Soy Protein Isolate Suppresses Bone Resorption and Improves Trabecular Microarchitecture in Spontaneously Hyperphagic, Rapidly Growing Male OLETF Rats.

BACKGROUND: Traditionally, milk proteins have been recommended for skeletal health; recently, soy proteins have emerged as popular alternatives. Excess adiposity appears detrimental to skeletal health, as obese adolescents have increased fracture rates compared with healthy controls. However, soy protein effects on skeletal health during excess adiposity remain unknown. OBJECTIVE: The study objective was to examine the effects of isocaloric diets containing milk protein isolate (MPI), soy protein isolate (SPI), or a 50/50 combination (MIX) as the sole protein source on metabolic health indicators and bone outcomes in rapidly growing, hyperphagic, male Otsuka Long Evans Tokushima Fatty (OLETF) rats. METHODS: OLETF rats, aged 4 wk, were randomly assigned to 3 treatment groups (MPI, SPI, or MIX, n = 20 per group) and provided with access to experimental diets ad libitum for 16 wk. RESULTS: Body mass did not differ between the groups, but SPI had lower percentage body fat than MPI (P = 0.026). Insulin was lower in MPI than in MIX (P = 0.033) or SPI (P = 0.044), but fasting blood glucose was not different between the groups. SPI significantly reduced serum cholesterol compared with MPI (P = 0.001) and MIX (P = 0.002). N-terminal propeptide of type I collagen (P1NP) was higher in MIX than MPI (P = 0.05); C-terminal telopeptide of type 1 collagen (CTx) was higher in MPI than SPI (P < 0.001) and MIX (P < 0.001); the P1NP to CTx ratio was significantly higher in SPI and MIX than in MPI (P < 0.001). Trabecular separation was reduced in SPI compared with MPI (P = 0.030) and MIX (P = 0.008); trabecular number was increased in SPI compared with MIX (P = 0.038). No differences were seen in cortical geometry and biomechanical properties. CONCLUSIONS: In the context of excess adiposity, soy- and milk-based proteins have comparable effects on cortical bone geometry and biomechanical properties, whereas soy-based proteins favorably affect the trabecular microarchitecture, and the combination of both proteins may offer additional benefits to bone remodeling in rapidly growing male OLETF rats.

Metformin improves lipid metabolism disorders through reducing the expression of microsomal triglyceride transfer protein in OLETF rats.

OBJECTIVE: This study aimed to investigate the role of MTP on lipid metabolism disorders in insulin-resistant rats and the potential mechanism through which metformin can improve lipid metabolism disorders. METHODS: 30 OLETF rats served as research subjects and 18 LETO rats of the same strain served as the control group (LETO group). After the first oral glucose tolerance test (at 8-week-old), 6 rats were randomly killed from each group. The remaining 24 OLETF rats were randomly divided into untreated group (OLETF group) and treated group (OLETF/M group, cured with metformin). By the end of the 10th and 20th week of treatment, MTP in the liver was measured for all rats in the study. RESULTS: All OLETF rats exhibited diabetic phenotypes at 18-week-old, with their triglyceride level higher than in LETO rats at the same age. In OLETF rats, MTP level in the liver was higher than in LETO rats at 18-week-old, and the difference was significant at 28-week-old [(13.79±1.47) vs. (8.20±1.14), p<0.05]. Treatment with metformin for 20weeks decreased triglyceride [(1.06±0.23) vs. (2.20±0.62) mmol/L, p<0.05] and total cholesterol [(1.90±0.19) vs. (2.36±0.14) mmol/L, p<0.05] in OLETF rats. Metformin also decreased MTP level in the liver [(7.65±1.31) vs. (13.79±1.47), p<0.01]. CONCLUSIONS: MTP may be associated with the lipid metabolism disorder in OLETF rats and metformin could improve lipid metabolism through reducing the expression of MTP.

A recombinant TGF-ß1 vaccine ameliorates diabetic nephropathy in OLETF rats.

AIM: The aim of this study was to investigate the potential of a recombinant vaccine encoding TGF-ß1 in OLETF rats with diabetic nephropathy (DN). METHODS: OLETF rats were treated with vehicle or TGF-ß1 vaccine. LETO rats were used as normal controls. At 42 weeks after immunization with vaccine, samples from blood, urine and kidney were collected for biochemical, histologic, immunohistochemical and molecular analyses. RESULTS: OLETF rats treated with the vaccine reduced blood glucose levels, improved renal pathological changes, and inhibited overexpression of TGF-ß1 and p-Smad3, as well as MCP-1, TNF-α and IL-1ß. CONCLUSION: TGF-ß1 vaccine attenuated diabetic nephropathy in OLETF rats through reduction of inflammation, improvement of kidney fibrosis and partial correction of glucose metabolism.

Enhanced Production of Nitric Oxide Leads to ATP Collapse in the Retinas of Otsuka Long-Evans Tokushima Fatty Rats, a Model of Human Diabetes.

PURPOSE: We determined nitric oxide (NO) production via inducible NO synthase (iNOS) by hyperglycemia using the retina of Otsuka Long-Evans Tokushima Fatty rats (OLETF rats), and investigated the relationship between ATP contents and NO production in the retinas of OLETF rats. METHODS: Long-Evans Tokushima Otsuka rats (LETO rats, normal rats) and OLETF rats (model rat for diabetes mellitus) aged 60 weeks of age were used. Plasma glucose (Glu) levels were determined using an Accutrend GCT System, and NO levels were measured by the microdialysis method as nitrite ([Formula: see text]). Cytochrome c oxidase (CCO) activity was measured using a Mitochondrial Isolation Kit and Cytochrome c Oxidase Assay Kit, and ATP levels were determined using a Sigma ATP Bioluminescent Assay Kit and a luminometer AB-2200. RESULTS: [Formula: see text] levels in the retinas of OLETF rats were significantly higher than in LETO rats, and the [Formula: see text] levels in the retinas of 60-week-old OLETF rats increased with increasing Glu. CCO activity in the retinas of OLETF rats showed no significant difference from that in LETO rats; however, ATP levels in the retinas of OLETF rats were significantly lower than those in LETO rats. The oral administration of aminoguanidine or disulfiram, an iNOS inhibitor, attenuated the decrease in ATP levels in the retinas of 60-week-old OELTF rats. CONCLUSION: The present study demonstrates that NO production via iNOS in the retinas of 60-week-old OLETF rats is caused by hyperglycemia, and that NO causes a decrease in ATP contents in the retinas of 60-week-old OELTF rats. It is possible that the low ATP contents caused by NO may affect the normal functioning of the retina in OLETF rats.

Femoral bone structure in Otsuka Long-Evans Tokushima Fatty rats.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) increases fracture risk despite normal to high levels of bone mineral density. Bone quality is known to affect bone fragility in T2DM. The aim of this study was to clarify the trabecular bone microstructure and cortical bone geometry of the femur in T2DM model rats. METHODS: Five-week-old Otsuka Long-Evans Tokushima Fatty (OLETF; n = 5) and Long-Evans Tokushima Otsuka (LETO; n = 5) rats were used. At the age of 18 months, femurs were scanned with micro-computed tomography, and trabecular bone microstructure and cortical bone geometry were analyzed. RESULTS: Trabecular bone microstructure and cortical bone geometry deteriorated in the femur in OLETF rats. Compared with in LETO rats, in OLETF rats, bone volume fraction, trabecular number and connectivity density decreased, and trabecular space significantly increased. Moreover, in OLETF rats, cortical bone volume and section area decreased, and medullary volume significantly increased. CONCLUSIONS: Long-term T2DM leaded to deterioration in trabecular and cortical bone structure. Therefore, OLETF rats may serve as a useful animal model for investigating the relationship between T2DM and bone quality.

Femoral bone structure in Otsuka Long-Evans Tokushima Fatty rats

OBJECTIVES: Type 2 diabetes mellitus (T2DM) increases fracture risk despite normal to high levels of bone mineral density. Bone quality is known to affect bone fragility in T2DM. The aim of this study was to clarify the trabecular bone microstructure and cortical bone geometry of the femur in T2DM model rats. METHODS: Five-week-old Otsuka Long-Evans Tokushima Fatty (OLETF; n = 5) and Long-Evans Tokushima Otsuka (LETO; n = 5) rats were used. At the age of 18 months, femurs were scanned with micro-computed tomography, and trabecular bone microstructure and cortical bone geometry were analyzed. RESULTS: Trabecular bone microstructure and cortical bone geometry deteriorated in the femur in OLETF rats. Compared with in LETO rats, in OLETF rats, bone volume fraction, trabecular number and connectivity density decreased, and trabecular space significantly increased. Moreover, in OLETF rats, cortical bone volume and section area decreased, and medullary volume significantly increased. CONCLUSIONS: Long-term T2DM leaded to deterioration in trabecular and cortical bone structure. Therefore, OLETF rats may serve as a useful animal model for investigating the relationship between T2DM and bone quality.

Rare sugar D-psicose prevents progression and development of diabetes in T2DM model Otsuka Long-Evans Tokushima Fatty rats.

BACKGROUND: The fundamental cause of overweight and obesity is consumption of calorie-dense foods. We have introduced a zero-calorie sweet sugar, d-psicose (d-allulose), a rare sugar that has been proven to have strong antihyperglycemic and antihyperlipidemic effects, and could be used as a replacement of natural sugar for the obese and diabetic subjects. AIM: Above mentioned efficacy of d-psicose (d-allulose) has been confirmed in our previous studies on type 2 diabetes mellitus (T2DM) model Otsuka Long-Evans Tokushima Fatty (OLETF) rats with short-term treatment. In this study we investigated the long-term effect of d-psicose in preventing the commencement and progression of T2DM with the mechanism of preservation of pancreatic ß-cells in OLETF rats. METHODS: Treated OLETF rats were fed 5% d-psicose dissolved in water and control rats only water. Nondiabetic control rats, Long-Evans Tokushima Otsuka (LETO), were taken as healthy control and fed water. To follow the progression of diabetes, periodic measurements of blood glucose, plasma insulin, and body weight changes were continued till sacrifice at 60 weeks. Periodic in vivo body fat mass was measured. On sacrifice, pancreas, liver, and abdominal adipose tissues were collected for various staining tests. RESULTS: d-Psicose prevented the commencement and progression of T2DM till 60 weeks through the maintenance of blood glucose levels, decrease in body weight gain, and the control of postprandial hyperglycemia, with decreased levels of HbA1c in comparison to nontreated control rats. This improvement in glycemic control was accompanied by the maintenance of plasma insulin levels and the preservation of pancreatic ß-cells with the significant reduction in inflammatory markers. Body fat accumulation was significantly lower in the treatment group, with decreased infiltration of macrophages in the abdominal adipose tissue. CONCLUSION: Our findings suggest that the rare sugar d-psicose could be beneficial for the prevention and control of obesity and hyperglycemia with the preservation of ß-cells in the progression of T2DM.

Adolescent rats are more prone to binge eating behavior: a study of age and obesity as risk factors.

Binge eating (BE) is characterized by repeated, intermittent over-consumption of food in a brief period of time. This study aims to advance the understanding of potential risk factors for BE such as obesity, overeating and adolescence as an age group. We used the Otsuka Long Evans Tokushima Fatty (OLETF) rat, a genetic overeating-induced obesity model with increased preferences for sweet and fat. Adolescent and adult rats from both strains (OLETF and the lean control strain, Long Evans Tokushima Otsuka [LETO]) received limited access to a palatable liquid diet (Ensure vanilla) for three weeks. Water and chow were available throughout the study, but access to Ensure was limited to two hours, three times a week (3TW group) or every work day (5TW group). As expected, OLETF rats consumed more Ensure and were more BE-prone (BEP) than LETO rats at both ages. Adolescent rats showed a significantly larger binge size as demonstrated by a greater increase in Ensure intake, compared to adults. Furthermore, while the adults reduced their chow intake, compensating for increased Ensure intake, the adolescents increased their chow intake too. Finally, the adolescent rats showed binge like behavior earlier in the study and they tended to be BEP more than the adults. Our findings in rats suggest that adolescents and in particular obese adolescents are at risk for BE, and BE can lead to overweight, thus providing the basis for examination of biological mechanisms of this process in animal models.

Anti-diabetic effects of benfotiamine on an animal model of type 2 diabetes mellitus / 대한수의학회지

Although benfotiamine has various beneficial anti-diabetic effects, the detailed mechanisms underlying the impact of this compound on the insulin signaling pathway are still unclear. In the present study, we evaluated the effects of benfotiamine on the hepatic insulin signaling pathway in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a type 2 diabetes mellitus model. OLETF rats treated with benfotiamine showed decreased body weight gain and reduced adipose tissue weight. In addition, blood glucose levels were lower in OLETF rats treated with benfotiamine. Following treatment with benfotiamine, the levels of Akt phosphorylation (S473/T308) in the OLETF groups increased significantly compared to the OLETF control group so that they were almost identical to the levels observed in the control group. Moreover, benfotiamine restored the phosphorylation levels of both glycogen synthase kinase (GSK)-3alpha/beta (S21, S9) and glycogen synthase (GS; S641) in OLETF rats to nearly the same levels observed in the control group. Overall, these results suggest that benfotiamine can potentially attenuate type 2 diabetes mellitus in OLETF rats by restoring insulin sensitivity through upregulation of Akt phosphorylation and activation of two downstream signaling molecules, GSK-3alpha/beta and GS, thereby reducing blood glucose levels through glycogen synthesis.

Chronic alcohol consumption, type 2 diabetes mellitus, insulin-like growth factor-I (IGF-I), and growth hormone (GH) in ethanol-treated diabetic rats.

AIMS: Alcohol has deleterious influences on glucose metabolism which may contribute to the development of type 2 diabetes mellitus (T2DM). Insulin-like growth factor I (IGF-I) and growth hormone (GH), which interact with insulin to modulate metabolic control, have been shown to be related to impaired glucose tolerance. This study was conducted to assess the possibility that altered circulating IGF-I and GH levels contribute to the exacerbation of T2DM by alcohol use in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. MAIN METHOD: OLETF rats were pair-fed a Lieber-DeCarli Regular Ethanol diet and LETO rats were pair-fed a control diet for 6 weeks. At 6 weeks, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and IGF-I and GH levels were evaluated. KEY FINDINGS: Prior to an IP-GTT, OLETF-Ethanol (O-E) group had significantly a decrease in the mean glucose levels compared to OLETF-Control (O-C) group. At 120 min post IP-GTT, the O-E group had significantly an increase in the mean glucose levels compared to O-C group. The serum IGF-I levels were significantly lower and the serum GH levels were significantly higher in the O-E group than in L-C group. SIGNIFICANCE: These results suggest that IGF-I and GH are prominent in defining the risk and development of T2DM, and may be adversely affected by heavy alcohol use, possibly mediating its diabetogenic effects. Thus, the overall glucose intolerance in the setting of alcoholism may be attributable to inappropriate alteration of IGF-I and GH levels.

Management of diabetic complications: a chemical constituents based approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Long term hyperglycemia leads to development of complications associated with diabetes. Diabetic complications are now a global health problem without effective therapeutic approach. Hyperglycemia and oxidative stress are important components for the development of diabetic complications. Over the past few decades, herbal medicines have attracted much attention as potential therapeutic agents in the prevention and treatment of diabetic complications due to their multiple targets and less toxic side effects. This review aims to assess the current available knowledge of medicinal herbs for attenuation and management of diabetic complications and their underlying mechanisms. MATERIAL AND METHODS: Bibliographic investigation was carried out by scrutinizing classical text books and peer reviewed papers, consulting worldwide accepted scientific databases (SCOPUS, PUBMED, SCIELO, NISCAIR, Google Scholar) to retrieve available published literature. The inclusion criteria for the selection of plants were based upon all medicinal herbs and their active compounds with attributed potentials in relieving diabetic complications. Moreover, plants which have potential effect in ameliorating oxidative stress in diabetic animals have been included. RESULTS: Overall, 238 articles were reviewed for plant literature and out of the reviewed literature, 127 articles were selected for the study. Various medicinal plants/plant extracts containing flavonoids, alkaloids, phenolic compounds, terpenoids, saponins and phytosterol type chemical constituents were found to be effective in the management of diabetic complications. This effect might be attributed to amelioration of persistent hyperglycemia, oxidative stress and modulation of various metabolic pathways involved in the pathogenesis of diabetic complications. CONCLUSION: Screening chemical candidate from herbal medicine might be a promising approach for new drug discovery to treat the diabetic complications. There is still a dire need to explore the mechanism of action of various plant extracts and their toxicity profile and to determine their role in therapy of diabetic complications. Moreover, a perfect rodent model which completely mimics human diabetic complications should be developed.

Protective Effects of Lithospermic Acid B on Diabetic Nephropathy in OLETF Rats Comparing with Amlodipine and Losartan / 당뇨병

BACKGROUND: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 and type 2 diabetic animal models. We examined the effects of LAB on the prevention of diabetic nephropathy compared with amlodipine, a calcium channel blocker, and losartan, an angiotensin receptor blocker, in Otsuka Long-Evans-Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. METHODS: LAB (20 mg/kg), amlodipine (10 mg/kg), or losartan (10 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. RESULTS: None of LAB, losartan, and amlodipine exhibited effects on blood glucose levels. Treatment with amlodipine or losartan resulted in similar reductions in blood pressure; however, LAB was less effective in lowering blood pressure. Albuminuria was markedly suppressed by losartan and LAB, but not by amlodipine. LAB treatment decreased levels of renal lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta1 (TGF-beta1). CONCLUSION: These results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing oxidative stress and inflammation as potent as losartan.

Effects of exercise and dietary therapies on renal function and morphological findings in the kidney and glucose-fatty metabolism in oletf rats. Use of oletf rats as a model of type II diabetes mellitus / 体力科学

The effects of exercise and dietary therapy on the prevention of diabetic nephropathy (DN) were compared. Thirty-two male OLETF rats were divided into four groups (Ex, Diet, Sed, Pre) . Fourteen LETO rats served as the normal controls. Therapy was conducted for 10 weeks from age 22 to 31 weeks. The Ex group was trained by voluntary exercise, and the Diet group had a restricted food intake resulting in the same BW as that of the Ex group. The Ex developed a significant increase in urinary albumin excretion compared to the Diet group, although significantly less than the Sed group. Blood pressure in the Ex group showed a tendency to be higher during therapy. BW and serum lipids were significantly reduced, and glucose intolerance was improved in both the Ex and Diet groups. There were no differences in the metabolic indices between the Ex and Diet groups. The Ex group showed a significantly heavier kidney weight and a tendency for enlargement of the glomerular area and volume. The protective effect of DN through improvement of the metabolic dis-order by exercise might be offset by exercise-induced renal loads. Control of exercise intensity and blood pressure appear to be important as well as the improvement of glucose intolerance and lipid metabolisms in exercise therapy to prevent an occurrence and development of DN.

Influence of plasma lipid level on the accumulation of glomerular extracellular matrix in OLETF diabetic rats / 中国糖尿病杂志

Objective To investigate the effect of changes in plasma lipid levels on the accumulation of glomerular extracellular matrix in type 2 diabetic rats.Methods Rats were divided into three groups,namely,normal control,diabetes mellitus treated with Fenofibrate,which was gastrically administrated in the dose of 20mg?kg -1 ?d -1 for 22 weeks.A quantitative analysis of the components of glomerular extracellular matrix (ECM) were performed with immunoperoxide (ABC) method and the computer imagine analysis system.Results The result showed that diabetic rats had significantly higher plasma lipid levels and accumulation of ECM including collagen Ⅳ,laminine and fibronectin than the normal control ( P