Normoglycemic Rats Research Articles

Hypoglycemic and antihyperglycemic effects of Abelmoschus esculentus and Alchornea cordifolia in normal and alloxan-induced diabetic rats

BackgroundAbelmoschus esculentus and Alchornea cordifolia are commonly used in Traditional Chinese Medicine (TCM) to treat several diseases. Abelmoschus esculentus is used to treat infertility and menorrhagia, while Alchornea cordifolia is used for the treatment of venereal diseases, cough, and diarrhoea. However, very few studies assessed the antidiabetic effects of these plants. Therefore, this study aimed to investigate the hypoglycemic and antihyperglycemic effects of aqueous extract of A. esculentus fruits and A. cordifolia leaves. Material and MethodsFresh Abelmoschus esculentus fruits and the powder from the dried leaves of Alchornea cordifolia leaves were prepared by maceration in the aqueous phase (200g/100mL and 50g/100mL respectively) for 24 hours, then filtered and concentrated in an oven at 45°C. Diabete was induced to male Wistar rats by a single intraperitoneal injection of alloxan (150 mg/kg, b.w). Rats with a blood glucose level greater than or equal to 200 mg/dL were selected, divided into groups and were daily administered orally with either aqueous extracts of A. esculentus at 30 mg/kg (AEAE30) or A. cordifolia at 400 mg/kg (AEAC400) for 14 consecutive days. For comparison, acarbose (100 mg/kg), glibenclamide (5 mg/kg), and metformin (500 mg/kg) were administered orally as reference drugs. Moreover, insuline was also used as a positive control and administered intraperitoneally at a dose of 5 IU/kg. Then, blood glucose levels, oral glucose tolerance test, oral maltose tolerance club, body weight and hemoglobin were assessed. For evaluation of the aqueous extracts in the intestinal transit, imodium (2 mg/kg, p.o) and fructine (5 mg/kg, p.o) were used as a positive control to determine the spasmolytic and laxative activities, respectively. The histopathological study of the liver, kidney, pancreas, testis, epididymis, and seminal vesicle was also carried out using the hematoxyline & eosin (H&E) technique. ResultsAEAE30 and AEAC400 significantly reduced (P<0.001) fasting blood glucose (FBG) levels and significantly prevented (P<0.001) postprandial glycemia in AI-db rats following oral glucose tolerance test (OGTT) and oral maltose tolerance test (OMTT) in alloxan-induced diabetic rats (AI-db). In normoglycemic and insulin-resistant (IR) rats, AEAE30 significantly prevented the post-prandial blood glucose level during the OGTT (P<0.01) only in normoglycemic rats. At the end of treatment, AEAE30 significantly reduced the relative weight of the liver (P<0.01) and significantly increased (P<0.001) the relative weight of the testes and pancreas while AEAC400 significantly increased the relative weight of the testes compared to untreated AI-db rats. The histopathological study revealed a restoration of alloxan-induced tissue damage close to the normal control group in AI-db animals treated with plant extracts, as well as an increase in sperm density in the epididymis unlike in the untreated AI-db group. ConclusionThese findings suggested that AEAE and AEAC exhibited hypoglycemic and antihyperglycemic activities and could be therefore a useful source of antidiabetic agent.

Antidiabetic activity and Safety evaluation of Triticum aestivum (wheatgrass) extract in Alloxan-induced diabetic rats model.

Triticum aestivum (wheatgrasses) extract was studied for antidiabetic activity using alloxan-induced diabetes mellitus in rats. Triticum aestivum at 50, 100, and 200 mg/kg showed significant antidiabetic activity; it effected profound reductions in blood glucose over 28 days, especially the higher doses of 100 and 200 mg/kg, which were more effective than Glibenclamide. At 2000 mg/kg, the extract did not lower the blood glucose of normoglycemic rats- an indication of its safety and lack of hypoglycemic responses under non-diabetic conditions. It would appear that the antidiabetic activity of Triticum aestivum is through the protection and regeneration of beta cells that enhance insulin secretion, which in turn increases the utilization of glucose and normalizes carbohydrate, fat, and protein metabolism. This gradual lowering of blood glucose levels brought on by Triticum aestivum is clinically highly desired. The elicited antidepressant effect of Triticum aestivum was very likely due to its antioxidant effects and beta-cell regeneration activity. Thus, Triticum aestivum can meet the demand for a nontoxic, safe alternative to orthodox antidiabetic agents. Triticum aestivum, antidiabetic activity, alloxan-induced diabetes, insulin secretion, beta-cell regeneration, glucose metabolism, safety, and Glibenclamide.

Sex Dependence in Control of Renal Haemodynamics and Excretion in Streptozotocin Diabetic Rats-Role of Adenosine System and Nitric Oxide.

Recently, we compared an interplay of the adenosine system and nitric oxide (NO) in the regulation of renal function between male normoglycaemic (NG) and streptozotocin-induced diabetic rats (DM). Considering the between-sex functional differences, e.g., in the NO status, we present similar studies performed in female rats. We examined if the theophylline effects (non-selective adenosine antagonist) in NG and DM females with or without active NO synthases differed from the earlier findings. In anaesthetised female Sprague Dawley rats, both NG and DM, untreated or after NO synthesis blockade with L-NAME, theophylline effects, on blood pressure, renal hemodynamics and excretion, and renal tissue NO were investigated. Renal artery blood flow (Transonic probe), cortical, outer-, and inner-medullary flows (laser-Doppler technique), and renal tissue NO signal (selective electrode) were measured. In contrast to males, in female NG and DM rats, theophylline induced renal vasodilation. In NO-deficient females, theophylline induced comparable renal vasodilatation, confirming the vasoconstrictor influence of the renal adenosine. In NG and DM females with intact NO synthesis, adenosine inhibition diminished kidney tissue NO, contrasting with an increase reported in males. Lowered baseline renal excretion in DM females suggested stimulation of renal tubular reabsorption due to the prevalence of antinatriuretic over natriuretic tubular action of adenosine receptors. An opposite inter-receptor balance pattern emerged previously from male studies. The study exposed between-sex functional differences in the interrelation of adenosine and NO in rats with normoglycaemia and streptozotocin diabetes. The findings also suggest that in diabetes mellitus, the abundance of individual receptor types can distinctly differ between females and males.

Hypoglycaemic Effects of an Aqueous Leaves Extract of Combretum micranthum in Normoglycaemic Rats

Background: In order to promote the Ivorian pharmacopoeia, we undertook the study of Combretum micranthum (Combretaceae), a plant commonly used in Ivory Coast for the treatment of diabetes. The aim of this study was to evaluate the hypoglycemic effects of an aqueous leaves extract of Combretum micranthum (EaqCM) in Wistar rats. Methods and Materials: A phytochemical screening study was performed. The pharmacological test on normoglycaemic rats was carried out in 4 groups of 5 rats per group. Rats in group 1 received 2 ml of distilled water, and rats in the test groups received doses ranging at 100 to 300 mg/kg B.W. of the EAqCM. Tests in pre-treated temporarily hyperglycemic rats were performed in 4 groups of 5 rats per group. The rats in groups 1 and 2 received 2ml of distilled water, the rats in test groups (3 and 4) received the dose of 10-2g/kg B.W. and 100 mg/kg B.W. respectively glibenclamide and EAqCM. Thirty minutes later, all rats except those in group 1 received anhydrous glucose. The protocol for testing post-treated hyperglycaemic rats is the same as that for pretreated rats, except that in this experiment glucose is administered to the animals before the test substances. Blood glucose is measured in the rats at regular intervals of 30, 60, 90, 120, 150, and 180 minutes after administration of the substances. Results: Qualitative phytochemical analysis of EAqCM revealed the presence of polyphenols, flavonoids, catechic, tannins, quinonic compounds, alkaloids, sterols, and polyterpenes. Pharmacological tests on the glycemia of normoglycemic rats showed that EAqCM has hypoglycemic properties at a dose of 100 mg/kgB.W. with a percentage reduction of 30%. In hyperglycemic rats, EAqCM and glibenclamide exhibited anti-hyperglycemic activity with respective percentages reduction of 57.47 % and 58.82 %. Conclusion: Antihyperglycemic effect of EAqCM in post-treated rats would probably be due to the presence of polyphenols and flavonoids in this extract. These results support the use of this plant in traditional medicine for the treatment of diabetes.

Extract of Schinus terebinthifolius Raddi intensifies morphological alterations in the colon of diabetic rats

There are several challenges in the treatment of diabetes mellitus. Some of these challenges include the discovery of bioactive compounds with the potential to be adjuncts in the treatment of diabetes mellitus. In this study, the effects of hydroethanolic extract of Schinus terebinthifolius Raddi on physiological, morphological, and quantitative parameters of the colon of diabetic rats were investigated. For this purpose, 16 90-day-old rats were randomly divided into four groups: Normoglycemics (N); normoglycemics treated with (50 mg/kg) the hydroethanolic extract of S. terebinthifolius Raddi (NA); streptozotocin-induced diabetics (D); and streptozotocin-induced diabetics treated with the hydroethanolic extract of S. terebinthifolius Raddi (DA). The diabetic rats had diarrhea, weight loss, increased water and food intake, and high blood glucose levels. In addition, atrophy of the entire intestinal wall and submucosa, hypertrophy of the muscularis mucosae, and changes in the histoarchitecture of the intestinal crypts and enterocytes were observed in groups NA, D, and DA. In addition, changes in collagen remodeling and the ganglia of the enteric nervous system, as well as changes in goblet cells and intraepithelial lymphocytes, were observed only in groups D and DA. Our results show that treatment with S. terebinthifolius Raddi extract does not protect the colon from the damage caused by diabetes, nor does it reverse physiological parameters. Moreover, the treatment caused morphological and quantitative changes in the colon of normoglycemic rats and intensified the damage caused by diabetes.

Somatostatin: a possible mediator of the long-term effects of experimental vertical gastrectomy on glucose metabolism in rats?

Sleeve gastrectomy (SG) is one of the most commonly performed bariatric surgeries. SG treats type 2 diabetes mellitus better than several drugs. The mechanisms that underlie this phenomenon are not clear. This study proposed that somatostatin (SST) isoforms SST-14 and SST-28 are key in the carbohydrate after SG. Surgeries were performed on 3 groups of Wistar rats: the fasting, surgery control, and SG groups. Plasma levels of glucose, insulin, SST-14, and SST-28 were measured at 2 survival periods after surgery. Islet SST receptor (SSTR) and cell populations were studied. We performed a pasireotide (SST-28 analogue) infusion assay in another group of rats to confirm the influence of SST-28 plasma levels on the delta-cell population. This study found an elevation in the insulin response after SG in animals but a decrease in the insulin response over the long term with a loss of beta-cell mass. An increase in duodenal SST-28-producing cells in the duodenum and a loss of pancreatic SST-14-producing cells were observed after SG in animals but not in controls. The expression of SSTR type 5 in delta-cell populations from each group and the ability of the pasireotide infusion assay to decrease the delta-cell population indicated the effect of SST-28 plasma levels on delta-cell maintenance. After SG initiates a compensatory response in the duodenum, beta-cell mass is depleted after loss of the brake that regulates SST-14 at the paracrine level in a nonobese, normoglycemic rat model. This was an experimental model, with no clinical translation to the human clinic, with a preliminary importance regarding new pathophysiologic perspectives or pathways.

Melatonin at repeated doses alleviates hyperglycemia-exacerbated cerebral ischemia-reperfusion injury at 72 h via anti-inflammation and anti-apoptosis

ObjectiveWe aimed to investigate how hyperglycemia would exacerbate cerebral ischemia-reperfusion injury (CIRI) in a rat model of type 1 diabetes mellitus (T1DM) and explore the beneficial effects of multiple doses of melatonin in T1DM induced CIRI. MethodThe T1DM rat model was induced with streptozocin, and melatonin (10 mg/kg) was injected at 0.5 h before ischemia as well as at 24 and 48 h after reperfusion. ResultsWhen compared to normoglycemic (NG) rats, T1DM rats had hyperglycemia with weight loss before CIRI. Despite comparable degrees of ischemia and initial reperfusion, T1DM rats tended to have greater weight loss and had worse neurological deficits and larger infarct volume than NG rats up to 72 h after CIRI. Persistent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway but not of apoptosis or calpains was a crucial factor in T1DM-mediated exacerbation of CIRI at 72 h. Despite lacking effects on baseline hyperglycemia, ischemia and initial reperfusion, melatonin at multiple doses lessened post-CIRI weight loss, neurological deficits and infarct volume in T1DM rats at 72 h. when compared to vehicle-treated T1DM rats with CIRI. Beneficial effects of melatonin treatment included decreased activation of NF-κB pathway, apoptosis and calpains, leading to reduced expression of inducible nitric oxide synthase and enhanced neuronal density. ConclusionMelatonin at multiple doses can alleviate T1DM-mediated exacerbation of CIRI at 72 h through anti-inflammation and anti-apoptosis.

Anti-hyperglycemic effect of two terpenoids isolated from Coula edulis on normoglycemic rats and in silico study of their potential inhibitors on α-amylase and dipeptidylpeptidase 4

Diabetes causes many deaths around the world, making the search for treatments a real challenge. Plant secondary metabolites are promising candidates because they act as scaffolds in biological processes. This study investigates anti-hyperglycaemic effect of two terpenoids isolated from Coula edulis and in silico study of their potential inhibitors on α-amylase and dipeptidypeptidase 4. After extraction and isolation of the two terpenoids, their structures were characterized using 1D and 2D NMR spectroscopic techniques. Subsequently the anti-hyperglycemic effect was achieved following an overload of starch on the one hand and glucose on the other hand in normoglycemic rats. Each isolated terpenoids was tested at a dose of 3 mg/kg.bw, the same for the reference compounds (Acarbose and glibenclamide). Conformational site analysis and docking parameters such as binding energy, inhibition constant, interaction profiles with diabetes target residues (α-amylase and dipeptidypeptidase 4) were determined using AutoDock 4.2 and Discovery Studio visualizer. The results showed that the terpenoids isolated from coula edulis were Taraxerol and 3β-(Z)-coumaroyltaraxerol, each of its two terpenoids considerably decreased the blood sugar levels in rats after overloading of starch and glucose solutions respectively. Their effects were similar to the reference drugs. Furthermore, the in-silico approach showed that these compounds have good docking scores with α-amylase and with DPP4. Taraxerol exhibited a docking score more than three times than the acarbose docking score. Only 3β-(Z)-coumaroyltaraxerol reacts with at least one amino acid of the α-amylase catalytic triad (Asp 300). Both interact with histidine (His 740) of the DPP4 catalytic triad. In view of this results, taraxerol and 3β-(Z)-coumaroyltaraxerol have anti-hyperglycemic effects and are good candidates for the development of new multitarget antidiabetics.&#x0D; Keywords: Coula edulis, RMN 1D and 2D, tarxerol, 3β-(Z)-coumaroyltaraxerol and Anti-hyperglycemia

Production of alginate macrocapsule device for long-term normoglycaemia in the treatment of type 1 diabetes mellitus with pancreatic cell sheet engineering

Type 1 diabetes-mellitus (T1DM) is characterized by damage of beta cells in pancreatic islets. Cell-sheet engineering, one of the newest therapeutic approaches, has also been used to create functional islet systems by creating islet/beta cell-sheets and transferring these systems to areas that require minimally invasive intervention, such as extrahepatic areas. Since islets, beta cells, and pancreas transplants are allogeneic, immune problems such as tissue rejection occur after treatment, and patients become insulin dependent again. In this study, we aimed to design the most suitable cell-sheet treatment method and macrocapsule-device that could provide long-term normoglycemia in rats. Firstly, mesenchymal stem cells (MSCs) and beta cells were co-cultured in a temperature-responsive culture dish to obtain a cell-sheet and then the cell-sheets macroencapsulated using different concentrations of alginate. The mechanical properties and pore sizes of the macrocapsule-device were characterized. The viability and activity of cell-sheets in the macrocapsule were evaluated in vitro and in vivo. Fasting blood glucose levels, body weight, and serum insulin & C-peptide levels were evaluated after transplantation in diabetic-rats. After the transplantation, the blood glucose level at 225 mg dl–1 on the 10th day dropped to 168 mg dl–1 on the 15th day, and remained at the normoglycemic level for 210 days. In this study, an alginate macrocapsule-device was successfully developed to protect cell-sheets from immune attacks after transplantation. The results of our study provide the basis for future animal and human studies in which this method can be used to provide long-term cellular therapy in T1DM patients.

Hepatoprotective Mechanisms Induced by Spinach Methanolic Extract in Rats with Hyperglycemia-An Immunohistochemical Analysis.

Spinach methanolic extract (SME) has a hepatoprotective effect due to its polyphenolic antioxidants; however, its action in parenchymal (PQ) and non-parenchymal (nPQ) cells remains unknown. This study investigates the hepatoprotective effect of SME on streptozotocin-induced hyperglycemic rats (STZ), focusing on immunohistochemical analyses. Methods: The extract was prepared, and the total polyphenols and antioxidant activity were quantified. Adult male Wistar rats were divided into four groups (n = 8): normoglycemic rats (NG), STZ-induced hyperglycemic (STZ), STZ treated with 400 mg/kg SME (STZ-SME), and NG treated with SME (SME) for 12 weeks. Serum liver transaminases and lipid peroxidation levels in tissue were determined. The distribution pattern and relative levels of markers related to oxidative stress [reactive oxygen species (ROS), superoxide dismutase-1, catalase, and glutathione peroxidase-1], of cytoprotective molecules [nuclear NRF2 and heme oxygenase-1 (HO-1)], of inflammatory mediators [nuclear NF-κB, TNF-α], proliferation (PCNA), and of fibrogenesis markers [TGF-β, Smad2/3, MMP-9, and TIMP1] were evaluated. Results: SME had antioxidant capacity, and it lowered serum transaminase levels in STZ-SME compared to STZ. It reduced NOX4 staining, and lipid peroxidation levels were related to low formation of ROS. In STZ-SME, the immunostaining for antioxidant enzymes increased in nPQ cells compared to STZ. However, enzymes were also localized in extra and intracellular vesicles in STZ. Nuclear NRF2 staining and HO-1 expression in PQ and nPQ were higher in STZ-SME than in STZ. Inflammatory factors were decreased in STZ-SME and were related to the percentage decrease in NF-κB nuclear staining in nPQ cells. Similarly, TGF-β (in the sinusoids) and MMP-9 (in nPQ) were increased in the STZ-SME group compared to the other groups; however, staining for CTGF, TIMP1, and Smad2/3 was lower. Conclusions: SME treatment in hyperglycemic rats induced by STZ may have hepatoprotective properties due to its scavenger capacity and the regulation of differential expression of antioxidant enzymes between the PQ and nPQ cells, reducing inflammatory and fibrogenic biomarkers in liver tissue.

Hypoglycemic and Antihyperglycemic Potential of Flavonoid Fraction from Citrus sinensis (L.) Osbeck in Normoglycemic and Diabetic Rats

Diabetes is one of the most prevalent diseases worldwide, and the search for therapeutic alternatives in developing countries has been focused on natural products, primarily from plants. This study evaluated the antihyperglycemic and hypoglycemic activities of the albedo (FA) and flavedo (FF) flavonoid fractions obtained from orange peels (often discarded) in normoglycemic Wistar rats. The flavonoid fractions were identified and quantified using HPLC-UV-DAD and compared with glibenclamide, repaglinide, saxagliptin, and acarbose. Additionally, both fractions were tested in a streptozotocin (65 mg/kg)/nicotinamide (100 mg/kg)-induced diabetic model. In normoglycemic rats, the highest glucose variation (%VG) occurred during the first hour after FA (112.8%) and FF (105.30%) administration at 100 mg/kg, indicating a hypoglycemic effect. In diabetic rats, FF at 100 mg/kg showed the highest %VG (140.41%) during the first hour after administration. HPLC-UV-DAD analysis revealed the presence of hesperidin (HSP) and naringenin (NGN), with the highest concentrations found in FA (HSP: 41.41%; NGN: 10.75%). These findings suggest potential antihyperglycemic effects of FA and FF fractions, possibly attributed to the presence of HSP and NGN. The results obtained in this work lay the foundations to explore the therapeutic applications of orange peels for controlling hyperglycemia in diabetes. In conclusion, our results suggest a reevaluation and revalorization of orange peels, as they contain pharmaceutically relevant flavonoids.

Pancreatic β-Cell Apoptosis in Normoglycemic Rats is Due to Mitochondrial Translocation of p53-Induced by the Consumption of Sugar-Sweetened Beverages.

Overstimulation of pancreatic β-cells can lead to dysfunction and death, prior to the clinical manifestations of type 2 diabetes (T2D). The excessive consumption of carbohydrates induces metabolic alterations that can affect the functions of the β-cells and cause their death. We analyzed the role of p53 in pancreatic β cell death in carbohydrate-supplemented Sprague Dawley rats. For four months, the animals received drinking water containing either 40% sucrose or 40% fructose. The glucose tolerance test was performed at week 15. Apoptosis was assessed with the TUNEL assay (TdT-mediated dUTP-nick end-labeling). Bax, p53, and insulin were assessed by Western blotting, immunofluorescence, and real-time quantitative PCR. Insulin, triacylglycerol, and serum glucose and fatty acids in pancreatic tissue were measured. Carbohydrate consumption promotes apoptosis and mobilization of p53 from the cytosol to rat pancreatic β-cell mitochondria before blood glucose rises. An increase in p53, miR-34a, and Bax mRNA was also detected (P < 0.001) in the sucrose group. As well as hypertriglyceridemia, hyperinsulinemia, glucose intolerance, insulin resistance, visceral fat accumulation, and increased pancreatic fatty acids in the sucrose group. Carbohydrate consumption increases p53 and its mobilization into β-cell mitochondria and coincides with the increased rate of apoptosis, which occurs before serum glucose levels rise.

1729-P: Role of ß-Cell Senescence in Islet Transplantation

Islet transplantation (Tx) is an effective intervention to prevent severe hypoglycemia and provide insulin independence in type 1 diabetes (T1D). Previous studies have shown that islets from older donors are less effective in reversing blood glucose (BG) than those of younger ones. Cellular senescence leads to age-related β-cell dysfunction and drives alloimmune responses to organs from older donors, but can be targeted with senolysis. However, the mechanism of pancreatic β-cell senescence in transplant grafts and its pathological significance are unknown. Therefore, we performed two types of islet Tx to test the hypothesis that cellular senescence may play a role in loss of graft functionality/viability and that the use of senolysis may ameliorate it: 1) overnight cultured 600 IEQ islets from normoglycemic rats were transplanted into kidney capsule of streptozotocin-induced diabetic immunodeficient mice (Stz-Ms). After 2 weeks, the grafts were removed and compared with the cultured islets (control). In Stz-Ms, the nuclear exclusion rate of Hmgb1 and p21-positive cells tended to increase, and the mRNA levels of p16, Il-6, and β-cells related genes were significantly higher than in control islets indicating β-cell senescence after transplantation. To test if the elimination of p16 positive senescent β-cells from transplanted islets improved BG levels, 2) 440 IEQ islets from INK-ATTAC mice (p16Ink4a mediated apoptosis through targeted activation of caspase) were transplanted into Stz-Ms and treated intraperitoneally with BB Homodimerizer (BB) or vehicle for 2 terms of 3 consecutive days, of which 2 weeks of rest. With senolysis, there was a decrease in fed glucose levels and p16 mRNA expression while expression of hallmark β-cell genes increased by 74%, which correlates with improved response to high glucose. In conclusion, islet transplantation increases β-cell senescence in grafts and senolysis improves β-cell function. This has important implications in increasing graft function and survival in the treatment of T1D. Disclosure K.Iwasaki: None. P.Carapeto: None. C.Aguayo-mazzucato: None. Funding Manpei Suzuki Diabetes Foundation

#5907 RENAL INJURY IN RELATION TO OBESITY AND THE ADDITIVE EFFECT OF HYPERTENSION IN FEMALE AND MALE OBESE AND LEAN ZSF1 RATS

Abstract Background and Aims Chronic kidney disease co-exists with heart failure with preserved ejection fraction (HFpEF), which is characterized by the presence of obesity, hypertension, and diabetes mellitus type 2. Obese ZSF1 rats, a model of HFpEF, exhibit multiple of these comorbidities that can disturb cardiac function. Little attention has been paid to how these comorbidities affect renal disease in the ZSF1 rats. HFpEF is found predominantly in women in whom obesity and hypertension are particularly prevalent. Therefore, we aimed to characterize the renal phenotype in female and male, lean and obese, ZSF1 rats and investigated additional effects of worsened hypertension on disease severity. Method Systolic blood pressure and renal function were assessed biweekly in female and male, lean and obese, ZSF1 rats from 12 to 26 weeks of age by tail-cuff plethysmography, urine collection via metabolic cages and plasma collection, respectively. From 19 weeks of age, rats were implanted with either a deoxycorticosterone acetate pellet (DOCA) and fed high salt diet (6% NaCl) or with a placebo pellet and fed a normal salt diet. At 26 weeks of age, terminal GFR was assessed via inulin clearance under isoflurane. Renal sections were processed for histological analysis. Results Lean and obese placebo ZSF1 rats, both female and male, were mildly hypertensive (systolic blood pressure 140-150 mmHg). All obese rats showed HFpEF, evidenced by elevated E/e’ ratio. In female normoglycemic ZSF1 rats, obesity associates with mild proteinuria, decreased GFR and glomerular hypertrophy. The addition of DOCA-salt worsened hypertension in female obese ZSF1 rats, but not in their lean counterparts. DOCA-salt-worsened hypertension enhanced proteinuria and triggered glomerulosclerosis in female obese rats. Male obese placebo ZSF1 rats were hyperglycemic and showed proteinuria, glomerular hypertrophy and sclerosis, and tubulo-interstitial damage. DOCA-salt worsened hypertension in both male lean and obese rats and further aggravated proteinuria, tubulo-interstitial damage, glomerular hypertrophy and sclerosis in obese male rats. No effect of DOCA-salt was observed on GFR in both male and female ZSF1 rats. Conclusion Female obese ZSF1 rats developed mild renal disease and DOCA-salt-worsened hypertension deteriorated renal function and structure in normoglycemic female obese ZSF1 rats similar to hyperglycemic male obese ZSF1 rats.

Renal injury in relation to obesity and the additive effect of hypertension in female and male obese and lean ZSF1 rats.

Heart failure with preserved ejection fraction (HFpEF) is characterized by obesity, hypertension, diabetes mellitus and chronic kidney disease. Obese ZSF1 rats, a model of HFpEF, exhibit multiple such comorbidities that can disturb cardiac function. Little attention has been paid to how these comorbidities affect renal disease in ZSF1 rats. HFpEF is found predominantly in women in whom obesity and hypertension are particularly prevalent. Therefore, we characterized renal phenotype in female and male, lean and obese, ZSF1 rats and investigated additional effects of worsened hypertension on disease severity. Systolic blood pressure and renal function were assessed biweekly from 12 to 26 weeks. From 19 weeks, rats were implanted with either a deoxycorticosterone acetate pellet and fed high salt diet (DS) or a placebo pellet and fed normal salt diet. At 26 weeks, terminal GFR was assessed via inulin clearance under isoflurane. Renal sections were processed for histological analysis. Lean and obese ZSF1 rats, both female and male, were mildly hypertensive (systolic blood pressure 140-150 mmHg). All obese ZSF1 rats showed HFpEF. In female normoglycemic ZSF1 rats, obesity associates with mild proteinuria, decreased glomerular filtration rate and glomerular hypertrophy. DS-worsened hypertension enhanced proteinuria and triggered glomerulosclerosis. Male obese ZSF1 rats were hyperglycemic and showed proteinuria, glomerular hypertrophy and sclerosis, and tubulo-interstitial damage. DS-worsened hypertension aggravated this phenotype in male ZSF1 rats. In conclusion, female obese ZSF1 rats develop mild renal dysfunction and DS-worsened hypertension compromises renal function and structure in normoglycemic female obese ZSF1 rats as in hyperglycemic male obese ZSF1 rats.

Addition of Resolvins D1 or E1 to Collagen Membranes Mitigates Their Resorption in Diabetic Rats

Uncontrolled diabetes is characterized by aberrant inflammatory reactions and increased collagenolysis. We have reported that it accelerates the degradation of implanted collagen membranes (CM), thus compromising their function in regenerative procedures. In recent years, a group of physiological anti-inflammatory agents called specialized pro-resolving lipid mediators (SPMs) have been tested as a treatment for various inflammatory conditions, either systemically or locally, via medical devices. Yet, no study has tested their effect on the fate of the biodegradable material itself. Here, we measured the in vitro release over time of 100 or 800 ng resolvin D1 (RvD1) incorporated into CM discs. In vivo, diabetes was induced in rats with streptozotocin, while buffer-injected (normoglycemic) rats served as controls. Resolvins (100 or 800 ng of RvD1 or RvE1) were added to biotin-labeled CM discs, which were implanted sub-periosteally over the calvaria of rats. Membrane thickness, density, and uniformity were determined by quantitative histology after 3 weeks. In vitro, significant amounts of RvD1 were released over 1-8 days, depending on the amount loaded. In vivo, CMs from diabetic animals were thinner, more porous, and more variable in thickness and density. The addition of RvD1 or RvE1 improved their regularity, increased their density, and reduced their invasion by the host tissue significantly. We conclude that addition of resolvins to biodegradable medical devices can protect them from excessive degradation in systemic conditions characterized by high degree of collagenolysis.

Comparative impact of streptozotocin on altering normal glucose homeostasis in diabetic rats compared to normoglycemic rats

Diabetes mellitus is a syndrome and an endocrine disorder, primarily considered as a loss of glucose homeostasis because of the insulin action and/or secretion or both. Currently there are more than 150 million people in the world affected by diabetes mellitus with a higher share of Asian and European countries. The current study aimed to investigate the comparative altering properties of streptozotocin (STZ), based on up-turn and down-turn configuration of biochemical, toxicological and hematological parameters in comparison with normoglycemic male albino rats. This comparative study was conducted among normoglycemic and STZ based induced-type 2 diabetic male albino rats groups. The male albino rats were intra-peritoneally injected with STZ with the dose rate of 65 mg/kg body weight for one time to developed type 2 diabetic model. Biochemical (blood glucose, uric acid, urea and creatinine), toxicological (AST, ALT and ALP) and hematological parameters (red and white blood cells) and their functional indices were evaluated in type 2 diabetic induced group along with normoglycemic rats. The STZ based induced- type 2 diabetic rats showed statistically significance (p < 0.001) higher level in the blood glucose, alongwith the change in the levels of biochemical parameters including urea, uric acid, and creatinine. Toxicological parameters comprising AST, ALT and ALP were also shown significance (p < 0.001) as sufficient after experimental evaluation of biologically important parameter in STZ based induced-type 2 diabetic rats. Likewise, the red blood cells, white blood cells and their efficient components were exposed significantly insufficient after the injecting of STZ to induce the rats as type 2 diabetic. The results of the current study indicates the comparatively higher levels of variation among biochemical, toxicological and hematological parameters in STZ based Induced-type 2 diabetic model as compared to normoglycemic group.

Nonselective and A2a-Selective Inhibition of Adenosine Receptors Modulates Renal Perfusion and Excretion Depending on the Duration of Streptozotocin-Induced Diabetes in Rats.

Long-lasting hyperglycaemia may alter the role of adenosine-dependent receptors (P1R) in the control of kidney function. We investigated how P1R activity affects renal circulation and excretion in diabetic (DM) and normoglycaemic (NG) rats; the receptors' interactions with bioavailable NO and H2O2 were also explored. The effects of adenosine deaminase (ADA, nonselective P1R inhibitor) and P1A2a-R-selective antagonist (CSC) were examined in anaesthetised rats, both after short-lasting (2-weeks, DM-14) and established (8-weeks, DM-60) streptozotocin-induced hyperglycaemia, and in normoglycaemic age-matched animals (NG-14, NG-60, respectively). The arterial blood pressure, perfusion of the whole kidney and its regions (cortex, outer-, and inner medulla), and renal excretion were determined, along with the in situ renal tissue NO and H2O2 signals (selective electrodes). The ADA treatment helped to assess the P1R-dependent difference in intrarenal baseline vascular tone (vasodilation in DM and vasoconstriction in NG rats), with the difference being more pronounced between DM-60 and NG-60 animals. The CSC treatment showed that in DM-60 rats, A2aR-dependent vasodilator tone was modified differently in individual kidney zones. Renal excretion studies after the ADA and CSC treatments showed that the balance of the opposing effects of A2aRs and other P1Rs on tubular transport, seen in the initial phase, was lost in established hyperglycaemia. Regardless of the duration of the diabetes, we observed a tonic effect of A2aR activity on NO bioavailability. Dissimilarly, the involvement of P1R in tissue production of H2O2, observed in normoglycaemia, decreased. Our functional study provides new information on the changing interaction of adenosine in the kidney, as well as its receptors and NO and H2O2, in the course of streptozotocin diabetes.

Ageratina adenophora (Spreng.) King & H. Rob. Standardized leaf extract as an antidiabetic agent for type 2 diabetes: An in vitro and in vivo evaluation.

Type 2 diabetes has become one of the major health concerns of the 21st century, marked by hyperglycemia or glycosuria, and is associated with the development of several secondary health complications. Due to the fact that chemically synthesized drugs lead to several inevitable side effects, new antidiabetic medications from plants have gained substantial attention. Thus, the current study aims to evaluate the antidiabetic capacity of the Ageratina adenophora hydroalcoholic (AAHY) extract in streptozotocin-nicotinamide (STZ-NA)-induced diabetic Wistar albino rats. The rats were segregated randomly into five groups with six rats each. Group I was normal control, and the other four groups were STZ-NA-induced. Group II was designated diabetic control, and group III, IV, and V received metformin (150mg/kg b.w.) and AAHY extract (200 and 400mg/kg b.w.) for 28days. Fasting blood glucose, serum biochemicals, liver and kidney antioxidant parameters, and pancreatic histopathology were observed after the experimental design. The study concludes that the AAHY extract has a significant blood glucose lowering capacity on normoglycemic (87.01 ± 0.54 to 57.21 ± 0.31), diabetic (324 ± 2.94 to 93 ± 2.04), and oral glucose-loaded (117.75 ± 3.35 to 92.75 ± 2.09) Wistar albino rats. The in vitro studies show that the AAHY extract has α-glucosidase and α-amylase inhibitory activities which can restore the altered blood glucose level, glycated hemoglobin, body weight, and serum enzymes such as serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, serum alkaline phosphatase, total protein, urea, and creatinine levels close to the normal range in the treated STZ-NA-induced diabetic rats. The evaluation of these serum biochemicals is crucial for monitoring the diabetic condition. The AAHY extract has significantly enhanced tissue antioxidant parameters, such as superoxide dismutase, glutathione, and lipid peroxidation, close to normal levels. The presence of high-quantity chlorogenic (6.47% w/w) and caffeic (3.28% w/w) acids as some of the major phytoconstituents may contribute to the improvement of insulin resistance and oxidative stress. The study provides scientific support for the utilization of A. adenophora to treat type 2 diabetes in the STZ-NA-induced diabetic rat model. Although the preventive role of the AAHY extract in treating Wistar albino rat models against type 2 diabetes mellitus is undeniable, further elaborative research is required for efficacy and safety assessment in human beings.

"Ficus johannis Boiss. leaves ethanolic extract ameliorate streptozotocin-induced diabetes in rats by upregulating the expressions of GCK, GLUT4, and IGF and downregulating G6P".

The leaves of Ficus johannis Boiss (F. johannis), commonly known as Fig tree, Anjir, and Teen, are used by the folk medicinal practitioners in Iran for controlling hyperglycemia in diabetic patients. This study investigated the pharmacological basis for antidiabetic effect of the ethanolic extract of F. johannis leaves using in vitro and in vivo experimental models. Qualitative screening of phytochemicals, estimation of total phenolic and flavonoid contents, and in vitro antioxidant and α-amylase inhibition assays were performed. Moreover, the High-performance liquid chromatography (HPLC) quantification, acute toxicity, glucose tolerance, and in vivo antidiabetic effect along with the evaluation of gene expressions involved in diabetes mellitus were carried out. Significant quantities of phenolic (71.208 ± 2.89 mgg-1 GAE) and flavonoid (26.38 ± 3.53 mgg-1 QE) were present. Inhibitory concentration (IC50) of the plant extract exhibited an excellent in vitro antioxidant (IC50 = 33.81µg/mL) and α-amylase (IC50 = 12.18µg/mL) inhibitory potential. The HPLC analysis confirmed the gallic acid (257.79 mgg-1) as main constituent of the extract followed by kaempferol (22.86 mgg-1), myricetin (0.16 mgg-1), and quercetin (3.22 mgg-1). Ethanolic extract displayed glucose tolerance in normo-glycemic rats. Streptozotocin-induced hyperglycemia declined dose dependently in the extract treated rats with improvement in lipid profile and liver and renal function biomarkers. The F. johannis-treated groups showed an increase in mRNA expressions of glucose transporter 4 (GLUT-4), glucokinase, insulin growth like factor 1 and peroxisomal proliferator activating receptor gamma in pancreas. However, the Glucose-6-phosphatase was downregulated. Present study suggests that the ethanolic extract of F. johannis leaves demonstrates a good anti-diabetic profile by improving insulin sensitivity, GLUT-4 translocation, and carbohydrate metabolism while inhibiting lipogenesis.