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D-allulose protects against diabetic nephropathy progression in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes

ABSTRACT: d-allulose is a rare sugar that has been reported to possess anti-hyperglycemic effects. In the present study, we hypothesized that d-allulose is effective in attenuating the progression of diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of type 2 diabetes mellitus. Drinking water with or without 3% d-allulose was administered to OLETF rats for 13 weeks. Long-Evans Tokushima Otsuka rats that received drinking water without d-allulose were used as non-diabetic control rats. d-allulose significantly attenuated the increase in blood glucose levels and progressive mesangial expansion in the glomerulus, which is regarded as a characteristic of diabetic nephropathy, in OLETF rats. d-allulose also attenuated the significant increases in renal IL-6 and tumor necrosis factor-α mRNA levels in OLETF rats, which is a proinflammatory parameter. Additionally, we showed that d-allulose suppresses mesangial matrix expansion, but its correlation with suppressing renal inflammation in OLETF rats should be investigated further. Collectively, our results support the hypothesis that d-allulose can prevent diabetic nephropathy in rats.

SUBMITTER: Niibo M

PROVIDER: S-EPMC8803202 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Sildenafil, a phosphodiesterase type 5 inhibitor, attenuates diabetic nephropathy in non-insulin-dependent Otsuka Long-Evans Tokushima Fatty rats.

Project description:BackgroundIt is well established that the pathogenesis of diabetic nephropathy is associated with abnormalities of renal nitric oxide (NO) generation. Many of the biological actions of NO are mediated by cGMP, which is rapidly degraded by phosphodiesterases. In this study, we evaluated the renoprotective effects of sildenafil (SIL), an inhibitor of phosphodiesterase-5, in type 2 diabetic rats.MethodsMale Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent diabetes model, and Long-Evans Tokushima Otsuka rats, a non-diabetic control, were treated with either SIL (2.5 mg·kg(-1) in drinking water) or undosed water for 28 weeks, starting at 30 weeks of age.ResultsSildenafil treatment significantly decreased albuminuria, attenuated glomerular hyperfiltration and resulted in a decrease in glomerular hypertrophy, in addition to a reduced glomerulosclerosis score and a dramatic decrease in the number of glomerular and tubulointerstitial proliferating cell nuclear antigen-positive cells in OLETF rats. This was accompanied by a significant reduction in renal cortical mRNA levels of collagen types I and III. The increased mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 in the OLETF rats were significantly or partially attenuated by SIL treatment.ConclusionsThis study suggests that SIL attenuated diabetic nephropathy due to its potent antiproliferative effects and its regulatory effects on extracellular matrix. This latter effect is thought to be a result of its ability to affect the balance between MMPs and their inhibitors.

| S-EPMC3058170 | biostudies-literature

Anti-obesity effects of granulocyte-colony stimulating factor in Otsuka-Long-Evans-Tokushima fatty rats.

Project description:Granulocyte-colony stimulating factor (G-CSF) has molecular structures and intracellular signaling pathways that are similar to those of leptin and ciliary neurotropic factor (CNTF). It also has immune-modulatory properties. Given that leptin and CNTF play important roles in energy homeostasis and that obesity is an inflammatory condition in adipose tissue, we hypothesized that G-CSF could also play a role in energy homeostasis. We treated 12 38-week-old male Otsuka-Long-Evans-Tokushima fatty rats (OLETF, diabetic) and 12 age-matched male Long-Evans-Tokushima rats (LETO, healthy) with 200 µg/day G-CSF or saline for 5 consecutive days. Body weight reduction was greater in G-CSF-treated OLETF (G-CSF/OLETF) than saline-treated OLETF (saline/OLETF) following 8 weeks of treatment (-6.9±1.6% vs. -3.1±2.2%, p<0.05). G-CSF treatment had no effect on body weight in LETO or on food intake in either OLETF or LETO. Body fat in G-CSF/OLETF was more reduced than in saline/OLETF (-32.2±3.1% vs. -20.8±6.2%, p<0.05). Energy expenditure was higher in G-CSF/OLETF from 4 weeks after the treatments than in saline/OLETF. Serum levels of cholesterol, triglyceride, interleukin-6 and tumor necrosis factor-α were lower in G-CSF/OLETF than in saline/OLETF. Uncoupling protein-1 (UCP-1) expression in brown adipose tissue (BAT) was higher in G-CSF/OLETF than in saline/OLETF, but was unaffected in LETO. Immunofluorescence staining and PCR results revealed that G-CSF receptors were expressed in BAT. In vitro experiments using brown adipocyte primary culture revealed that G-CSF enhanced UCP-1 expression from mature brown adipocytes via p38 mitogen-activated protein kinase pathway. In conclusion, G-CSF treatment reduced body weight and increased energy expenditure in a diabetic model, and enhanced UCP-1 expression and decreased inflammatory cytokine levels may be associated with the effects of G-CSF treatment.

| S-EPMC4140798 | biostudies-literature

UDP-induced relaxation is enhanced in aorta from female obese Otsuka Long-Evans Tokushima Fatty rats.

Project description:Uridine 5'-diphosphate (UDP) plays an important role in controlling vascular tone; however, UDP-mediated response in metabolic syndromes, including obesity and type 2 diabetes in females, remains unclear. In this study, we investigated UDP-mediated response in the aorta of female obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats. In OLETF rat aortas precontracted by phenylephrine (PE) (vs. LETO), (1) UDP-induced relaxation was increased, whereas acetylcholine (ACh)-induced relaxation was decreased; (2) no UDP- or ACh-induced relaxations were observed in endothelial denudation, whereas UDP-induced small contraction was observed; and (3) NG-nitro-L-arginine [L-NNA, a nitric oxide (NO) synthase inhibitor] eliminated UDP-induced relaxation and small contraction, whereas caused contrasting responses by ACh, including slight relaxations (LETO) and contractions (OLETF). Indomethacin, a cyclooxygenase inhibitor, eliminated the difference in UDP- and ACh-induced relaxations between the groups by increased UDP-induced relaxation in the LETO group and increased ACh-induced relaxation in the OLETF group. MRS2578, a P2Y6 receptor antagonist, eliminated the difference in UDP-induced relaxations between the groups by decreasing UDP-induced relaxation in the OLETF group. MRS2578 had no effect on UDP-induced contraction in endothelium-denuded aortas. Therefore, these findings demonstrate opposite trends of relaxations by UDP and ACh in OLETF and LETO rat aortas. These differences may be attributed to the imbalance between NO and vasoconstrictor prostanoids upon stimulations. Increased UDP-induced relaxation in OLETF rat aorta may be caused by the activation of endothelial MRS2578-sensitive P2Y6 receptor.

| S-EPMC5842156 | biostudies-literature

Otsuka Long-Evans Tokushima fatty rats with Roux-en-Y gastric bypass surgery

Project description:Objective: The mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We previously observed temporal migrations in small intestinal glycolysis, suggesting that glucose excretion may contribute to glucose homeostasis. This study aimed to evaluate the mechanisms underlying serum glucose excretion and its contribution to glucose homeostasis by using 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography. Design: FDG distribution in reconstructed intestinal limbs of sham- or RYGB-operated obese rats was identified. RNA sequencing was performed in areas of high or low FDG uptake.

2023-11-01 | GSE161404 | GEO

Effect of fosinopril on the renal cortex protein expression profile of Otsuka Long-Evans Tokushima Fatty rats.

Project description:Angiotensin-converting enzyme inhibitors (ACEIs) can reduce urinary protein excretion and postpone the deterioration of renal function. However, the mechanisms of renal protection are not yet fully understood. To investigate the mechanisms of ACEIs in the treatment of diabetic nephropathy (DN), the present study determined the effects of the ACEI fosinopril (FP) on the profiling of renal cortex protein expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats using Long-Evans Tokushima Otsuka (LETO) rats as controls. Urinary protein levels at 24 h were examined using the Broadford method. PAS staining was performed to observe renal histopathological changes. The kidney cortices of OLETF, FP-treated OLETF and LETO rats were examined using soluble and insoluble high-resolution subproteomic analysis methodology at age of 36 and 56 weeks. Differentiated proteins were further confirmed using western blotting analysis. The results demonstrated that FP significantly decreased the glomerulosclerosis index and reduced the 24 h urinary protein excretion of OLETF rats. Additionally, 17 proteins significantly changed following FP-treatment. Amongst these proteins, the abundances of the stress-response protein heat shock protein family A member 9 and the antioxidant glutathione peroxidase 3 were particularly increased. These results indicated that FP ameliorated diabetic renal injuries by inhibiting oxidative stress. In conclusion, the differentially expressed proteins may improve our understanding of the mechanism of ACEIs in the OLETF rats.

| S-EPMC6909786 | biostudies-literature

Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes.

Project description:This study aimed to determine whether taurine supplementation improves metabolic disturbances and diabetic complications in an animal model for type 2 diabetes. We investigated whether taurine has therapeutic effects on glucose metabolism, lipid metabolism, and diabetic complications in Otsuka Long- Evans Tokushima fatty (OLETF) rats with long-term duration of diabetes. Fourteen 50-week-old OLETF rats with chronic diabetes were fed a diet supplemented with taurine (2%) or a non-supplemented control diet for 12 weeks. Taurine reduced blood glucose levels over 12 weeks, and improved OGTT outcomes at 6 weeks after taurine supplementation, in OLETF rats. Taurine significantly reduced insulin resistance but did not improve β-cell function or islet mass. After 12 weeks, taurine significantly decreased serum levels of lipids such as triglyceride, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Taurine significantly reduced serum leptin, but not adiponectin levels. However, taurine had no therapeutic effect on damaged tissues. Taurine ameliorated hyperglycemia and dyslipidemia, at least in part, by improving insulin sensitivity and leptin modulation in OLETF rats with long-term diabetes. Additional study is needed to investigate whether taurine has the same beneficial effects in human diabetic patients.

| S-EPMC3509183 | biostudies-literature

Mechanisms underlying lysophosphatidylcholine-induced potentiation of vascular contractions in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat aorta.

Project description:BACKGROUND AND PURPOSE: The effect of lysophosphatidylcholine (LPC) on aortic contractions in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetic model, was studied. EXPERIMENTAL APPROACH: Using OLETF rats and control (Long Evans Tokushima Otsuka (LETO)) rats, the effects of LPC on the contractions induced by high-K(+) (10-40 mM), UK14,304 (10 approximately 100 nM; a selective alpha(2)-adrenoceptor agonist) and sodium orthovanadate (SOV; 10 microM approximately 3 mM) in endothelium-denuded aortae were compared. Aortic ERK activity and the mRNA expression for GPR4 (a putative LPC receptor) were also measured. KEY RESULTS: OLETF rats exhibited (vs. age-matched LETO rats): (1) greater potentiation of high-K(+)-induced contraction by 10 microM LPC - a potentiation attenuated by 10 microM genistein, protein tyrosine kinase (PTK) inhibitor, (2) greater potentiation of UK14,304 (10 approximately 100 nM)-induced contractions by LPC (1 microM approximately 10 microM) - a potentiation attenuated by 10 microM genistein, 50 microM tyrphostin A23 (PTK inhibitor) or 10 microM PD98059 (MEK 1/2 inhibitor), (3) greater basal and LPC (1 microM)-induced ERK activities, (4) greater basal and 100 nM UK14,304-stimulated ERK2 activities in both the absence and presence of 10 microM LPC, (5) greater SOV (10 microM approximately 3 mM)-induced contractions, (6) greater potentiation of SOV-induced contractions by 10 microM LPC - a potentiation suppressed by 10 microM PD98059 or 10 microM genistein, (7) upregulation of GPR4 mRNA. CONCLUSIONS AND IMPLICATIONS: These results suggest that the LPC-induced potentiation of contractions in the OLETF rat aorta may be attributable to increased PTKs or ERK activity and/or to receptor upregulation.

| S-EPMC2014696 | biostudies-other

Otsuka Long-Evans Tokushima fatty rats with Roux-en-Y gastric bypass surgery

Project description:Otsuka Long-Evans Tokushima fatty rats with Roux-en-Y gastric bypass surgery

| PRJNA678226 | ENA

Investigation of Metabolism of Exogenous Glucose at the Early Stage and Onset of Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats Using [1, 2, 3-13C]Glucose Breath Tests.

Project description:This study aimed to evaluate changes in glucose metabolism at the early stage and onset of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Specifically, after the oral administration of [1, 2, 3-13C]glucose, the levels of exhaled 13CO2, which most likely originated from pyruvate decarboxylation and tricarboxylic acid, were measured. Eight OLETF rats and eight control rats (Long-Evans Tokushima Otsuka [LETO]) were administered 13C-glucose. Three types of 13C-glucose breath tests were performed thrice in each period at 2-week intervals. [3-13C]glucose results in a 13C isotope at position 1 in the pyruvate molecule, which provides 13CO2. The 13C at carbons 1 and 2 of glucose is converted to 13C at carbons 2 and 1 of acetate, respectively, which produce 13CO2. Based on metabolic differences of the labeled sites, glucose metabolism was evaluated using the results of three breath tests. The increase in 13CO2 excretion in OLETF rats was delayed in all three breath tests compared to that in control rats, suggesting that OLETF rats had a lower glucose metabolism than control rats. In addition, overall glucose metabolism increased with age in both groups. The utilization of [2-13C]glucose was suppressed in OLETF rats at 6-12 weeks of age, but they showed higher [3-13C]glucose oxidation than control rats at 22-25 weeks of age. In the [1-13C]glucose breath test, no significant differences in the area under the curve until 180 minutes (AUC180) were observed between OLETF and LETO rats of any age. Glucose metabolism kinetics were different between the age groups and two groups of rats; however, these differences were not significant based on the overall AUC180 of [1-13C]glucose. We conclude that breath 13CO2 excretion is reduced in OLETF rats at the primary stage of prediabetes, indicating differences in glucose oxidation kinetics between OLETF and LETO rats.

| S-EPMC4970713 | biostudies-literature

Coriandrum sativum seeds extract mitigate progression of diabetic nephropathy in experimental rats via AGEs inhibition.

Project description:Inthe present study, we have demonstrated the phytochemical composition of petroleum ether extract of C. sativum (CPE) seeds by using chromatographic, spectroscopic as well spectrometric analysis. CPE was evaluated for its possible role in mitigation of diabetic nephropathy (DN) in Streptozotocin (STZ)-nicotinamide (NAD) induced type 2 diabetes model. Administration of CPE at doses of 100, 200, and 400 mg/kg for 45 days has produced significant attenuation of elevated biochemical parameters including serum glucose, lipid and creatinine levels. CPE has also reserved albuminuria and elevated creatinine clearance in treated diabetic rats. Advanced glycation end products (AGEs) formation in kidneyswas also considerably reduced along with noteworthy increase in level of superoxide dismutase (SOD), glutathione (GSH), and decrease in lipid peroxidation in terms of thiobarbituric acid reactive species (TBARS). Molecular docking studies were also employed to reveal out the possible mechanism. In conclusion, using STZ-NAD model, we have successfully predicted that by assets of bioactive constituents CPE might inhibit the progression of DN. C. sativum may act as potential adjuvant for antidiabetic therapy and needs to be investigated further.

| S-EPMC6405108 | biostudies-literature

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