93 results on '"Takeshi Ohta"'
Search Results
2. Bilateral midbrain transection induced hyperphagia accelerates the development of diabetes in Spontaneously Diabetic Torii (SDT) rats
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Yukihito Ishii, Takeshi Ohta, Makoto Ito, and Tomohiko Sasase
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medicine.medical_specialty ,business.industry ,Type 2 diabetes ,medicine.disease ,Body weight ,Midbrain ,Animal model ,Endocrinology ,Plasma insulin level ,nervous system ,Diabetes mellitus ,Internal medicine ,medicine ,Cumulative incidence ,Overeating ,business - Abstract
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.
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- 2021
3. Effects of excessive sodium chloride loading in the spontaneously diabetic torii (SDT) fatty rats, a preclinical model of type 2 diabetes mellitus
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Masami Shinohara, Soon Hui Teoh, Dai Nakae, Keiichi Ohata, Rika Morimoto, Noriko Kemuriyama, Katsuhiro Miyajima, Tatsuya Maekawa, Takeshi Ohta, François Briand, Yuka Nakamura, Kinuko Uno, and Yuichi Shinozaki
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Male ,medicine.medical_specialty ,Urinary system ,Renal function ,Type 2 diabetes ,Sodium Chloride ,Toxicology ,Rats, Sprague-Dawley ,Blood serum ,Internal medicine ,medicine ,Animals ,Humans ,Obesity ,Blood urea nitrogen ,Kidney ,business.industry ,Albumin ,Type 2 Diabetes Mellitus ,medicine.disease ,Rats ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Female ,business - Abstract
Type 2 diabetes mellitus represents an international health concern with its growing number of patients worldwide. At the same time, excessive salt consumption is also seen as a major cause of diseases such as hypertension and may expedite renal complications in diabetic patients. In this study, we investigated the effects of excessive sodium chloride supplementation on the kidney of the Spontaneously Diabetic Torii-Leprfa (SDT fatty) rat, an obese type 2 diabetes model. Male and female SDT fatty rats and normal Sprague-Dawley (SD) rats at 5 weeks of age were loaded with 0.3% sodium chloride (NaCl) in drinking water for 13 weeks. Blood serum and urinary parameters were observed throughout the experiment and kidney samples were examined in histopathological and genetical analyses. Significant changes on the body weight, blood pressure, urine volume, creatinine clearance, blood urea nitrogen (BUN), relative gene expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-β (TGF-β) were observed in the salt-loaded male SDT fatty rats. Urinary L-type fatty acid-binding protein (L-FABP) and albumin levels were higher observed in the salt-loaded male SDT fatty rats throughout the period, but urinary albumin levels in the female SDT fatty rats remain unchanged. In the kidney, slight Armani-Ebstein changes, tubular degeneration, hyaline cast, and inflammatory cell infiltration were observed in female SDT fatty rats while the levels of some changes were higher in the salt-loaded group. The kidney of the salt-loaded male SDT fatty rats demonstrated a higher degree of lesions compared to the female group and the male unloaded group. Histopathological changes in salt-loaded SDT fatty rats show that excessive salt consumption may act as a diabetic pathology exacerbation factor, but the pathology may be influenced by gender difference. Urinary L-FABP levels may act as a useful biomarker to detect slight tubular damages in the kidney. Excessive salt loading was shown to exacerbate the renal injury in SDT fatty rats.
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- 2021
4. The sphingosine‐1‐phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats
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Takahisa Yamada, Takeshi Ohta, Kazuma Kobayashi, Katsuhiro Miyajima, Tomohiko Sasase, Yukihito Ishii, and Yoshiaki Katsuda
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Blood Glucose ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Lymphocyte ,Inflammation ,Type 2 diabetes ,immunomodulation ,SDT rat ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Fibrosis ,hemic and lymphatic diseases ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,Animals ,Medicine ,sphingosin-1-phosphate receptor modulator ,Receptor modulator ,Sphingosine-1-Phosphate Receptors ,Pharmacology ,diabetes ,Fingolimod Hydrochloride ,business.industry ,Incidence ,medicine.disease ,Fingolimod ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,030220 oncology & carcinogenesis ,medicine.symptom ,business ,medicine.drug - Abstract
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.
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- 2020
5. Analysis of haemodynamics and angiogenic response to ischaemia in the obese type 2 diabetic model Spontaneously Diabetic Torii Lepr fa (SDT fatty) rats
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Yasutaka Murai, Takeshi Ohta, Hironobu Tadaki, Naoya Imagawa, Shiro Heitaku, Takahisa Yamada, and Tomohiko Sasase
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0301 basic medicine ,medicine.medical_specialty ,Physiology ,Ischemia ,Hemodynamics ,Femoral artery ,Hindlimb ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine.artery ,medicine ,Pharmacology ,medicine.diagnostic_test ,business.industry ,Blood flow ,medicine.disease ,Intermittent claudication ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,Metabolic syndrome ,medicine.symptom ,business ,Partial thromboplastin time - Abstract
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.
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- 2020
6. Conventional and novel impacts of ferric citrate on iron deficiency anemia and phosphorus metabolism in rats
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Akio Iida, Mutsuyoshi Matsushita, Takeshi Ohta, and Takahisa Yamada
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Male ,medicine.medical_specialty ,040301 veterinary sciences ,Anemia ,medicine.drug_class ,chemistry.chemical_element ,Administration, Oral ,Urine ,Ferric Compounds ,Phosphorus metabolism ,0403 veterinary science ,Rats, Sprague-Dawley ,03 medical and health sciences ,Oral administration ,Laboratory Animal Science ,Internal medicine ,medicine ,Animals ,030304 developmental biology ,0303 health sciences ,iron deficiency anemia ,General Veterinary ,Full Paper ,Anemia, Iron-Deficiency ,Transferrin saturation ,Phosphorus ,phosphorus metabolism ,04 agricultural and veterinary sciences ,Iron Deficiencies ,medicine.disease ,ferric citrate ,Phosphate binder ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,Endocrinology ,chemistry ,Iron-deficiency anemia - Abstract
Ferric citrate is an oral iron-based phosphate binder, being known to affect iron status and improve iron deficiency anemia (IDA) in chronic kidney disease (CKD) patients. We examined whether oral administration of ferric citrate could change iron status and improve anemia without affecting phosphorus metabolism in iron deficiency anemia rats. In Normal rat study, normal rats were fed a diet containing 0.3 or 3% ferric citrate for 11 days for setting the dose and administration period of ferric citrate. The effects of ferric citrate on iron status- and phosphorus metabolism-related parameters were evaluated using blood and urine samples. Next, an iron deficiency anemia was induced by feeding iron-depleted diet in rats. After 7 days of starting the iron-depleted diet, 0.3% ferric citrate was administered for 7 days by dietary admixture. Iron status- and phosphorus metabolism-related parameters were evaluated with blood and urine samples. In Normal rat study, 3% ferric citrate treatment increased serum iron level and transferrin saturation (TSAT), and decreased serum phosphorus level, intact fibroblast growth factor 23 (iFGF23) level, and urinary phosphorus excretion, but 0.3% ferric citrate treatment showed no effects. On the other hand, in Iron deficiency anemia rat study, 0.3% ferric citrate treatment increased iron status-related parameters and improved anemia, but did not show any apparent changes in phosphorus metabolism-related parameters. In conclusion, ferric citrate could have hematopoietic effects without affecting phosphorus metabolism, and could be a potential option for the treatment of IDA in patients without CKD.
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- 2020
7. Hyperglycemia contributes to the development of Leydig cell hyperplasia in male Spontaneously Diabetic Torii rats
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Naoto Ogawa, Tomohiko Sasase, Fumio Fukai, Yoshitomi Nakane, Yoshikazu Higami, Yusuke Kemmochi, and Takeshi Ohta
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tumors ,insulin ,endocrine system ,medicine.medical_specialty ,Leydig ,040301 veterinary sciences ,Spontaneously Diabetic Torii (SDT) rats ,medicine.medical_treatment ,Integrin ,Toxicology ,Pathology and Forensic Medicine ,0403 veterinary science ,Extracellular matrix ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,biology ,Leydig cell ,urogenital system ,business.industry ,Insulin ,hyperplasia ,04 agricultural and veterinary sciences ,Hyperplasia ,medicine.disease ,Pathophysiology ,Fibronectin ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,biology.protein ,Original Article ,Vitronectin ,hyperglycemia ,business - Abstract
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.
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- 2020
8. Pathological Features of Diabetic Retinopathy in Spontaneously Diabetic Torii Fatty Rats
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Hiroko Takano, Mina Kobayashi, Rina Takagi, Takeshi Ohta, Machiko Shimmura, Fumihiko Toyoda, Yoshiaki Tanaka, Tomohiko Sasase, Akihiro Kakehashi, and Nozomi Kinoshita
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Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,medicine.medical_specialty ,Time Factors ,Article Subject ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,Severity of Illness Index ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Retina ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Pathological ,Diabetic Retinopathy ,lcsh:RC648-665 ,Glial fibrillary acidic protein ,biology ,business.industry ,Retinal ,Diabetic retinopathy ,medicine.disease ,Rats, Zucker ,Vascular endothelial growth factor ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Disease Progression ,030221 ophthalmology & optometry ,biology.protein ,business ,Immunostaining ,Research Article - Abstract
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.
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- 2019
9. Chronic treatment of <scp>JTP</scp> ‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats
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Takahisa Yamada, Takeshi Ohta, Kazuhito Harada, Hironobu Tadaki, Yasufumi Toriniwa, Sumiaki Fukuda, and Tomohiko Sasase
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0301 basic medicine ,Agonist ,endocrine system ,medicine.medical_specialty ,Time Factors ,Physiology ,medicine.drug_class ,Enteroendocrine cell ,Carbohydrate metabolism ,Tachyphylaxis ,Receptors, G-Protein-Coupled ,Mice ,03 medical and health sciences ,Oleoylethanolamide ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,Insulin Secretion ,medicine ,Animals ,Humans ,Pharmacology ,Dose-Response Relationship, Drug ,medicine.disease ,Rats ,Rats, Zucker ,Glucose ,HEK293 Cells ,030104 developmental biology ,Endocrinology ,GPR119 ,chemistry ,030220 oncology & carcinogenesis ,Intestinal L Cells - Abstract
G-protein coupled receptor 119 (GPR119) expression in pancreatic β-cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose-stimulated insulin secretion (GSIS) and glucagon-like peptide-1 (GLP-1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP-109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP-109192 on GSIS in the rat pancreatic β-cell line (INS1E) cells and on GLP-1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP-109192 on GSIS in Sprague-Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6 weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP-109192 increased intracellular cAMP levels (EC50 value: 3.6 nmol/L) and enhanced GSIS in the INS1E cells and GLP-1 secretion in GLUTag cells. In SD rats, a single administration of JTP-109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity.
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- 2019
10. Glomerular hyperfiltration with hyperglycemia in the spontaneously diabetic Torii (SDT) fatty rat, an obese type 2 diabetic model
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M Sugimoto, Yukihito Ishii, F Kuroki, Yusuke Kemmochi, Dai Nakae, Masao Yamanaka, Katsuhiro Miyajima, Tomohiko Sasase, Ryuhei Sano, Sumiaki Fukuda, Yuzo Yasui, and Takeshi Ohta
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Male ,medicine.medical_specialty ,Physiology ,Urinary system ,Renal function ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Diabetes Mellitus, Experimental ,Diabetic nephropathy ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Glucosides ,Internal medicine ,medicine ,Animals ,Diabetic Nephropathies ,Obesity ,Dapagliflozin ,Benzhydryl Compounds ,Sodium-Glucose Transporter 2 Inhibitors ,Kidney ,business.industry ,urogenital system ,General Medicine ,Articles ,Glomerular Hypertrophy ,medicine.disease ,female genital diseases and pregnancy complications ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Hyperglycemia ,business ,Glomerular hyperfiltration ,Kidney disease ,Glomerular Filtration Rate - Abstract
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.
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- 2021
11. The amelioration of T2DM rat femoral bone achieved by anti-osteoporosis of caprine CSN1S2 protein through bone morphogenetic protein signaling pathway
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Tomohiko Sasase, Takeshi Ohta, Fatchiyah Fatchiyah, and Bambang Setiawan
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Glycation End Products, Advanced ,Male ,medicine.medical_specialty ,Osteoporosis ,Bone Morphogenetic Protein 2 ,Core Binding Factor Alpha 1 Subunit ,Bone morphogenetic protein 2 ,General Biochemistry, Genetics and Molecular Biology ,Bone and Bones ,Downregulation and upregulation ,Glycation ,Bone Density ,Osteogenesis ,Internal medicine ,medicine ,Animals ,Femur ,Rats, Wistar ,Osteoblasts ,Chemistry ,Goats ,Granule (cell biology) ,medicine.disease ,Milk Proteins ,Rats ,RUNX2 ,Endocrinology ,Diabetes Mellitus, Type 2 ,Immunohistochemistry ,Femoral bone ,Signal Transduction - Abstract
We investigated the potential anti-glycation and anti-osteoporosis properties of Caprine milk CSN1S2 protein on the serum AGEs and sRAGE level, osteogenic factors expressions, femoral bone mesostructure, histomorphometry, and hydroxyapatite crystals changes in T2DM rats. Varying doses of Caprine milk CSN1S2 protein (0, 375, 750, and 1500mg/kg BW) were used to treat the control and T2DM rats. We measured AGEs and sRAGE level; RUNX2, OSX, BMP2, and Caspase-3 expressions in rats using ELISA and immunohistochemistry, respectively. The mesostructure and histomorphometry of femoral bone was analyzed using SEM Microscope and BoneJ software, then hydroxyapatite crystal size was determined using SEM-XRD. T2DM rats showed a high level of AGEs and a low level of sRAGE, the RUNX2, OSX, & BMP2 expression was down regulated, BV, BV.TV, Tb.Th, Tb.Sp, increased and SMI levels declined, respectively. Vice versa, after administration of the CSN1S2 protein to T2DM rats, improvement in all levels of molecular and cellular markers was achieved. In the CSN1S2 highest dose, AGEs level declined and sRAGE level elevated in T2DM rats. The 375 and 750 mg/kgBW of CSN1S2 protein was able to upregulate the RUNX2, OSX, and BMP2 expression in T2DM rats, thus improving the normalization of osteoclasts and osteoblasts number. The whole dose of CSN1S2 triggered the thickening of trabecular bone wall, granule formation, and normalized the trabecular thickness (Tb.Th) parameter of T2DM rats. The hydroxyapatite crystal size was increased in the highest dose of CSN1S2-treated T2DM rats. This study indicated that CSN1S2 protein had a protective effect against osteoporosis in the T2DM rat bones by means of glycation pathway inhibition, bone histomorphometry and mesostructure improvement via bone morphometric protein signaling.
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- 2020
12. The Caprine Casein-Alpha-S2 Protein Modulates the Molecular Mechanism 2 of Insulin Signal Transduction in Type2 Diabetes Rat
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Takeshi Ohta, Rista Nikmatu Rohmah, Hazna Noor Meidinna, Fatchiyah Fatchiyah, and Lidwina Faraline Triprisila
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0303 health sciences ,medicine.medical_specialty ,biology ,Chemistry ,Cholesterol ,Insulin ,medicine.medical_treatment ,030302 biochemistry & molecular biology ,Type 2 diabetes ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Insulin receptor ,chemistry.chemical_compound ,Endocrinology ,Diabetes mellitus ,Casein ,Internal medicine ,biology.protein ,medicine ,Signal transduction ,GLUT4 - Abstract
This study purpose was to investigate the association of casein-alpha-S2 protein of Caprine milk and molecular mechanismofinsulin signaltransduction in type2 diabetes mellitus (T2DM). The Caprine milk CSN1S2 protein treatment of 0, 375, 750, and 1500mg/kg BW were conducted to the control and T2DM rats. We observed several physiological parameters of all rats. The levels of insulin and TNF-α in the plasma were measured using ELISA.The expressions of proteins and mRNA levels of diabetes-related genes in the pancreas tissues were analyzed using Western Blotting and Real-Time PCR, respectively. Our study found that diabetic rats had lower body weight, food intake, and fecal weight compared with control rats. The Caprine milk CSN1S2 protein consumption affected the body weight of diabetic rats to increase, especially at the dose of 750mg/kg BW.Interestingly, the genes associated with insulin signaling were improved by the CSN1S2 protein treatment in diabetic rats, although their blood glucose and cholesterol level were not affected. The diabetic rats showed an elevated insulin level and GLUT4 protein expression after treatment. We also reported that the CSN1S2-treated diabetic rats had a gradually reduced expression of TNF-α and VCAM-1 in dose-dependent. Moreover, the 750mg/kg BW of CSN1S2 treatment enhanced the mRNA expressions of INS-receptor, GLUT4, IGF-1, CAMKK, and CAMKIV in diabetic rats. The ability of Caprine milk CSN1S2 protein to regulate the molecular mechanisms in the diabetes-signaling pathway indicated its potential therapeutic effects on diabetes management.
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- 2020
13. Author response for 'The sphingosine-1-phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats'
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Takeshi Ohta, Yukihito Ishii, Yoshiaki Katsuda, Takahisa Yamada, Katsuhiro Miyajima, Kazuma Kobayashi, and Tomohiko Sasase
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medicine.medical_specialty ,Endocrinology ,business.industry ,Diabetes mellitus ,Incidence (epidemiology) ,Internal medicine ,medicine ,medicine.disease ,business ,Sphingosine 1-phosphate Receptor Modulator - Published
- 2020
14. Sodium-glucose cotransporters: Functional properties and pharmaceutical potential
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Takeshi Ohta, Ryuhei Sano, and Yuichi Shinozaki
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0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Review Article ,Sodium–glucose cotransporter 1 ,030204 cardiovascular system & hematology ,Sodium–glucose cotransporter 2 ,Sodium-Glucose Transport Proteins ,Diseases of the endocrine glands. Clinical endocrinology ,Cell membrane ,03 medical and health sciences ,0302 clinical medicine ,Sodium-Glucose Transporter 1 ,Sodium-Glucose Transporter 2 ,Internal Medicine ,medicine ,Diabetes Mellitus ,Monosaccharide ,Animals ,Humans ,Hypoglycemic Agents ,Sodium-Glucose Transporter 2 Inhibitors ,Review Articles ,chemistry.chemical_classification ,business.industry ,Antidiabetic drugs ,Glucose transporter ,Transporter ,General Medicine ,RC648-665 ,Solute carrier family ,030104 developmental biology ,medicine.anatomical_structure ,Glucose ,chemistry ,Biochemistry ,Basal (medicine) ,Sodium/Glucose Cotransporter 2 ,business ,Cotransporter - Abstract
Glucose is the most abundant monosaccharide, and an essential source of energy for most living cells. Glucose transport across the cell membrane is mediated by two types of transporters: facilitative glucose transporters (gene name: solute carrier 2A) and sodium–glucose cotransporters (SGLTs; gene name: solute carrier 5A). Each transporter has its own substrate specificity, distribution, and regulatory mechanisms. Recently, SGLT1 and SGLT2 have attracted much attention as therapeutic targets for various diseases. This review addresses the basal and functional properties of glucose transporters and SGLTs, and describes the pharmaceutical potential of SGLT1 and SGLT2., Sodium–glucose cotransporter 1 and sodium–glucose cotransporter 2 have attracted much attention as therapeutic targets for various diseases.
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- 2020
15. GPR52 Accelerates Fatty Acid Biosynthesis in a Ligand-Dependent Manner in Hepatocytes and in Response to Excessive Fat Intake in Mice
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Mitsuo Wada, Hiroyuki Ogasawara, Takashi Miki, Suzawa Koichi, Tatsuya Maekawa, Eun Young Lee, Takeshi Ohta, Kayo Yukawa, and Yoshihisa Yamamoto
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0301 basic medicine ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Science ,02 engineering and technology ,Human Metabolism ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Biosynthesis ,Internal medicine ,medicine ,Receptor ,Molecular Biology ,Fatty acid synthesis ,chemistry.chemical_classification ,Gene knockdown ,Multidisciplinary ,Cholesterol ,Fatty acid ,021001 nanoscience & nanotechnology ,Ligand (biochemistry) ,030104 developmental biology ,Endocrinology ,chemistry ,Lipogenesis ,0210 nano-technology - Abstract
Summary Gpr52 is an orphan G-protein-coupled receptor of unknown physiological function. We found that Gpr52-deficient (Gpr52−/−) mice exhibit leanness associated with reduced liver weight, decreased hepatic de novo lipogenesis, and enhanced insulin sensitivity. Treatment of the hepatoma cell line HepG2 cells with c11, the synthetic GPR52 agonist, increased fatty acid biosynthesis, and GPR52 knockdown (KD) abolished the lipogenic action of c11. In addition, c11 induced the expressions of lipogenic enzymes (SCD1 and ELOVL6), whereas these inductions were attenuated by GPR52-KD. In contrast, cholesterol biosynthesis was not increased by c11, but its basal level was significantly suppressed by GPR52-KD. High-fat diet (HFD)-induced increase in hepatic expression of Pparg2 and its targets (Scd1 and Elovl6) was absent in Gpr52−/− mice with alleviated hepatosteatosis. Our present study showed that hepatic GPR52 promotes the biosynthesis of fatty acid and cholesterol in a ligand-dependent and a constitutive manner, respectively, and Gpr52 participates in HFD-induced fatty acid synthesis in liver., Graphical abstract, Highlights • Hepatosteatosis is inherently an adaptive response to overnutrition to store energy • On the other hand, it can be a pathological condition causing insulin resistance • High-fat diet increases PPARγ2 expression and lipogenesis in liver via GPR52 • Gpr52 ablation protects mice from developing hepatosteatosis and insulin resistance, Human Metabolism; Molecular Biology
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- 2020
16. Author response for 'Analysis of hemodynamics and angiogenic response to ischemia in the obese type 2 diabetic model Spontaneously Diabetic Torii Lepr fa (SDT fatty) rats'
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Hironobu Tadaki, Shiro Heitaku, Yasutaka Murai, Naoya Imagawa, Tomohiko Sasase, Takahisa Yamada, and Takeshi Ohta
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medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Ischemia ,medicine ,Hemodynamics ,medicine.disease ,business - Published
- 2019
17. Pathophysiological Characteristics of Non-Alcoholic Steatohepatitis-Like Changes in Cholesterol-Loaded Type 2 Diabetic Rats
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T. Yamada, M. Muramatsu, E Riya, Takeshi Ohta, Yasufumi Toriniwa, Katsuhiro Miyajima, Yukihito Ishii, Shinichi Kume, Susumu Takekoshi, T Matsui, Kanae Kitatani, and S Ohshida
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medicine.medical_specialty ,Physiology ,Type 2 diabetes ,Cholesterol, Dietary ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Triglyceride ,Lipid peroxide ,business.industry ,Cholesterol ,General Medicine ,medicine.disease ,Rats ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Steatohepatitis ,business ,Hepatic fibrosis - Abstract
Spontaneously Diabetic Torii (SDT) fatty rats, a new obese diabetic model, reportedly presented with features of non-alcoholic steatohepatitis (NASH) after 32 weeks of age. We tried to accelerate the onset of NASH in SDT fatty rats using dietary cholesterol loading and noticed changes in the blood choline level which is expected to be a NASH biomarker. Body weight and biochemical parameters were measured from 8 to 24 weeks of age. At 16, 20, 24 weeks, pathophysiological analysis of the livers were performed. Hepatic lipids, lipid peroxides, and the expression of mRNA related to triglyceride (TG) synthesis, inflammation, and fibrosis were evaluated at 24 weeks. Hepatic fibrosis was observed in SDT fatty rats fed cholesterol-enriched diets (SDT fatty-Cho) from 16 weeks. Furthermore, hepatic lipids and lipid peroxide were significantly higher in SDT fatty-Cho than SDT fatty rats fed normal diets at 24 weeks. Hepatic mRNA expression related to TG secretion decreased in SDT fatty-Cho, and the mRNA expression related to inflammation and fibrosis increased in SDT fatty-Cho at 24 weeks. Furthermore, SDT fatty-Cho presented with increased plasma choline, similar to human NASH. There were no significant changes in the effects of feeding a cholesterol-enriched diet in Sprague-Dawley rats. SDT fatty-Cho has the potential to become a valuable animal model for NASH associated with type 2 diabetes and obesity.
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- 2018
18. Depression-related behavioural and neuroendocrine changes in the Spontaneously Diabetic Torii (SDT) fatty rat, an animal model of type 2 diabetes mellitus
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Takeshi Ohta, Kazuo Sasagawa, Yukihito Ishii, Katsuya Sakimura, Shinichi Kume, and Tatsuya Maekawa
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0301 basic medicine ,Pharmacology ,medicine.medical_specialty ,Physiology ,business.industry ,Glutamate receptor ,Type 2 Diabetes Mellitus ,Hippocampus ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,chemistry ,Corticosterone ,Physiology (medical) ,Diabetes mellitus ,Internal medicine ,medicine ,Neurotransmitter ,Prefrontal cortex ,business ,030217 neurology & neurosurgery ,Behavioural despair test - Abstract
Depression is one of the most common psychiatric diseases and is commonly comorbid with type 1 or 2 diabetes mellitus (DM). However, the pathophysiology underlying the depressive state in DM remains poorly understood. Animal models are useful tools to investigate the association between depression and DM. In the present study we investigated whether the Spontaneously Diabetic Torii (SDT) fatty rat, a novel animal model of type 2 DM, shows depression-related features. We assessed depression-like behaviour, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and neurotransmitter levels in the brain. Behaviour was evaluated using a forced swimming test, and the HPA axis was evaluated with changes in plasma corticosterone levels after a swimming stress exposure or dexamethasone challenge. In addition, serotonin (5-hydroxytryptamine; 5-HT), noradrenaline, glutamate and γ-aminobutyric acid (GABA) concentrations in the frontal cortex, hippocampus and brain stem were measured. In the forced swimming test, SDT fatty rats exhibited increased duration of immobility compared with control Sprague-Dawley (SD) rats. Moreover, basal corticosterone levels were significantly elevated in SDT fatty compared with control SD rats. However, there were no stress-induced increases or changes in dexamethasone-induced suppression of corticosterone in SDT fatty compared with control SD rats. Furthermore, there were significant changes in 5-HT concentrations in the prefrontal cortex, and in GABA and glutamate concentrations in the hippocampus in SDT fatty compared with controls. The results of the present study suggest that the SDT fatty rat may be an appropriate model for diabetes with comorbid depression associated with neurotransmitter impairments and aberrant basal HPA hyperactivity.
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- 2018
19. Pathophysiological analyses of skeletal muscle in obese type 2 diabetes SDT fatty rats
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Toshiyuki Shoda, Akiko Anagawa-Nakamura, Sohei Katsumi, Yusuke Kemmochi, Yuzo Yasui, Akemi Takahashi, Takeshi Ohta, Eriko Taniai-Riya, Takahisa Yamada, Kochi Kakimoto, Kaoru Toyoda, Yu Motohashi, and Akihiro Kaneshige
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0301 basic medicine ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Type 2 diabetes ,SDT fatty rat ,Toxicology ,Pathology and Forensic Medicine ,sarcopenia ,03 medical and health sciences ,Grip strength ,0302 clinical medicine ,Diabetes mellitus ,Internal medicine ,medicine ,skeletal muscle ,diabetes ,business.industry ,Skeletal muscle ,medicine.disease ,musculoskeletal system ,Obesity ,Pathophysiology ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Sarcopenia ,Histopathology ,Original Article ,business - Abstract
Sarcopenia is the age-related decrease of muscle mass and function. Diabetes and obesity are known to be risk factors that exacerbate sarcopenia, but the underlying mechanism of diabetes-related sarcopenia is still unknown. Obese type 2 diabetes SDT fatty rats show early onset of severe diabetes and there have been no reports on the characteristics of their skeletal muscle. Therefore, pathophysiological analyses were performed for the skeletal muscle in these rats. Diabetic male SDT fatty rats were sacrificed at 8, 16, 24, 32 and 40 weeks of age. Age-matched Sprague Dawley (SD) rats were used as the normal control. In addition to biological blood parameters, the soleus and the extensor digitorum longus muscles were examined for muscle weight, histopathology, and protein synthesis and degradation. Muscle grip strength was also examined. These results revealed that the muscle weights of the SDT fatty rats were significantly decreased from 16 weeks of age. The mean cross-sectional area of muscle fibers in the SDT fatty rats decreased from 24 weeks of age. Increased intramyocellular lipid accumulation, identified by immunohistochemistry for adipophilin and TEM, was observed in the SDT fatty rats from 8 weeks of age. Plasma insulin-like growth factor (IGF)-1 levels and muscle strength in the SDT fatty rats decreased at 24 weeks of age and thereafter. These pathophysiological findings have been reported both in sarcopenia in aged humans and in patients with diabetes. In conclusion, the SDT fatty rat was considered to be a useful model for analysis of diabetes-related sarcopenia.
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- 2018
20. Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model
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Takeshi Ohta, Tomoyuki Saito, Shinichi Kume, Tohru Matsui, Katsuhiro Miyajima, Yasufumi Toriniwa, Kinuko Uno, Takahisa Yamada, Tatsuya Maekawa, and Yukihito Ishii
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medicine.medical_specialty ,Cirrhosis ,medicine.medical_treatment ,SDT fatty rat ,Eating ,03 medical and health sciences ,0302 clinical medicine ,Laboratory Animal Science ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,Internal medicine ,Hyperlipidemia ,medicine ,Animals ,Hypoglycemic Agents ,RNA, Messenger ,Full Paper ,Pioglitazone ,General Veterinary ,business.industry ,Insulin ,NASH ,Lipid metabolism ,Organ Size ,medicine.disease ,Metformin ,Diet ,Rats ,Disease Models, Animal ,Cholesterol ,Endocrinology ,030220 oncology & carcinogenesis ,Female ,Thiazolidinediones ,030211 gastroenterology & hepatology ,business ,Hepatic fibrosis ,medicine.drug - Abstract
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease, and some patients develop hepatic cirrhosis/carcinoma. Animal models play key roles in the development of new therapies for NASH. In this study, the pharmacological effects of metformin and pioglitazone were investigated in female Spontaneously Diabetic Torii (SDT) fatty rats to verify the utility of this model. The anti-diabetic drugs were administered to SDT fatty rats fed a cholesterol-enriched diet from 4 to 25 weeks, and changes in food intake, body weight, and blood chemistry parameters were evaluated every 4 weeks. The hepatic lipid content, mRNA expression in relation to lipid synthesis, inflammation, and fibrosis, and histopathological analyses were performed at 25 weeks. Pioglitazone improved hyperglycemia, hyperlipidemia, and abnormalities in hepatic parameters. The insulin levels were lower than those in the control rats before 16 weeks. Plasma glucose levels in the metformin-treated rats were lower than those in the control rats, and plasma alanine aminotransferase levels temporarily decreased. The lipid content and some mRNA expression in relation to fibrosis in the liver decreased with pioglitazone treatment, and the mRNA expression of microsomal triglyceride transfer protein increased. Hepatic fibrosis observed in the SDT fatty rats improved with pioglitazone treatment; however, the effect with metformin treatment was partial. These results in both drugs are in line with results in the human study, suggesting that the SDT fatty rat is useful for developing new anti-NASH drugs that show potential to regulate glucose/lipid metabolism.
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- 2018
21. Pathophysiological abnormalities in the brains of Spontaneously Diabetic Torii-Lepr fa (SDT fatty) rats, a novel type 2 diabetic model
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Tatsuya Maekawa, Takeshi Ohta, and Shinichi Kume
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0301 basic medicine ,medicine.medical_specialty ,General Veterinary ,business.industry ,Hippocampus ,Hippocampal formation ,medicine.disease ,Pathophysiology ,S100A9 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Atrophy ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,Tumor necrosis factor alpha ,Alzheimer's disease ,business ,030217 neurology & neurosurgery - Abstract
In recent years, a relationship between diabetes and neurodegenerative diseases, such as Parkinson's disease, Alzheimer disease or depression, has been proposed. In this study, pathophysiological changes in the brain, especially in the hippocampus, of male SDT fatty rats with obesity and hyperglycemia were investigated. Brains of SD rats and SDT fatty rats were collected at 32 and 58 weeks of age, and parietal cortical thickness and number of pyramidal cells in the hippocampal cornu ammonis 1 and 3 (CA1 and CA3) regions were measured. At 58 weeks of age, the parietal cortical thickness and number of pyramidal cells in the hippocampal CA1 and CA3 regions were lower in SDT fatty rats than in age-matched SD rats. Measurements of mRNA in rat brains at 58 weeks of age showed that the expression of genes related to inflammatory responses (S100a9, TNFα, NF-κB) was elevated in SDT fatty rats. From the aforementioned results, changes suggestive of brain atrophy and impairment in cognitive function were observed in male SDT fatty rat brains.
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- 2018
22. Non-Obese Type 2 Diabetic Rat Models-GK Rat and SDT Rat
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Phanthila Sirichaiyakul, Takayuki Gotoh, Takeshi Ohta, Rumpar Techasakulsin, Chikako Yoshida, Taiichiro Kamiya, Suhattaya Furuta, Tomohiko Sasase, Masami Shinohara, and Takahisa Yamada
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medicine.medical_specialty ,business.industry ,Diabetic rat ,Disease ,Type 2 diabetes ,medicine.disease ,Pathophysiology ,Impaired glucose tolerance ,medicine.anatomical_structure ,Insulin resistance ,Endocrinology ,Internal medicine ,Diabetes mellitus ,medicine ,Pancreas ,business - Abstract
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.
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- 2018
23. Pathophysiological profiles of SDT fatty rats, a potential new diabetic peripheral neuropathy model
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Hironobu Tadaki, Yu Motohashi, Shinichi Kume, Tatsuya Maekawa, Tomohiko Sasase, Katsuhiro Miyajima, and Takeshi Ohta
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Male ,medicine.medical_specialty ,Phlorizin ,030209 endocrinology & metabolism ,Nerve fiber ,Toxicology ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Diabetic Neuropathies ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Obesity ,Pharmacology ,Autonomic nerve ,business.industry ,medicine.disease ,Pathophysiology ,Rats ,Disease Models, Animal ,Peripheral neuropathy ,Endocrinology ,medicine.anatomical_structure ,Blood pressure ,chemistry ,Sciatic nerve ,Rats, Transgenic ,business ,030217 neurology & neurosurgery - Abstract
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.
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- 2017
24. Hepatocellular adenoma with severe fatty change in a male Spontaneously Diabetic Torii rat
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Toshiyuki Shoda, Yuzo Yasui, Yusuke Kemmochi, Akemi Takahashi, Takeshi Ohta, Eriko Taniai-Riya, Kaoru Toyoda, Katsuhiro Miyajima, Kochi Kakimoto, and Akiko Anagawa-Nakamura
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0301 basic medicine ,medicine.medical_specialty ,microscopic finding ,hepatocellular adenoma ,Case Report ,Vacuole ,Toxicology ,liver ,Stain ,Pathology and Forensic Medicine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Oil Red O ,biology ,fatty change ,business.industry ,Mesenchymal stem cell ,Spontaneously Diabetic Torii rat ,Hepatocellular adenoma ,Hyperplasia ,medicine.disease ,digestive system diseases ,Proliferating cell nuclear antigen ,030104 developmental biology ,Endocrinology ,chemistry ,030220 oncology & carcinogenesis ,Keratin 8 ,biology.protein ,business - Abstract
The Spontaneously Diabetic Torii (SDT) rat is a rat model of nonobese type 2 diabetes mellitus, and hepatocellular adenomas have not been reported in this model. We report a hepatocellular adenoma with severe fatty change in a male 42-week-old SDT rat fed a high-fat diet. At necropsy, the animal had a whitish nodular mass of approximately 2 cm in diameter in the right medial lobe. Histologically, the mass was well demarcated from the surrounding tissues, slightly compressing the adjacent hepatic parenchyma and widely compartmented by fibrous connective tissues. The mass consisted of vacuolated tumor cells resembling hepatocytes with a solid and occasionally trabecular growth pattern. Abundant neutral lipids, which were positive for fat with Oil Red O stain and which ultrastructurally had moderately dense material, were contained within the vacuoles of the tumor cells. Immunohistochemically, the tumor cells showed an increase in immunoreactivity or number for Cytokeratin 8/18 and proliferating cell nuclear antigen but were negative for mesenchymal markers. From these findings, the mass could be distinguished from hepatocellular hyperplasia and was diagnosed as hepatocellular adenoma. In rats, hepatocellular adenoma accompanied by severe fatty change is rare, and this is the first report of a hepatocellular tumor with severe fatty change in a SDT rat.
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- 2016
25. Spontaneously Diabetic Torii (SDT) Fatty Rat, a Novel Animal Model of Type 2 Diabetes Mellitus, Shows Blunted Circadian Rhythms and Melatonin Secretion
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Takeshi Ohta, Tatsuya Maekawa, Katsuya Sakimura, and Shinichi Kume
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0301 basic medicine ,medicine.medical_specialty ,Article Subject ,AANAT ,Endocrinology, Diabetes and Metabolism ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Melatonin ,03 medical and health sciences ,chemistry.chemical_compound ,Pineal gland ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,medicine ,Circadian rhythm ,lcsh:RC648-665 ,Triglyceride ,Endocrine and Autonomic Systems ,business.industry ,Type 2 Diabetes Mellitus ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Arylalkylamine ,business ,030217 neurology & neurosurgery ,medicine.drug ,Research Article - Abstract
In patients with diabetes mellitus (DM), impairments of circadian rhythms, including the sleep–wake cycle, blood pressure, and plasma melatonin concentrations, are frequently observed. Animal models of DM are also reported to show aberrant circadian rhythms. However, the changes in the circadian rhythms of plasma soluble substances, including melatonin, in diabetic animals are controversial. In the present study, we investigated the circadian rhythms of spontaneous locomotor activity, metabolic parameters (plasma glucose, triglyceride, and total cholesterol), and plasma melatonin concentrations in Spontaneously Diabetic Torii (SDT) fatty rats, a novel animal model of type 2 DM. Although SDT fatty rats exhibited low locomotor activity in the dark phase, no phase shifts were observed. The circadian variations of plasma metabolic parameters were more apparent in the SDT fatty rats compared with control Sprague–Dawley (SD) rats. The circadian rhythms of plasma melatonin concentrations were significantly impaired in SDT fatty rats. To get an insight into the mechanism underlying the impaired melatonin secretion in SDT fatty rats, the expression of arylalkylamine N-acetyltransferase (Aanat) and acetylserotonin O-methyltransferase (Asmt) mRNA, which encode the rate-limiting enzymes for melatonin synthesis, was investigated in the pineal gland. There were no significant differences in Aanat and Asmt expression between the control SD and SDT fatty rats. These results suggest that SDT fatty rats show impaired circadian rhythms and dysregulated melatonin secretion.
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- 2018
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26. Is the Occlusion Site of the Lenticulostriate Artery Identified on Admission Related to Clinical Prognosis in Patients with Lacunar Stroke?
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Yuichiro Inatomi, Takeshi Ohta, Yukio Ando, Makoto Nakajima, Masaki Naganuma, and Toshiro Yonehara
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Male ,medicine.medical_specialty ,Lacunar stroke ,Time Factors ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Basal (phylogenetics) ,Leukocyte Count ,0302 clinical medicine ,Patient Admission ,Risk Factors ,Internal medicine ,White blood cell ,Occlusion ,medicine ,Humans ,Triglycerides ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Rehabilitation ,Hypertriglyceridemia ,Magnetic resonance imaging ,Odds ratio ,Cerebral Arteries ,medicine.disease ,Prognosis ,Confidence interval ,medicine.anatomical_structure ,Diffusion Magnetic Resonance Imaging ,Treatment Outcome ,Multivariate Analysis ,Stroke, Lacunar ,Cardiology ,Surgery ,Female ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Background The mechanism of lacunar stroke (LS) is rather speculative due to the lack of neuropathological evidence in clinical practice. To explore the significance of the occlusion site of the lenticulostriate artery (LSA) to this mechanism, we investigated the characteristics and prognosis of patients with LS with proximal occlusions. Materials and Methods We studied 202 patients with acute LS in the region of the LSA. The presumed occlusion site of the LSA was assessed on coronal, diffusion-weighted magnetic resonance images. Based on the distance from the basal surface of the hemisphere to the proximal site of the lacunar infarct, patients were divided into 3 groups: proximal, middle, and distal site occlusions, and their characteristics and outcomes were compared. Results White blood cell counts, blood glucose, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and admission National Institutes of Health Stroke Scale score were statistically different among the 3 groups. In multivariate analysis, both high levels of white blood cells (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.01-1.33) and triglyceride (OR, 1.31; 95% CI, 1.09-1.61) were positively related to the proximal occlusion site. Proximal occlusion (OR, 3.98; 95% CI, 1.06-16.11) was related to poor outcome at discharge. Conclusions Proximal occlusion of the LSA was independently related to elevated triglyceride and white blood cell counts. Patients with LS with proximal LSA occlusion had severe neurological deficits both on admission and at discharge.
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- 2017
27. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice
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Yukihito Ishii, Tsuneo Imanaka, Akio Kobayashi, Daisuke Tomimoto, Chihiro Okuma, Takeshi Ohta, Nobuya Ogawa, and Makoto Kakutani
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Glucose uptake ,Adipose tissue ,Mice, Inbred Strains ,Type 2 diabetes ,Biology ,Carbohydrate metabolism ,Diet, High-Fat ,Weight Gain ,Triacylglycerol ,NEFA ,Insulin resistance ,Internal medicine ,Oxazines ,medicine ,Animals ,Spiro Compounds ,Diacylglycerol O-Acyltransferase ,Obesity ,Pharmacology ,Glucose Transporter Type 4 ,Tumor Necrosis Factor-alpha ,Insulin ,Body Weight ,lcsh:RM1-950 ,nutritional and metabolic diseases ,Lipid Metabolism ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Glucose ,Endocrinology ,lcsh:Therapeutics. Pharmacology ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,biology.protein ,Molecular Medicine ,Acyl Coenzyme A ,Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 ,GLUT4 - Abstract
Type 2 diabetes mellitus (T2DM) arises primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important in the development of T2DM, including obesity. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase 1 inhibitor, reduced body weight depending on dietary fat in diet-induced obesity (DIO) rats in our previous study. Here, the effect of JTT-553 on glucose metabolism was evaluated using body weight reduction in T2DM mice. JTT-553 was repeatedly administered to DIO and KK-A(y) mice. JTT-553 reduced body weight gain and fat weight in both mouse models. In DIO mice, JTT-553 decreased insulin, non-esterified fatty acid (NEFA), total cholesterol (TC), and liver triglyceride (TG) plasma concentrations in non-fasting conditions. JTT-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in DIO mice. In KK-A(y) mice, JTT-553 decreased glucose, NEFA, TC and liver TG plasma concentrations in non-fasting conditions. JTT-553 also decreased glucose, insulin, and TC plasma concentrations in fasting conditions. In addition, JTT-553 decreased TNF-α mRNA levels and increased GLUT4 mRNA levels in adipose tissues in KK-A(y) mice. These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight.
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- 2015
28. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis
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Takeshi Ohta, Hideyuki Taniuchi, Tatsuya Ishigure, Jun Nishiu, Hiromi Hamada, Ryuhei Sano, Hironobu Tadaki, Chihiro Okuma, Shinichi Kume, Shohei Sakata, and Makoto Kakutani
- Subjects
Male ,Monoacyglycerol acyltransferase ,medicine.medical_specialty ,JTP-103237 ,Gene Expression ,Piperazines ,Diglycerides ,chemistry.chemical_compound ,Bacterial Proteins ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Enzyme Inhibitors ,Triglycerides ,Diacylglycerol kinase ,Pharmacology ,chemistry.chemical_classification ,Antigens, Bacterial ,Triglyceride ,Lipogenesis ,lcsh:RM1-950 ,Fatty Acids ,Fatty liver ,Fatty acid ,Metabolism ,Triazoles ,medicine.disease ,Sterol ,Fatty Liver ,Mice, Inbred C57BL ,Disease Models, Animal ,lcsh:Therapeutics. Pharmacology ,de novo lipogenesis ,Endocrinology ,Intestinal Absorption ,Liver ,chemistry ,Molecular Medicine ,Sterol Regulatory Element Binding Protein 1 ,Acyltransferases - Abstract
Aim Monoacyglycerol acyltransferases (MGATs) are known to play important roles in intestinal TG absorption. In contrast, the role of MGATs in the liver is still unclear. We investigated the effects of JTP-103237, a novel MGAT inhibitor, on hepatic MGAT activity and hepatic lipid metabolism. Results JTP-103237 reduced hepatic triglyceride content and hepatic MGAT activity in a high sucrose very low fat (HSVLF) diet induced fatty liver model. Interestingly, JTP-103237 suppressed not only triglyceride (TG) and diacylglycerol (DG) synthesis, but also fatty acid (FA) synthesis (de novo lipogenesis) in this model. JTP-103237 also suppressed lipogenesis-related gene expression, such as sterol regulatory element-binding protein 1-c. Moreover, JTP-103237 decreased plasma glucose levels and total cholesterol and reduced the accumulation of epididymal fats in HSVLF diet fed mice. Conclusion In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.
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- 2015
29. Investigation of Gender Difference of Physiological Response in Gonadectomy in Sprague-Dawley (SD) Rats
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Yukihito Ishii, Takeshi Ohta, Yasufumi Toriniwa, Masami Shinohara, Yu Motohashi, T. Yamada, Hideaki Yamashiro, S. Kimura, and Katsuhiro Miyajima
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Bone mineral ,medicine.medical_specialty ,Environmental Engineering ,Bone density ,business.industry ,Adipose tissue ,medicine.disease ,Industrial and Manufacturing Engineering ,Bone remodeling ,Insulin resistance ,Endocrinology ,Internal medicine ,Hyperlipidemia ,medicine ,Ovariectomized rat ,business ,Testosterone - Abstract
Aim: Sex hormones, including testosterone and estrogen, result in various pathophysiological changes in the body. To evaluate the pathophysiological changes following gonadectomy in male and female rats, we performed gonadectomy at the same age in male and female Sprague-Dawley (SD) rats. Methods: Male and female Sprague-Dawley rats castrated by bilaternal orchidectomy and ovariectomy at 6 weeks of age (six animals of each sex per group). Food intake, body weight, and clinical chemical parameters such as glucose, insulin, triglyceride and total cholesterol levels, were examined every 4 weeks from 8 to 40 weeks of age. Statistical analysis of differences between Original Research Article Miyajima et al.; BJMMR, 9(6): 1-8, 2015; Article no.BJMMR.19115 2 control and gonadectomized rats was performed using the F-test, followed by the Student’s t-test or Aspin-Welch’s t-test. Results: In orchidectomized (ORX) rats, food intakes and body weights were decreased, whereas in ovariectomized (OVX) rats, the body weights were significantly elevated without an obvious change in food intake. In clinical chemical analysis, hypercholesterolemia was observed in both ORX and OVX rats, but the triglyceride level was obviously decreased only in ORX rats during the observational period. In OVX rats, decrease of insulin sensitivity and significant increase of adipose tissue weights were observed. In bone metabolic analysis, bone mineral content in ORX rats and bone mineral density in OVX rats were decreased, respectively. Conclusion: Both orchidectomy and ovariectomy in rats affect glucose/lipid and bone metabolism, and especially, the glucose metabolism was deteriorated in OVX rats. Both male and female sex hormones play a key role in metabolic disease, such as diabetes, hyperlipidemia and osteoporosis.
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- 2015
30. Effect of Isolation Stress on Glucose/Lipid Metabolism in Spontaneously Diabetic Torii (SDT) Fatty Rats
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T. Yamada, Hideaki Yamashiro, Takeshi Ohta, Yasufumi Toriniwa, Yu Motohashi, Masami Shinohara, Yukihito Ishii, and Katsuhiro Miyajima
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medicine.medical_specialty ,Environmental Engineering ,business.industry ,Cholesterol ,Blood sugar ,Lipid metabolism ,medicine.disease ,Acclimatization ,Obesity ,Industrial and Manufacturing Engineering ,Pathophysiology ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,Diabetes mellitus ,Medicine ,Histopathology ,business - Abstract
Aim: The Spontaneously Diabetic Torii (SDT) fatty rat is a novel obese type 2 dia betic model, showing hyperphagia, obesity, and diabetes mellitus from a young age. In this study, we investigated the effects of isolation stress on pathophysiology in SDT fatty rats. Methods: SDT fatty rats (4 weeks old) were housed 3 per cage for 2 weeks and separated as males or females so as each gender will be placed in a separate cage to avoid mating. After acclimatization in 6 weeks of age, the rats were exposed to isolation stress (IS) (one rat per cage, using 5 animals in each sex). In the control group, each sex of experimental rats were housed
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- 2015
31. Pharmacological Characterization of [trans-5′-(4-Amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2′,3′-dihydrospiro(cyclohexane-1,1′-inden)-4-yl]acetic Acid Monobenzenesulfonate (JTT-553), a Novel Acyl CoA:Diacylglycerol Transferase (DGAT) 1 Inhibitor
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Nobuya Ogawa, Yoshiyuki Akiyama, Takeshi Ohta, Chihiro Okuma, Yoshiaki Ohkuma, Makoto Kakutani, Daisuke Tomimoto, and Yukihito Ishii
- Subjects
Pharmacology ,medicine.medical_specialty ,Triglyceride ,Sterol O-acyltransferase ,Pharmaceutical Science ,Adipose tissue ,General Medicine ,Acyl-CoA ,chemistry.chemical_compound ,Acetic acid ,Oleic acid ,Endocrinology ,chemistry ,Biochemistry ,Internal medicine ,medicine ,Chylomicron ,Diacylglycerol kinase - Abstract
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the final step in triglyceride (TG) synthesis. This enzyme is considered to be a potential therapeutic target for obesity and diabetes. Here, results of an investigation of the pharmacological effects of JTT-553 [trans-5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl]acetic acid monobenzenesulfonate, a novel DGAT1 inhibitor, are reported. To measure the inhibitory activity of JTT-553 against DGAT1, TG synthesis using [(14)C]-labeled oleoyl-CoA was evaluated. Similarly, the inhibitory activity of JTT-553 against DGAT2, an isozyme of DGAT1, and acyl-CoA cholesterol acyltransferase (ACAT) 1, which is highly homologous to DGAT1, were evaluated. JTT-553 selectively inhibited human DGAT1 and showed comparable inhibitory effects on the activity of human, rat, and mouse DGAT. In vivo, JTT-553 suppressed plasma TG and chylomicron TG levels after olive oil loading in Sprague-Dawley (SD) rats. JTT-553 also inhibited TG synthesis in epididymal fat after [(14)C] oleic acid injection in C57BL/6J mice. Food intake was evaluated in SD rats fed 3.1%, 13%, or 35% (w/w) fat diets. In rats fed the 35% fat diet, JTT-553 reduced food intake. This reduction of food intake was observed 2 h after feeding, lasted for 24 h, and correlated with dietary fat content. Furthermore, JTT-553 reduced daily food intake and body weight gain in diet-induced obese rats after 4-week repeated administration. JTT-553 exerted multiple effects on intestinal fat absorption, adipose fat synthesis, and food intake, and consequently induced body weight reduction. Therefore, JTT-553 is expected to be an effective novel therapeutic agent for the treatment of obesity.
- Published
- 2015
32. Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin
- Author
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Shinichi Kume, Tomohiko Sasase, Hironobu Tadaki, Yoshiaki Katsuda, Kaoru Toyoda, Kochi Kakimoto, Yusuke Kemmochi, Yu Motohashi, Takeshi Ohta, and Yasuko Mera
- Subjects
Blood Glucose ,medicine.medical_specialty ,peripheral neuropathy ,Original ,Phlorizin ,Type 2 diabetes ,SDT fatty rat ,Sodium-Glucose Transport Proteins ,General Biochemistry, Genetics and Molecular Biology ,Diabetes Mellitus, Experimental ,Nephropathy ,Diabetes Complications ,Rats, Sprague-Dawley ,Diabetic nephropathy ,chemistry.chemical_compound ,Diabetic Neuropathies ,Diabetes mellitus ,Internal medicine ,retinopathy ,Hyperlipidemia ,diabetic complications ,medicine ,Albuminuria ,Animals ,Diabetic Nephropathies ,Diabetic Retinopathy ,General Veterinary ,business.industry ,Rats, Inbred Strains ,General Medicine ,medicine.disease ,Disease Models, Animal ,Kidney Tubules ,Phlorhizin ,Endocrinology ,Peripheral neuropathy ,Diabetes Mellitus, Type 2 ,chemistry ,Hyperglycemia ,nephropathy ,Eye disorder ,Female ,Animal Science and Zoology ,business - Abstract
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.
- Published
- 2015
33. Bone morphological analyses in Spontaneously Diabetic Torii (SDT) fatty rats
- Author
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Toshie Sugiyama, Takahisa Yamada, Shuichi Kimura, Masaya Hirata, and Takeshi Ohta
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,genetic structures ,Bone density ,Osteoporosis ,Type 2 diabetes ,SDT fatty rat ,Bone and Bones ,Laboratory Animal Science ,Bone Density ,Internal medicine ,Diabetes mellitus ,Bone quality ,Diabetes Mellitus ,medicine ,Animals ,Tibia ,Bone mineral ,General Veterinary ,business.industry ,Body Weight ,Rats, Inbred Strains ,Note ,medicine.disease ,bone quality ,Pathophysiology ,Rats ,Endocrinology ,diabetic osteoporosis ,Female ,sense organs ,business - Abstract
The Spontaneously Diabetic Torii (SDT) fatty rat, a model for obese type 2 diabetes, shows bone quantitative abnormalities, namely low bone mineral density (BMD). The objective of this study was to evaluate bone morphological changes, in particular identifying the bone qualitative abnormalities, in the SDT fatty rat. Male SDT fatty rats showed increases in total trabecular area and trabecular number and decreases in trabecular thickness in cancellous bones of the proximal tibia, indicating trabecular miniaturization. The SDT fatty rat is useful for investigation of pathophysiological changes in bone quality in diabetic osteoporosis.
- Published
- 2015
34. Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in spontaneously diabetic Torii rats
- Author
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Takashi Miki, Asuka Morita, Eun Young Lee, Harukiyo Kawamura, Tomohiko Sasase, Katsuhiro Miyajima, Nobuya Inagaki, Toshihiko Iwanaga, Eri Mukai, and Takeshi Ohta
- Subjects
Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Interleukin-1beta ,Hemorrhage ,Inflammation ,Diabetes Mellitus, Experimental ,Islets of Langerhans ,chemistry.chemical_compound ,Endocrinology ,Fibrosis ,Insulin-Secreting Cells ,Internal medicine ,Diabetes mellitus ,Crotalid Venoms ,Internal Medicine ,Animals ,Trimeresurus ,Medicine ,geography ,geography.geographical_feature_category ,Cell Death ,business.industry ,Sunitinib ,Pancreatic islets ,General Medicine ,Streptozotocin ,medicine.disease ,Islet ,Rats ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,chemistry ,medicine.symptom ,business ,Signal Transduction ,medicine.drug - Abstract
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.
- Published
- 2014
35. Pathophysiological analysis of the progression of hepatic lesions in STAM mice
- Author
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Yukihito Ishii, Takeshi Ohta, T. Konuma, Katsuhiro Miyajima, Y. Saigo, Yasufumi Toriniwa, Tomoyuki Saito, and M. Muramatsu
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Physiology ,medicine.disease_cause ,Diet, High-Fat ,Pathogenesis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Insulin resistance ,Fibrosis ,Non-alcoholic Fatty Liver Disease ,Pregnancy ,Internal medicine ,Diabetes mellitus ,Hyperinsulinemia ,Medicine ,Animals ,business.industry ,Body Weight ,nutritional and metabolic diseases ,General Medicine ,Organ Size ,medicine.disease ,Streptozotocin ,Pathophysiology ,Mice, Inbred C57BL ,Endocrinology ,Liver ,030220 oncology & carcinogenesis ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,business ,Oxidative stress ,medicine.drug - Abstract
Nonalcoholic steatohepatitis (NASH) is a current health issue since the disease often leads to hepatocellular carcinoma; however, the pathogenesis of the disease has still not been fully elucidated. In this study, we investigated the pathophysiological changes observed in hepatic lesions in STAM mice, a novel NASH model. STAM mice, high fat-diet (HFD) fed mice, and streptozotocin (STZ) treated mice were prepared, and changes over time, such as biological parameters, mRNA expression, and histopathological findings, were evaluated once animal reached 5, 7, and 10 weeks of age. STZ mice presented with hyperglycemia and an increase in oxidative stress in immunohistochemical analyses of Hexanoyl-lysine: HEL from 5 weeks, with fibrosis in the liver also being observed from 5 weeks. HFD mice presented with hyperinsulinemia from 7 weeks and the slight hepatosteatosis was observed at 5 weeks, with changes significantly increasing until 10 weeks. STAM mice at 10 weeks showed significant hepatic changes, including hepatosteatosis, hypertrophic hepatocytes, and fibrosis, indicating pathological changes associated with NASH. These results suggested that the increase in oxidative stress with hyperglycemia triggered hepatic lesions in STAM mice, and insulin resistance promoted lesion formation with hepatic lipid accumulation. STAM mice may be a useful model for elucidating the pathogenesis of NASH with diabetes.
- Published
- 2017
36. Investigation of Pharmacological Responses to an Anti-Diabetic Drug Pioglitazone in Female Spontaneously Diabetic Torii (SDT) Fatty Rats, A New Obese Type 2 Diabetic Rat
- Author
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Takeshi Ohta, Masami Shinohara, Murai Y, T. Yamada, and Katsuhiro Miyajima
- Subjects
chemistry.chemical_classification ,Drug ,medicine.medical_specialty ,Diabetic rat ,business.industry ,Activator (genetics) ,media_common.quotation_subject ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,medicine.disease ,Endocrinology ,chemistry ,Diabetes mellitus ,Internal medicine ,medicine ,Receptor ,business ,Pioglitazone ,media_common ,Glycemic ,medicine.drug - Abstract
Rigorous glycemic control is essential to prevent the development of diabetes and onset of diabetic complications. Peroxisome proliferator-activated receptor (PPAR) γ activator pioglitazone is an anti-diabetic drug that exhibits glucose-lowering effects by enhancing insulin sensitivity in peripheral tissues. However, increases in body weight are a concerning finding associated with treatment with pioglitazone. In this study, the pharmacological effects of pioglitazone were investigated in female Spontaneously Diabetic Torii (SDT) fatty rats, a new obese type 2 diabetic rat, to verify utility of this model.
- Published
- 2017
37. Physiological changes induced by salt intake in female Spontaneously Diabetic Torii-Leprfa(SDT fatty) rat, a novel obese type 2 diabetic model
- Author
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Yusuke Kemmochi, Yoshiaki Katsuda, Takeshi Ohta, Katsuhiro Miyajima, Yukihito Ishii, Mimi Maki, Ryuhei Sano, and Kochi Kakimoto
- Subjects
Creatinine ,medicine.medical_specialty ,Kidney ,business.industry ,Glomerulosclerosis ,Renal function ,General Medicine ,medicine.disease ,Obesity ,chemistry.chemical_compound ,Blood pressure ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Internal medicine ,Diabetes mellitus ,medicine ,Salt intake ,General Agricultural and Biological Sciences ,business - Abstract
Salt plays an important role in the control of blood pressure in obesity and diabetes mellitus. In this study, we investigated physiological changes such as blood pressure and renal function in salt-loaded female Spontaneously Diabetic Torii-Lepr(fa) (SDT fatty) rats. SDT fatty rats were given 1% NaCl in drinking water for 14 weeks, from 4 to 18 weeks of age. Significant salt-sensitive hypertension was observed in the salt-loaded SDT fatty rats. Moreover, the salt-loaded rats showed a decrease of creatinine clearance and deterioration on pathological renal findings, including glomerulosclerosis and tubular and interstitial lesions. Female SDT fatty rat is a useful model for investigating the mechanisms of high salt sensitivity in obesity and diabetes mellitus.
- Published
- 2014
38. Pharmacological Effect of α-Glucosidase Inhibitor Voglibose in a Novel Obese Diabetic Model
- Author
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Katsuhiro Miyajima, Yusuke Kemmochi, T. Yamada, Takeshi Ohta, and Masami Shinohara
- Subjects
medicine.medical_specialty ,Diabetic rat ,business.industry ,α glucosidase ,Therapeutic effect ,General Medicine ,medicine.disease ,Original research ,Obesity ,Endocrinology ,Internal medicine ,Voglibose ,medicine ,business ,medicine.drug - Abstract
Aim: This study was conducted to investigate the preventive or therapeutic effect of αglucosidase inhibitor voglibose in a new model rat, Spontaneously Diabetic Torii-Lepr fa (SDT fatty) rat, which is a novel type 2 diabetic rat showing obesity, hyperglycemia and Original Research Article
- Published
- 2014
39. JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Improves Hyperglycemia and Dyslipidemia Independent of Suppression of Food Intake in Diabetic Rats
- Author
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Tomohiko Sasase, Makoto Kakutani, Shohei Sakata, Takeshi Ohta, Makoto Ito, Hiromi Yamamoto, and Yasuko Mera
- Subjects
Male ,medicine.medical_specialty ,Article Subject ,Enteroendocrine Cells ,Endocrinology, Diabetes and Metabolism ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Microsomal triglyceride transfer protein ,Diabetes Complications ,Endocrinology ,Gastrointestinal Agents ,Glucagon-Like Peptide 1 ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,medicine ,Animals ,Hypoglycemic Agents ,Obesity ,Pancreas ,Dyslipidemias ,Hypolipidemic Agents ,Gastrointestinal agent ,lcsh:RC648-665 ,biology ,business.industry ,Lipid metabolism ,Organ Size ,Lipid Metabolism ,medicine.disease ,Glucagon-like peptide-1 ,Malonates ,Rats ,Rats, Zucker ,medicine.anatomical_structure ,Liver ,Lipotoxicity ,Hyperglycemia ,Benzamides ,biology.protein ,Carrier Proteins ,business ,Dyslipidemia ,Research Article - Abstract
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.
- Published
- 2014
40. Gender Differences in Metabolic Disorders and Related Diseases in Spontaneously Diabetic Torii-LeprfaRats
- Author
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Yoshiaki Katsuda, Shuichi Kimura, Bin Tong, Takeshi Ohta, Takahisa Yamada, Katsuhiro Miyajima, and Tomohiko Sasase
- Subjects
Male ,Aging ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Blood lipids ,Hyperlipidemias ,Review Article ,Diabetic angiopathy ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Severity of Illness Index ,Nephropathy ,Sex Factors ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Hyperlipidemia ,Animals ,Insulin ,Medicine ,Diabetic Nephropathies ,Obesity ,Sex Characteristics ,lcsh:RC648-665 ,Behavior, Animal ,business.industry ,Microcirculation ,Feeding Behavior ,medicine.disease ,Rats ,Disease Models, Animal ,Diabetes Mellitus, Type 2 ,Disease Progression ,Osteoporosis ,Female ,Rats, Transgenic ,Energy Intake ,business ,Diabetic Angiopathies ,Sex characteristics - Abstract
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.
- Published
- 2014
41. Metabolic Disorders and Diabetic Complications in Spontaneously Diabetic ToriiLeprfaRat: A New Obese Type 2 Diabetic Model
- Author
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Yusuke Kemmochi, Katsuhiro Miyajima, Shuichi Kimura, Mimi Maki, Yukihito Ishii, Kenji Fukui, Tomohiko Sasase, and Takeshi Ohta
- Subjects
medicine.medical_specialty ,lcsh:RC648-665 ,Hematology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Review Article ,Type 2 diabetes ,medicine.disease ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Obesity ,Nephropathy ,Endocrinology ,Blood pressure ,Internal medicine ,Diabetes mellitus ,Hyperlipidemia ,medicine ,business ,Retinopathy - Abstract
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.
- Published
- 2013
42. Diabetic mouse models
- Author
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Yoshiaki Katsuda, Masami Shinohara, Takahisa Yamada, Tong Bin, and Takeshi Ohta
- Subjects
medicine.medical_specialty ,business.industry ,Diabetic animal ,Cancer ,Diabetic mouse ,Disease ,Bioinformatics ,medicine.disease ,Obesity ,Diabetic complication ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,Etiology ,business - Abstract
The number of patients with lifestyle-related diseases, such as cardiovascular disease, diabetes mellitus, hypertension, atherosclerosis, and cancer, is increasing all over the world, and that of diabetics is increasing especially rapidly. Diabetic animal models have played a key role in elucidating the etiology of diabetes and developing anti-diabetic drugs. In this review, we overviewed characteristics of diabetic mouse models and pharmacological evaluation using the diabetic models.
- Published
- 2013
43. Inhibition of Postprandial Hyperglycemia Prevents the Incidence of Diabetes in Spontaneously Diabetic Torii (SDT) Rats
- Author
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Takeshi Ohta, Takahisa Yamada, Katsuhiro Miyajima, Masami Shinohara, and Takuji Yamamoto
- Subjects
medicine.medical_specialty ,Endocrinology ,Postprandial ,General Veterinary ,business.industry ,Internal medicine ,Diabetes mellitus ,Incidence (epidemiology) ,medicine ,medicine.disease ,business ,Agronomy and Crop Science - Published
- 2012
44. Pancreatic Abnormalities at a Young Age in Spontaneously Diabetic Torii (SDT) Rats
- Author
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Takeshi Ohta, Takuji Yamamoto, Takahisa Yamada, and Masami Shinohara
- Subjects
Young age ,medicine.medical_specialty ,Endocrinology ,General Veterinary ,business.industry ,Internal medicine ,Medicine ,business ,Agronomy and Crop Science - Published
- 2012
45. Diabetic Peripheral Neuropathy in Spontaneously Diabetic Torii-Leprfa (SDT Fatty) Rats
- Author
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Eimei Sato, Tomohiko Sasase, Mutsuyoshi Matsushita, Daisuke Tomimoto, Yusuke Kemmochi, Takayuki Yamaguchi, Yasuko Mera, Hironobu Tadaki, and Takeshi Ohta
- Subjects
medicine.medical_specialty ,General Veterinary ,business.industry ,Motor nerve conduction velocity ,Sural nerve ,Type 2 diabetes ,medicine.disease ,Nerve conduction velocity ,Animal model ,Peripheral neuropathy ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,business ,Pioglitazone ,medicine.drug - Abstract
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.
- Published
- 2012
46. Elevated glucagon-like peptide-1 on a high-fat diet feeding prevents the incidence of diabetes mellitus in Spontaneously Diabetic Torii Leprfa rats
- Author
-
Takahiro Hata, Mutsuyoshi Matsushita, Gimpei Tanoue, Katsuhiro Miyajima, Takayuki Yamaguchi, Takeshi Ohta, Eimei Sato, Yasuko Mera, Tomohiko Sasase, and Yukihito Ishii
- Subjects
medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Fatty liver ,Adipose tissue ,Type 2 diabetes ,medicine.disease ,Glucagon-like peptide-1 ,Endocrinology ,Fat diet ,Incretin Hormone ,Diabetes mellitus ,Internal medicine ,medicine ,business - Abstract
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.
- Published
- 2012
47. Effect of phlorizin on metabolic abnormalities in Spontaneously Diabetic Torii (SDT) rats
- Author
-
Takahisa Yamada, Hisayo Morinaga, Takuji Yamamoto, and Takeshi Ohta
- Subjects
medicine.medical_specialty ,endocrine system diseases ,Glycogen ,Glucokinase ,business.industry ,Phlorizin ,Glucose uptake ,digestive, oral, and skin physiology ,nutritional and metabolic diseases ,Lipid metabolism ,Type 2 diabetes ,medicine.disease ,Renal glucose reabsorption ,carbohydrates (lipids) ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,Medicine ,Liver function ,business - Abstract
The Spontaneously Diabetic Torii (SDT) rat is a novel model for nonobese type 2 diabetes. In this study we investigated the glycolipid metabolic changes with phlorizin-treatment, which inhibits intestinal glucose uptake and renal glucose reabsorption, in male SDT rats. Phlorizin (100 mg/kg, b.i.d., s.c.) was administered for 4 weeks to SDT rats from 20 to 24 weeks of age. As a result, phlorizin reduced the development of hyperglycemia and decreased the hemoglobin A1c (HbA1c) levels. In the liver, phlorizin increased mRNA levels of glucokinase, the enzymes related with the glycogen cascade and the proteins associated with lipid metabolism. In conclusion, chronic administration of phlorizin in SDT rats produced a good glycemic control and an improvement in liver function.
- Published
- 2012
48. Pathophysiological Changes in Pre-Diabetic Stage of Spontaneously Diabetic Torii (SDT) Rats
- Author
-
Takahisa Yamada, Katsuhiro Miyajima, and Takeshi Ohta
- Subjects
medicine.medical_specialty ,insulin ,General Veterinary ,diabetes ,business.industry ,Insulin ,medicine.medical_treatment ,medicine.disease ,Pathophysiology ,SDT rat ,medicine.anatomical_structure ,Endocrinology ,Pre diabetes ,pre-diabetes ,STZ ,Internal medicine ,Diabetes mellitus ,Medicine ,Stage (cooking) ,business ,Pancreas ,Agronomy and Crop Science - Abstract
The Spontaneously Diabetic Torii (SDT) rat is a new model of non-obese type 2 diabetes. In the present study, researchers investigated pathophysiological changes of male SDT rats in pre-diabetic stage from 8-16 weeks of age. In oral glucose tolerance test at 12 weeks of age, SDT rats showed glucose intolerance and decrease of glucose-stimulated insulin secretion. Different doses of Streptozotocin (STZ) were administered to SDT rats or SD rats and the pancreatic weakness was examined. SDT rats treated with STZ at a dose level of 20 mg kg-1 were diabetic within 1 week after treatment whereas SD rats got the diabetes after 30 mg kg-1 STZ was received. Insulin tolerance test was performed at 8, 16 and 24 weeks of age in order to examine the insulin sensitivity and the K value was calculated. Interestingly in SDT rats at 16 weeks of age, insulin sensitivity was increased as compared with that in SD rats. Pathohistological changes in pancreas such as atrophy of islets, multiple irregular projection of islets and islet fibrosis were observed in SDT rats at 15 weeks of age. In this study, SDT rat is a useful model for the analysis of the progression of pre-diabetes and the onset of type 2 diabetes.
- Published
- 2011
49. Quantitative Trait Gene Responsible for Intramuscular Fat Content in the Rat
- Author
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Takeshi Ohta, Takuji Yamamoto, Youji Muramatsu, Hideki Tanomura, and Takahisa Yamada
- Subjects
Candidate gene ,medicine.medical_specialty ,General Veterinary ,QTL ,Biology ,Quantitative trait locus ,intramuscular fat ,marbling ,Endocrinology ,Internal medicine ,medicine ,rat ,Intramuscular fat ,Agronomy and Crop Science ,Gene ,QTG - Abstract
Marbling defined by the amount and distribution of intramuscular fat, socalled Shimofuri is an economically important trait of beef cattle in Japan. A rat Quantitative Trait Locus (QTL) responsible for intramuscular fat content has been mapped to the ~10-cM genomic region on chromosome 1 by utilizing the Otsuka Long-Evans Tokushima Fatty (OLETF) rat and OLETF-derived congenic strain. In this study, we have attempted to identify the Quantitative Trait Gene (QTG) for the intramuscular fat content QTL by using the OLETF rat. For this purpose, we performed refinement of the intramuscular fat content QTL genomic region to a ~2.3-cM region by use of informative recombinants selected from the OLETF-derived congenic strain, functional retrieval of positional candidate gene, mRNA level analysis and polymorphism search of physiologically relevant positional candidate gene, Pnlip and analysis of cosegregation of the intramuscular fat content QTL with Variable Number of Tandem Repeat (VNTR) in Pnlip by use of informative recombinants. This study suggests that Pnlip encoding pancreatic lipase is the QTG for the intramuscular fat content QTL.
- Published
- 2011
50. JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, ameliorates impaired glucose and lipid metabolism in Zucker diabetic fatty rats
- Author
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Takeshi Ohta, Kochi Kakimoto, Takashi Kawai, Takahiro Hata, Yukiharu Kuroki, Yasuko Mera, Yukihito Ishii, and Makoto Kakutani
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Carbohydrate metabolism ,Diabetes Mellitus, Experimental ,Eating ,chemistry.chemical_compound ,Endocrinology ,Insulin resistance ,Glucagon-Like Peptide 1 ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Insulin ,Triglycerides ,Glycated Hemoglobin ,Glucose tolerance test ,biology ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Body Weight ,Glucose transporter ,Lipid metabolism ,Lipid Metabolism ,medicine.disease ,Malonates ,Rats ,Rats, Zucker ,Glucose ,Adipose Tissue ,chemistry ,Benzamides ,biology.protein ,Glycated hemoglobin ,Carrier Proteins ,business ,GLUT4 - Abstract
Aim: Microsomal triglyceride transfer protein (MTP) takes part in the mobilization of triglyceride-rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT-130, a novel intestine-specific MTP inhibitor, on impaired glucose and lipid metabolism in Zucker diabetic fatty (ZDF) rats. Methods: Male ZDF rats were fed a regular powdered diet with or without JTT-130 as a food admixture (0.01–0.02%) for 6 weeks. Food intake, body weight, blood biochemical parameters, fecal lipid contents, hepatic lipid contents, tissue mRNA levels and glucose utilization in adipose tissues were assessed. An intraperitoneal glucose tolerance test (IPGTT) and histological analysis of the pancreas were performed. Results: JTT-130 treatment decreased food intake, glycated hemoglobin, plasma levels of glucose, triglycerides and total cholesterol, hepatic levels of triglycerides and cholesterol and hepatic mRNA levels of glucose-6-phosphatase, phosphoenolpyruvate carboxykinase and fructose-1,6-bisphosphatase. JTT-130 treatment increased fecal levels of free fatty acids and cholesterol, plasma levels of glucagon-like peptide-1 and peptide YY, mRNA levels of glucose transporter 4 (GLUT4) and lipoprotein lipase in adipose tissues and GLUT4 in muscle and glucose utilization in adipose tissues. Plasma insulin decreased after 2 weeks and increased after 4 weeks of JTT-130 treatment. Plasma glucose in the JTT-130-treated rats was lower with higher plasma insulin than in the control rats during the IPGTT. The islets of the JTT-130-treated rats were larger and contained more insulin than those of the control rats. Conclusions: JTT-130 ameliorates impaired glucose and lipid metabolism in the ZDF rats thereby suggesting that JTT-130 could be useful for prevention and treatment of type 2 diabetes.
- Published
- 2011
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