scholarly journals Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

2020 ◽  
Author(s):  
Luc Bergougnan ◽  
Grit Andersen ◽  
Leona Plum-Moerschel ◽  
Maria Francesca Evaristi ◽  
Bruno Poirier ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
G Protein ◽  
Positive Control ◽  
Diabetic Rats ◽  
Protective Effects ◽  
Protective Properties ◽  
Heart Rate Decrease ◽  
Sphingosine 1 Phosphate ◽  
Mean Differences

SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. A dose-response study in diabetic rats with 5-week SAR247799 treatment demonstrated, at sub-lymphocyte-reducing doses, renal function and endothelial biomarker improvements and was used to select doses for human investigation. Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD<7%) (n=54), were randomized, in two sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. The maximum FMD change from baseline versus placebo for all treatments was reached on day 35; mean differences versus placebo were 0.60% (95% CI -0.34%-1.53%; p=0.203) for 1 mg SAR247799, 1.07% (95% CI 0.13%-2.01%; p=0.026) for 5 mg SAR247799 and 0.88% (95% CI -0.15%-1.91%; p=0.093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. These data provide the first human evidence for endothelial-protective properties of S1P1 activation, with SAR247799 being at least as effective as the clinical benchmark, sildenafil.

scholarly journals Probiotics ameliorate pioglitazone-associated bone loss in diabetic rats

2020 ◽  
Author(s):  
Ahmad Gholami ◽  
Mohammad Hossein Dabbaghmanesh ◽  
Younes Ghasemi ◽  
Pedram Talezadeh ◽  
Farhad Koohpeyma ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Bone Loss ◽  
Lactobacillus Reuteri ◽  
Diabetic Rats ◽  
Urinary Calcium ◽  
Diabetic Patients ◽  
Protective Effects

Abstract Background Pioglitazone as a PPAR-g agonist are used for management of type 2 diabetes mellitus. Nevertheless, evidence showed that the therapeutic modulation of PPARg activity using Pioglitazone may be linked with bone mass reduction and fracture risk in type 2 diabetes mellitus patients. The objective of the current research was to inspect the preventive role of some types of probiotic strains including ( Lactobacillus acidophilus , Lactobacillus reuteri , Lactobacillus casei , Bifidiobacterum longum and Bacillus coagulans ) against pioglitazone-induced bone loss. Methods Streptozotocin (60 mg/kg) was administered for diabetes induction. Diabetic rats were fed orally with pioglitazone (300 mg/kg) and probiotics (1×109 CFU/ml/day) alone and in combination of both for 4 weeks. Dual energy X-ray absorptiometry (DEXA) were used to asses BMD, BMC and area of the femur, spine and tibia at the experiment termination. Serum glucose, serum calcium, alkaline phosphatase, phosphorus, BUN, Creatinine, and urine calcium were also analyzed. Results Administration of pioglitazone and probiotics alone and in combination significantly improved elevated blood glucose. Pioglitazone treatment significantly increased urinary calcium and BUN, and decreased ALP and creatinine. Co-treatment of probiotics with pioglitazone significantly decreased urinary calcium, creatinine and ALP. Pioglitazone showed detrimental effects on femur-BMD whereas treatment with probiotics remarkably ameliorated these effects. Among the tested probiotics Bifidiobacterum longum displayed the best protective effects on pioglitazone-induced bone loss in diabetic rats. Conclusion This study suggests probiotic supplementation in diabetic patients on pioglitazone regime could be considering as a good strategy to ameliorate bone loss induced by pioglitazone.

scholarly journals Macrophylloflavone: A New Biflavonoid from Garcinia macrophylla Mart. (Clusiaceae) for Antibacterial, Antioxidant, and Anti-Type 2 Diabetes Mellitus Activities

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Hawa Purnama Celala Ary Cane ◽  
Nurdin Saidi ◽  
Mustanir Yahya ◽  
Darusman Darusman ◽  
Erlidawati Erlidawati ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Spectroscopic Data ◽  
Ethyl Acetate Extract ◽  
Positive Control ◽  
Diabetic Rats ◽  
Antioxidant Assay ◽  
Diabetes Mellitus Treatment

Investigations of antibacterial, antioxidant, and anti-type 2 diabetes mellitus activities have been carried out on Garcinia macrophylla Mart. plant extract fractions. An isolate from a fraction of ethyl acetate extract was characterized with spectroscopic data. A new biflavonoid compound was found to have a skeleton of 5,7,4′,5″,7″,3‴,4‴-heptahydroxyflavanone[3-6″] flavones which was named macrophylloflavone (1). The compound was evaluated for its antibacterial activity against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 with cephazolin as a positive control, antioxidant assay against 2,2 diphenyl-1-picrylhydrazyl (DPPH) with ascorbic acid as the positive control, and anti-type 2 diabetes mellitus treatment with metformin as a positive control. The biflavonoid compound exhibited a good inhibition for bacteria and free radical DPPH. Furthermore, biflavonoid compound treatment on the diabetic rats suggested its ability to decrease the blood glucose level. This study provided evidence that the plant has antibacterial, antioxidant, and antidiabetic properties.

scholarly journals Protective effects of calorie restriction on insulin resistance and islets function in STZ-induced type 2 diabetes rats

2020 ◽  
Author(s):  
Li Zhang ◽  
Ying-juan Huang ◽  
Jia-pan Sun ◽  
Ting-ying Zhang ◽  
Tao-li Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Uptake ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Chow Diet ◽  
Protective Effects ◽  
Insulin Tolerance ◽  
Calorie Diet

Abstract Background Caloric restriction (CR), as the only approved scientific method that can retard aging, has become more and more attractive in the treatment of type 2 diabetes mellitus (T2DM) due to increasingly common high calorie diet and sedentary lifestyle. This study aimed to evaluate its role in T2DM treatment and further explored the potential molecular mechanism.Methods A total of 60 male SD rats were used in this study. Diabetes model was induced by 8 weeks of high-fat diet (HFD) followed by a single dose of streptozotocin injection (30mg/kg). Subsequently, the diabetic rats were fed ab libitum of 28g/day (diabetic control) or 20g/day (30% CR regimen) with HFD for 20 weeks. Meanwhile, normal rats had free standard chow diet served as vehicle control. Body mass, plasma glucose, and lipid profile were monitored. After diabetes-related functional tests being done, rats were sacrificed at 10 and 20 weeks, and glucose uptake in fresh muscle were determined. Liver and pancreas were prepared for histopathology and histochemical evaluations, and western blotting and immunofluorescence were applied to detect alterations in AKT/AS160/GLUT4 signaling. Results 30% CR significantly attenuated hyperglycemia and dyslipidemia, leading to alleviation of glucolipotoxicity, thus protected islets secretion, retarding the exhaustion of islets function. Insulin resistance was also markedly ameliorated, as indicated by notably improved insulin tolerance and HOMA-IR. However, glucose uptake in skeletal muscle was not significantly improved, and the up-regulation of AKT/AS160/GLUT4 signaling in muscle induced by 30% CR attenuated gradually over time. However, the consecutive decrease in AKT/AS160/GLUT4 signaling in white adipose tissue was significantly reversed by 30% CR. Conclusion 30% CR could protect islets function from hyperglycemia and dyslipidemia, and improve insulin resistance with probable mechanism related to the up-regulation of AKT/AS160/GLUT4 signaling.

scholarly journals Probiotics Ameliorate Pioglitazone-associated Bone Loss in Diabetic Rats

2020 ◽  
Author(s):  
Ahmad Gholami ◽  
Mohammad Hossein Dabbaghmanesh ◽  
Younes Ghasemi ◽  
Pedram Talezadeh ◽  
Farhad Koohpeyma ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Bone Loss ◽  
Lactobacillus Reuteri ◽  
Diabetic Rats ◽  
Urinary Calcium ◽  
Diabetic Patients ◽  
Protective Effects

Abstract Background: Pioglitazone as a PPAR-g agonist are used for management of type 2 diabetes mellitus. Nevertheless, evidence showed that the therapeutic modulation of PPARg activity using Pioglitazone may be linked with bone mass reduction and fracture risk in type 2 diabetes mellitus patients. The objective of the current research was to inspect the preventive role of some types of probiotic strains including (Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei, Bifidiobacterum longum and Bacillus coagulans) against pioglitazone-induced bone loss.Methods: Streptozotocin (60 mg/kg) was administered for diabetes induction. Diabetic rats were fed orally with pioglitazone (300 mg/kg) and probiotics (1×109 CFU/ml/day) alone and in combination of both for 4 weeks. Dual energy X-ray absorptiometry (DEXA) were used to asses BMD, BMC and area of the femur, spine and tibia at the experiment termination. Serum glucose, serum calcium, alkaline phosphatase, phosphorus, BUN, Creatinine, and urine calcium were also analyzed. Results: Administration of pioglitazone and probiotics alone and in combination significantly improved elevated blood glucose. Pioglitazone treatment significantly increased urinary calcium and BUN, and decreased ALP and creatinine. Co-treatment of probiotics with pioglitazone significantly decreased urinary calcium, creatinine and ALP. Pioglitazone showed detrimental effects on femur-BMD whereas treatment with probiotics remarkably ameliorated these effects. Among the tested probiotics Bifidiobacterum longum displayed the best protective effects on pioglitazone-induced bone loss in diabetic rats.Conclusion:This study suggests probiotic supplementation in diabetic patients on pioglitazone regime could be considering as a good strategy to ameliorate bone loss induced by pioglitazone.

Blockade of Renin Angiotensin System Ameliorates the Cardiac Arrhythmias and Sympathetic Neural Remodeling in Hearts of Type 2 DM Rat Model

2020 ◽  
Vol 20 (3) ◽  
pp. 464-478 ◽  
Author(s):  
Yomna M. Yehya ◽  
Abdelaziz M. Hussein ◽  
Khaled Ezam ◽  
Elsayed A. Eid ◽  
Eman M. Ibrahim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiac Arrhythmias ◽  
Sympathetic Nerve ◽  
Renin Angiotensin System ◽  
Diabetic Rats ◽  
Angiotensin System ◽  
Type 2 Dm ◽  
Type 2 Diabetic ◽  
Diabetes Induction

Objectives:: The present study was designed to investigate the effects of renin angiotensin system (RAS) blockade on cardiac arrhythmias and sympathetic nerve remodelling in heart tissues of type 2 diabetic rats. Methods:: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group: normal rats, b) DM group; after type 2 diabetes induction, rats received 2ml oral saline daily for 4 weeks, c) DM+ ACEi: after type 2 diabetes induction, rats were treated with enalapril (10 mg/kg, orally for 4 weeks) and d) DM+ ARBs: after type 2 diabetes induction, rats were treated with losartan (30 mg/kg, orally for 4 weeks). Results:: In type 2 diabetic rats, the results demonstrated significant prolongation in Q-T interval and elevation of blood sugar, HOMA-IR index, TC, TGs, LDL, serum CK-MB, myocardial damage, myocardial MDA, myocardial norepinephrine and tyrosine hydroxylase (TH) density with significant reduction in serum HDL, serum insulin and myocardial GSH and CAT. On the other hand, blockade of RAS at the level of either ACE by enalapril or angiotensin (Ag) receptors by losartan resulted in significant improvement in ECG parameters (Q-T), cardiac enzymes (CK-MB), cardiac morphology, myocardial oxidative stress (low MDA, high CAT and GSH) and myocardial TH density. Conclusions:: RAS plays a role in the cardiac sympathetic nerve sprouting and cardiac arrhythmias induced by type 2 DM and its blockade might have a cardioprotective effect via attenuation of sympathetic nerve fibres remodelling, myocardial norepinephrine contents and oxidative stress.

Discovery of a potent G-protein-coupled receptor 119 agonist for the treatment of type 2 diabetes

2021 ◽  
Vol 35 ◽  
pp. 116071
Author(s):  
Suresh Pola ◽  
Shailesh R. Shah ◽  
Harikishore Pingali ◽  
Pandurang Zaware ◽  
Baban Thube ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Role of TLR4/MyD88/NF-κB signaling in heart and liver-related complications in a rat model of type 2 diabetes mellitus

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052199759
Author(s):  
Jiajia Tian ◽  
Yanyan Zhao ◽  
Lingling Wang ◽  
Lin Li
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Signaling Pathway ◽  
Rat Model ◽  
Fasting Blood Glucose ◽  
Diabetic Rats ◽  
Primary Response ◽  
Monocyte Chemoattractant Protein 1

Aims To analyze expression of members of the Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB signaling pathway in the heart and liver in a rat model of type 2 diabetes mellitus (T2DM). Our overall goal was to understand the underlying pathophysiological mechanisms. Methods We measured fasting blood glucose (FBG) and insulin (FINS) in a rat model of T2DM. Expression of members of the TLR4/MyD88/NF-κB signaling pathway as well as downstream cytokines was investigated. Levels of mRNA and protein were assessed using quantitative real-time polymerase chain reaction and western blotting, respectively. Protein content of tissue homogenates was assessed using enzyme-linked immunosorbent assays. Results Diabetic rats had lower body weights, higher FBG, higher FINS, and higher intraperitoneal glucose tolerance than normal rats. In addition, biochemical indicators related to heart and liver function were elevated in diabetic rats compared with normal rats. TLR4 and MyD88 were involved in the occurrence of T2DM as well as T2DM-related heart and liver complications. TLR4 caused T2DM-related heart and liver complications through activation of NF-κB. Conclusions TLR4/MyD88/NF-κB signaling induces production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, leading to the heart- and liver-related complications of T2DM.

scholarly journals Metabolic syndrome in premenopausal and postmenopausal women with type 2 diabetes: loss of protective effects of premenopausal status

2014 ◽  
Vol 13 (1) ◽  
Author(s):  
Manouchehr Nakhjavani ◽  
Mehrnaz Imani ◽  
Mehrdad Larry ◽  
Arash Aghajani-Nargesi ◽  
Afsaneh Morteza ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Postmenopausal Women ◽  
Protective Effects

scholarly journals The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Kira V. Derkach ◽  
Vera M. Bondareva ◽  
Oxana V. Chistyakova ◽  
Lev M. Berstein ◽  
Alexander O. Shpakov
Keyword(s):  
Type 2 Diabetes ◽  
High Fat Diet ◽  
Low Dose ◽  
Diabetic Rats ◽  
Brain Serotonin ◽  
Serotonin Level ◽  
High Fat ◽  
Brain Serotonin Level ◽  
The Brain

In the last years the treatment of type 2 diabetes mellitus (DM2) was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg) on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS) at a daily dose of 20 μg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC) activity in the hypothalamus and normalized AC stimulation byβ-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications.

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