients compared with age-matched controls. Interestingly, we observed the reexpression of PDX-1 in the nuclei of islet-like cell clusters. Conclusions Our results indicated the benefits of avoiding glucose toxicity by pancreas transplantation which induced PDX-1 expression in the native pancreata of type 2 diabetic recipients, resulting in regeneration of β cells in the native pancreata.

Development of β-Cells in the Native Pancreas After Pancreas Allo-Transplantation in the Spontaneously Diabetic Torii Rat

We previously demonstrated the development of beta-cells in the native pancreas after syngeneic pancreas transplantation (PTx) in a model of type 2 diabetes, namely the Spontaneously Diabetic Torii (SDT; RT1 a) rat. In this study, we evaluated the effect of fully allogeneic PTx (allo-PTx) under immunosuppression on the native pancreases in the recipients. Diabetic 25-week-old SDT rats were divided into two groups: untreated controls and PTx-treated recipients. Dark Agouti (RT1 a) pancreases were then transplanted into the SDT rats. FK506 was administered daily postoperatively. Each group was examined for 15 weeks. Control SDT rats showed a disappearance of the pancreatic and duodenal homeobox-1 (PDX-1) expression of the pancreases with the development of diabetes. In addition, the islets were gradually replaced by fibrosis, thus resulting in a marked decrease in the beta-cell mass at 40 weeks of age. On the other hand, in PTx recipients, islet-like cell clusters were found in the native pancreases. The beta-cell mass significantly increased in the native pancreases in the recipients at 10 and 15 weeks posttransplantation in comparison to the age-matched controls. Moreover, we observed the re-expression of PDX-1 in the islet-like cell clusters. Interestingly, insulin and glucagon double-positive stained cells in the mesenchyme and insulin single-positive cells in the ductal epithelium were also observed. Our results indicated that the benefits of avoiding glucose toxicity by allo-PTx under immunosuppression could therefore induce the PDX-1 expression in the native pancreases, thus potentially resulting in the development of beta-cells in type 2 diabetic recipients.

NO-independent mechanism mediates tempol-induced renal vasodilation in SHR

We investigated whether tempol, a superoxide dismutase mimetic, affected renal hemodynamics and arterial pressure in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. We also examined whether tempol affected exaggerated renal vasoconstrictor responses to ANG II in SHR. To test whether the effects of tempol were due to a restored NO system, we used the NOS inhibitor N(w)-nitro-L-arginine methyl ester (L-NAME). Renal blood flow (RBF) and mean arterial pressure (MAP) were measured in vivo by electromagnetic flowmetry and arterial catheterization in 10- to 12-wk-old anesthetized SHR and SD rats. Systolic arterial pressure (SAP) was measured in conscious rats using the tail cuff method. Tempol (1 mM) was given in the drinking water to SD (SD-T) and SHR (SHR-T) for 5-7 days for RBF measurements and for 15 days for SAP measurements. Age-matched SD (SD-C) and SHR (SHR-C) were used as controls. ANG II (1-4 ng) was administered as a bolus via a renal artery catheter. L-NAME was administered intravenously for 15-20 min. Renal vascular resistance (RVR) was elevated in SHR-C compared with SD-C. In SHR-T, baseline RVR was not different from SD-C and SD-T rats. Tempol had no effect on RVR in SD. L-NAME elevated RVR to the same extent in all four groups. Arterial pressure was not affected by tempol. The RVR responses to ANG II were higher in SHR-C than in the SD-C group. ANG II responses were not different between SHR-T and SD-T. Overall, tempol reduced the renovascular responses to ANG II in SHR. L-NAME elevated the effects of ANG II in SD-C rats but had no effect on the ANG II responses in the other groups. Thus L-NAME treatment did not influence tempol's effects on baseline RVR or ANG II responses. We conclude that in SHR, tempol has a significant renal vasodilator effect and that it normalizes the increased renovascular ANG II sensitivity. As the effects of L-NAME are not greater in SHR-T rats, it is not likely that the elevated renal resistance and ANG II sensitivity in SHR are due to reactive oxygen species-induced quenching of nitric oxide.

Development of Islet‐Like Cell Clusters After Pancreas Transplantation in the Spontaneously Diabetic Torri Rat

Pancreas transplantation (PTx) has evolved as a clinical therapy to achieve sustained euglycemia. However, it remains unclear if naive diseased islets of the pancreas benefit from the avoidance of glucose toxicity by PTx. In the present study, using an animal model of type 2 diabetes, the Spontaneously Diabetic Torii (SDT; RT1a) rat, we syngeneically transplanted nondiabetic 10-week-old pancreaticduodenal grafts into diabetic 25-week-old recipients. In the control SDT rats that received no treatment, hyperglycemia developed with a mean onset time of 25 +/- 3.9 weeks of age. Few normal islet cells were found from 25 weeks and none at 40 weeks. However, in the PTx rats, the onset age (graft age) of diabetes was significantly prolonged (47 +/- 18.2 weeks). Moreover, we found that the beta-cell mass was significantly increased in the naive pancreases of 40-week-old PTx recipients (PTx40-naive). Interestingly, islet-like cell clusters of varying size were found close to ductal structures of PTx40-naive pancreases, suggesting that these cells are derived from ductal cells. Furthermore, pancreatic and duodenal homeobox factor-1 (PDX-1) was more clearly expressed in the nuclei of PTx40-naive pancreatic islet-like cell clusters. Our results demonstrate the development of duct-derived beta cells in the pancreas of type 2 diabetic recipients after PTx.

Beneficial effects of pancreas transplantation: Regeneration of pancreatic islets in the spontaneously diabetic Torii rat

Aims Type 2 diabetes is characterized by a combination of insulin resistance and pancreatic beta-cell dysfunction. Although pancreas transplantation (PTx) is mainly performed in patients with type 1 disease, both clinical and experimental data have demonstrated that PTx improves insulin sensitivity in type 2 diabetic recipients. However, it remains unclear whether PTx has the potential to induce islet neogenesis in a recipient's native pancreas. Methods Nondiabetic 10-week-old and diabetic (defined as blood glucose level >250 mg/dL) 25-week-old (average onset age of diabetes) male spontaneously diabetic Torii (SDT; RT1 a) rats served as donors and recipients, respectively. Results In nontreated control SDT rats, beta-cell mass gradually decreased and blood glucose levels progressively increased (>600 mg/dL after 40 weeks of age). In PTx rats, however, the onset of diabetes was significantly delayed (>47.5 ± 18.2 [graft age] versus 25.2 ± 3.9 weeks in control rats). On immunohistochemical staining, insulin-secreting islets were observed in the naive pancreata of 40-week-old recipients with PTx (PTx40w), whereas no islets were found in 40-week-old control SDT rats. Moreover, the islets in the native pancreata of PTx40w recipients were located close to ductal structures, and PDX-1 (pancreatic duodenal homeobox-1)–positive cells were more clearly visible. These results indicate the possibility of beta-cell regeneration in the recipient native pancreas by avoiding glucose toxicity under normoglycemic condition achieved by PTx. Conclusions Pancreas transplantation has beneficial effects on impaired islet, inducing regeneration in the spontaneously diabetic Torii rat.

Stage-dependent effect of pancreatic transplantation on diabetic ocular complications in the Spontaneously Diabetic Torii rat.

In terms of the temporal relationship between pancreas transplantation (PTx) and reversal of diabetic ocular complications, it has been difficult but important to determine a "point of no return." Thus, it is of great clinical interest to evaluate the efficacy of PTx on diabetic ocular complications. A spontaneous type 2 diabetic model of Spontaneously Diabetic Torii (SDT; RT1) rats was used in the present study, and syngeneic PTx was performed. In the control SDT rats that received no treatment, hyperglycemia (>250 mg/dL) was developed from 25.2+/-3.9 weeks of age. Lens opacity was observed in all rats at 15 weeks after the onset of diabetes. Fluorescein angiography and immunohistochemistry detected the nonperfusion area and neovascularization in the retina at 5 weeks of diabetes. Daily insulin treatment could not prevent or reverse the ocular changes in our experiment. Fluorescein filling defect of the retinal vessels was observed at 10 weeks of diabetes. However, in the PTx rats, normoglycemia was achieved at all experimental time points. Diabetic cataract and retinopathy could have been prevented and improved if PTx had been performed at 5 weeks, but not at 10 weeks after the onset of diabetes. With PTx treatment, an inhibition of angiogenesis in the retina at 5 weeks after the onset of diabetes was demonstrated by immunohistochemistry. Our results indicate that the potential use of the SDT rat for diabetes study and the positive effect of PTx performed before the "point of no return" could prevent and cure diabetic ocular complications.

Diabetic Features of Female SDT Rats with Spontaneous Type 2 Diabetes Mellitus

Diabetic Features of Female SDT Rats with Spontaneous Type 2 Diabetes Mellitus