Diabetes Mellitus Rats Research Articles

Effect of Germinated Black Rice Krisna Extract on Fasting Blood Glucose and Body Weight in Diabetes Mellitus Rats

Effect of Germinated Black Rice Krisna Extract on Fasting Blood Glucose and Body Weight in Diabetes Mellitus Rats

The enamel thickness of gestational diabetes mellitus rat offspring

Objective: To determine the molar enamel thickness of rat offsprings born to diabetic rat.Material and Methods: This research used sixteen rat offsprings born to 8 diabetic rats who had been injected with STZ dose of 40 mg / kg and 16 rat offsprings born to 8 control rats. Rat offsprings were decapitated on day 5 after birth and taken right mandibular molar tooth germ. Tooth germ then embedded in paraffin block. Haematoxylin eosin staining performed for histological analysis. Enamel thickness measured on the images using ImageJ Software at 5 field of view.Results: The enamel thickness on the Diabetes Mellitus (DM) group (333.02 ± 135.81 µm) were lower than control group (415.39 ± 146.17 µm). Mann Whitney test results showed a significant difference between the DM and control group.Conclusion: It was concluded that enamel thickness decreases in gestational diabetes mellitus rat offspring.

Perbaikan kadar trigliserida dan Hs-CRP pada tikus Wistar Diabetes Mellitus tipe 2 dengan biskuit biji bunga matahari

Diabetes Mellitus is a group of metabolic diseases characterized by hyperglycemia due to defects in insulin secretion or insulin action. Increased glucose allows free fatty acids to enter as raw material for forming triglycerides. Hs-CRP can be used to identify the most sensitive inflammatory markers in diabetes. This study aims to analyze the effect of sunflower seed biscuits on triglyceride levels and Hs-CRP in Wistar rats with type 2 diabetes mellitus. The method is a true experiment with a randomized pre-post test with a control group design. The research sample size was 24 male Wistar rats, divided into four control groups K(-), K(+), and treatment P1, P2. The intervention was carried out for 28 days, and triglycerides were measured by spectrophotometer, and Hs-CRP was measured using the ELISA method. Statistical analysis used three tests, namely the Paired T-Test, the Kruskal Wallis test, and the Spearman correlation test. There are differences after the intervention and changes between groups with triglyceride values before intervention 145 mg/dl and after intervention 145 mg/dl and Hs-CRP values before intervention 14.8 mg/l and after intervention 14,8 mg/l. Changes between groups of triglyceride and Hs-CRP levels after statistical tests (p= 0,000) and (p= 0,000), respectively. The conclusion is a provision of sunflower seed biscuits showed an effect on triglyceride and Hs-CRP levels of type 2 diabetes mellitus rats. The lowest decrease in triglyceride and Hs-CRP levels was found in the treated rats with a dose of 1440 mg / 200 g of rats

Micro ribonucleic acid-363 regulates the phosphatidylinositol 3-kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus.

Aims/IntroductionGlucose metabolic disorder is the main cause for type 2 diabetes progression. Exploring the molecular mechanisms of metabolic disorder are crucial for type 2 diabetes treatment.Materials and MethodsMicro ribonucleic acid (miR)‐363, NOTCH1 and forkhead box C2 (FOXC2) expressions in high glucose (HG)‐treated HepG2 cells and the livers of type 2 diabetes mellitus rats were assessed using quantitative polymerase chain reaction. Protein levels of NOTCH1, FOXC2 and phosphatidylinositol 3‐kinase (PI3K)/serine/threonine protein kinase (Akt)‐related proteins were evaluated using western blot. Lipid accumulation was determined using Oil Red O staining. Then glucose consumption, blood glucose level and glycogen content were detected using kits. Finally, dual luciferase reporter assay was used to verify the binding relationship between miR‐363 and NOTCH1, and the binding relationship between miR‐363 and FOXC2.ResultsMiR‐363 was significantly upregulated in the livers of diabetic rats and HG‐induced HepG2 cells, whereas NOTCH1 and FOXC2 were downregulated. In HG‐induced HepG2 cells, miR‐363 inhibitor markedly increased glucose consumption and uptake, and reduced accumulation of lipid droplets. Then NOTCH1 and FOXC2 were identified as downstream targets of miR‐363. NOTCH1 overexpression or FOXC2 overexpression could ameliorate glucose and lipids metabolism disorder in type 2 diabetes model cells. In addition, we found that FOXC2 inhibition abolished the effect of NOTCH1 overexpression on HG‐induced HepG2 cells. Finally, we proved that the PI3K/Akt pathway was the downstream pathway of FOXC2.ConclusionMiR‐363 was considered as a key regulator of glucose and lipids metabolism in type 2 diabetes mellitus, which regulated PI3K/Akt axis by targeting NOTCH1 and FOXC2, thus leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes.

Electroacupuncture at "Zusanli"(ST36) ameliorates tau hyperphosphorylation in pancreas and hippocampus of diabetic rats

To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36) on the phosphorylated tau levels in pancreas and hippocampus of type 2 diabetes mellitus (T2DM) rats，so as to explore the underlying mechanism of EA in diabetic demention rats. Forty-eight male Sprague-Dawley rats were randomly divided into control, model and EA groups, with 16 rats in each group. The T2DM model was established by 6 weeks of high-fat, high-sugar diet as well as intrape-ritoneal injection of streptozocin (STZ) solution (35 mg/kg). After that, EA (2 Hz, 0.1 mA) was applied to unilateral "Zusanli"(ST36) for 30 min, once a day, 6 times a week for 4 weeks. The survival rate was recorded every week, and the fasting blood glucose (FBG) was detected on the 1st, 6th and 11th week. The level of serum insulin (INS) was measured by using ELISA. The morphological structure of pancreas islet was observed by H.E. staining. The expressions of phosphorylated tau at the sites of Ser 396 (pS396) and Thr 231 (pT231), total tau (Tau5), phosphorylated glycogen synthase kinase-3β (pGSK-3β) and total glycogen synthase kinase-3β (GSK-3β) in pancreas and hippocampus were detected by Western blot. The expression and distribution of pS396 and pT231 in pancreas and hippocampus were assayed with immunohistochemistry. Compared with the control group, the survival rate presented a significant decline, the contents of FBG and INS were obviously higher(P<0.01), and the structure of the pancreas islet appeared shrunken, obscure and disordered in the model group. Furthermore, the levels of pS396, pT231 in pancreas and hippocampus were obviously higher in the model group(P<0.01)，while the level of pGSK-3β in pancreas and hippocampus was significantly lower in the model group(P<0.01). In comparison with the model group, the survival rate of EA group was higher. Following 4 weeks' interventions, the enhanced levels of tau phosphorylation and GSK-3β activity in pancreas and hippocampus were partly reversed in the EA group compared to the model group(P<0.05，P<0.01). EA at ST36 can reduce the level of tau phosphorylation via regulating the activity of GSK-3β in the pancreas and hippocampus of T2DM rats, which may be related with the effect of EA on the brain function in T2DM rats.

Tetramethylpyrazine alleviates diabetes-induced high platelet response and endothelial adhesion via inhibiting NLRP3 inflammasome activation

BackgroundThe inflammatory state of diabetes promotes high platelet response and endothelial adhesion, which are the main risk factors for cardiovascular events. Tetramethylpyrazine (TMP) is an amide alkaloid isolated from the traditional Chinese medicine Rhizoma Ligustici Chuanxiong, which has been widely used in the clinical treatment of ischemic cardiovascular disease. PurposeThis study aimed to investigate whether TMP could alleviate diabetes-induced high platelet response and endothelial adhesion and the underlying mechanisms. MethodsType 2 diabetes mellitus (T2DM) rat model was established by high-fat feeding combined with low dose of streptozotocin. Rats in the TMP treatment group were administered with TMP (100 or 200 mg/kg) for 21 days. Cultured human umbilical vein endothelial cells (HUVECs) were stimulated with glucose (5.5 mM) to induce endothelial activation. The NOD-like receptor protein 3 (NLRP3) over- and low-expressing cell models were established via transfection of NLRP3 lentivirus plasmid into HUVECs. INF39 (25 mg/kg), a chemical inhibitor of NLRP3 inflammasome, was used to explore the role of NLRP3 in T2DM associated high platelet response and endothelial adhesion. ResultsTMP effectively improved the prothrombotic phenotypes and inhibited the expression of vascular inflammatory factors and adhesion molecules in T2DM rats. TMP inhibited NLRP3 inflammasome and reduced the adhesion of HUVECs to platelets and monocytes in vitro. Over-expression of NLRP3 blocked the effect of TMP on HUVECs activation and adhesion, while TMP had no effect on NLRP3 low-expressing HUVECs. The NLRP3 inhibitor INF39 produced similar effects of TMP on diabetes-induced high platelet response, endothelial adhesion and vascular inflammation. ConclusionTMP ameliorates diabetes-induced high platelet response and endothelial adhesion via inhibiting NLRP3 inflammasome activation in T2DM rats, which provide a new basis for the clinical prevention and treatment of diabetes-associated cardiovascular events.

Glucose Transporter 4 and Peroxisome Proliferator-Activated Receptor-Alpha Overexpression Association With Cardioprotective Effects of Myoinositol and Metformin Combination in Type 2 Diabetic Rat Model

Background: Type 2 diabetes mellitus (DM) has many complications associated with increased morbidity and mortality. Cardiovascular complications are one of these serious complications. Therefore, there is a need for early and effective management to hamper them. This study aimed to evaluate the cardioprotective efficacy of metformin and myoinositol combination through exploring the associated underlying mechanisms in type 2 DM rat model. Methods: Type 2 DM model was induced in rats by streptozotocin and high-fat diet. Rats were treated with metformin (150 mg/kg) and/or myoinositol (50 mg/kg) by oral gavage once daily for 4 weeks. Immunohistochemistry was used to assess the drugs’ cardioprotective efficacy by estimating troponin T, nuclear factor kappa B (NF-kappaB) and tumor necrosis factor alpha (TNF-alpha). Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to investigate peroxisome proliferator-activated receptor-alpha (PPARalpha) and glucose transporter 4 (GLUT-4) expression levels in the skeletal muscles, respectively. Results: This study found that metformin and myoinositol combination was associated with GLUT-4 and PPARalpha overexpression, together with better lipid profile than metformin alone in diabetic rats. Additionally, the combination of both drugs improved troponin C and decreased creatine kinase MB isoenzyme, NF-kappaB and TNF-alpha cardiac levels. Conclusion: The current study indicated that myoinositol in combination with metformin had better cardioprotective effect than metformin alone in type 2 DM. This favorable effect was exhibited through upregulation of GLUT-4 and PPARalpha receptors expression in skeletal muscles, thus increasing insulin sensitivity and improving lipid profile. J Endocrinol Metab. 2021;11(5):140-151 doi: https://doi.org/10.14740/jem765

UHPLC-MS-Based Serum and Urine Metabolomics Reveals the Anti-Diabetic Mechanism of Ginsenoside Re in Type 2 Diabetic Rats.

Panax ginseng was employed in the treatment of “Xiao-Ke” symptom, which nowadays known as diabetes mellitus, in traditional Chinese medicine for more than a thousand years. Ginsenoside Re was the major pharmacologic ingredient found abundantly in ginseng. However, the anti-diabetic of Ginsenoside Re and its underlying mechanism in metabolic level are still unclear. Serum and urine metabolomic method was carried out to investigate the anti-diabetic pharmacological effects and the potential mechanism of Ginsenoside Re on high-fat diet combined streptozotocin-induced type 2 diabetes mellitus (T2DM) rats based on ultra-high-performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS). Serum and urine samples were collected from the control group (CON), T2DM group, metformin (MET) treatment group, and ginsenoside Re treatment group after intervention. The biochemical parameters of serum were firstly analyzed. The endogenous metabolites in serum and urine were detected by UHPLC-MS. The potential metabolites were screened by multivariate statistical analysis and identified by accurate mass measurement, MS/MS, and metabolite databases. The anti-diabetic-related metabolites were analyzed by KEGG metabolic pathway, and its potential mechanism was discussed. The treatment of ginsenoside Re significantly reduced the blood glucose and serum lipid level improved the oxidative stress caused by T2DM. Biochemical parameters (urea nitrogen, uric acid) showed that ginsenoside Re could improve renal function in T2DM rats. Respective 2 and 6 differential metabolites were found and identified in serum and urine of ginsenoside Re compared with T2DM group and enriched in KEGG pathway. Metabolic pathways analysis indicated that the differential metabolites related to T2DM were mainly involved in arachidonic acid metabolism, Vitamin B6, steroid hormone biosynthesis, and bile secretion metabolic pathways. This study verified the anti-diabetic and anti-oxidation effects of ginsenoside Re, elaborated that ginsenoside Re has a good regulation of the metabolic disorder in T2DM rats, which could promote insulin secretion, stimulated cannabinoid type 1 receptor (CB1), and CaMKK β to activate AMPK signaling pathway, inhibited insulin resistance, and improved blood glucose uptake and diabetic nephropathy, so as to play the role of anti-diabetic.

Progression of diabetes is associated with changes in the ileal transcriptome and ileal-colon morphology in the UC Davis Type 2 Diabetes Mellitus rat.

Deterioration in glucose homeostasis has been associated with intestinal dysbiosis, but it is not known how metabolic dysregulation alters the gastrointestinal environment. We investigated how the progression of diabetes alters ileal and colonic epithelial mucosal structure, microbial abundance, and transcript expression in the University of California Davis Type 2 Diabetes Mellitus (UCD‐T2DM) rat model. Male UCD‐T2DM rats (age ~170 days) were included if <1‐month (n = 6, D1M) or 3‐month (n = 6, D3M) post‐onset of diabetes. Younger nondiabetic UCD‐T2DM rats were included as a nondiabetic comparison (n = 6, ND, age ~70 days). Ileum villi height/crypt depths and colon crypt depths were assessed by histology. Microbial abundance of colon content was measured with 16S rRNA sequencing. Ileum and colon transcriptional abundances were analyzed using RNA sequencing. Ileum villi height and crypt depth were greater in D3M rats compared to ND. Colon crypt depth was greatest in D3M rats compared to both ND and D1M rats. Colon abundances of Akkermansia and Muribaculaceae were lower in D3M rats relative to D1M, while Oscillospirales, Phascolarctobacterium, and an unidentified genus of Lachnospiraceae were higher. Only two transcripts were altered by diabetes advancement within the colon; however, 2039 ileal transcripts were altered. Only colonic abundances of Sptlc3, Enpp7, Slc7a15, and Kctd14 had more than twofold changes between D1M and D3M rats. The advancement of diabetes in the UCD‐T2DM rat results in a trophic effect on the mucosal epithelia and was associated with regulation of gastrointestinal tract RNA expression, which appears more pronounced in the ileum relative to the colon.

Integrated molecular biology and metabonomics approach to understand the mechanism underlying reduction of insulin resistance by corn silk decoction

Ethnopharmacological relevanceCorn silk is composed of the style and stigma of Zea mays L. Its medical value was first reported in “Southern Yunnan Materia Medica” in the Ming Dynasty. It was considered to be a heat-clearing and diuretic drug. In “Zhejiang Folk Herbal Medicine,” the following has been reported: “Corn silk needs one liang. Decoction in water can cure diabetes.” Recent studies have shown that corn silk can lower blood sugar levels; however, to date, corn silk has undergone simple pharmacodynamic evaluations, with both its degree and mechanism of action remaining unclear. Aim of the studyThis study aimed to investigate the mechanism of action of corn silk, with respect to having antioxidative ability, reducing insulin resistance, and having a hypoglycemic effect. Materials and methodsIn this study, a type 2 diabetes mellitus (T2DM) rat model was established via a high sugar and high fat diet combined with streptozotocin (35 mg/kg) administration. Wistar rats were administered corn silk decoction and metformin via gavage for four weeks, and the fasting blood glucose (FBG) and body weight were measured every two weeks. After the experiment, the insulin level, insulin index, and glycogen content were determined. Hematoxylin-eosin staining was used to observe the morphological changes of the skeletal muscle tissue in rats. The levels of malondialdehyde and superoxide dismutase in the serum and skeletal muscle were detected, and the mRNA content and protein levels of key proteins in the JNK-IRS-GLUT4 signaling pathway were determined using real-time quantitative polymerase chain reaction and western blotting. Then, ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry, combined with multiple statistical analyses, was used to identify potential biomarkers in the serum of T2DM rats, for determining the key metabolic pathways responsible for the action of corn silk. ResultsThe results showed that corn silk could reduce FBG, insulin level, and glycogen content in T2DM rats; reduce the level of oxidative stress in serum and skeletal muscle; restore the pathological structure of skeletal muscle; inhibit the phosphorylation of c-Jun N-terminal kinase (JNK) and insulin receptor substrate (IRS) in skeletal muscle; and upregulate the expression of glucose transporter type 4 (GLUT4) for transport of glucose and to reduce insulin resistance. Moreover, metabonomic analysis elucidated that corn silk could significantly affect 26 biomarkers (such as pentosidine, palmitic acid, lysoPC, and p-Cresol sulfate) and metabolic pathways (such as phenylalanine metabolism, phospholipid metabolism, bile acid metabolism, and biosynthesis of unsaturated fatty acids). ConclusionThe interaction between endogenous metabolites and proteins in signaling pathways was analyzed using metabonomics and molecular biology methods. Corn silk inhibited JNK-IRS-GLUT4 signal transduction in skeletal muscle via antioxidative effects, by increasing the sensitivity of peripheral tissue to insulin, by reducing insulin resistance, and through hypoglycemic effects.

Single Intraosseous Simvastatin Application Induces Endothelial Progenitor Cell Mobilization and Therapeutic Angiogenesis in a Diabetic Hindlimb Ischemia Rat Model.

Endothelial progenitor cells have shown the ability to enhance neovascularization. In this study, the authors tested whether intraosseous delivery of simvastatin could mobilize endothelial progenitor cells and enhance recovery in a hindlimb ischemia model. There are eight groups of rats in this study: normal control; type 1 diabetes mellitus control group control without drug intervention; and type 1 diabetes mellitus rats that randomly received intraosseous simvastatin (0, 0.5, or 1 mg) or oral simvastatin administration (0, 20, or 400 mg). All type 1 diabetes mellitus rats had induced hindlimb ischemia. The number of endothelial progenitor cells in peripheral blood, and serum markers, were detected. The recovery of blood flow at 21 days after treatment was used as the main outcome. The authors demonstrated that endothelial progenitor cell mobilization was increased in the simvastatin 0.5- and 1-mg groups compared with the type 1 diabetes mellitus control and simvastatin 0-mg groups at 1, 2, and 3 weeks. Serum vascular endothelial growth factor levels were significantly increased at 2 weeks in the simvastatin 0.5- and 1-mg groups, in addition to the increase of the blood flow and the gastrocnemius weight at 3 weeks. Similar increase can also been seen in simvastatin 400 mg orally but not in simvastatin 20 mg orally. These findings demonstrate that a single intraosseous administration of simvastatin mobilized endothelial progenitor cells at a dose one-hundredth of the required daily oral dose in rats, and this potent mobilization of endothelial progenitor cells markedly improved diabetic limb ischemia by means of neovascularization.

Alleviation Effects of GQD, a Traditional Chinese Medicine Formula, on Diabetes Rats Linked to Modulation of the Gut Microbiome.

Gegen Qinlian Decoction (GQD) is a Chinese herbal medicine that has been reported to significantly decrease blood glucose levels, which is suggested to be related to interactions with the gut microbiota. However, the protective effect of GQD on intestinal barrier function with regard to its influence on the gut microbiota has not been explored to date. In this study, we investigated the role of the gut microbiota in mediating the hypoglycemic mechanism of GQD in type 2 diabetes mellitus (T2DM) rats induced by a single intraperitoneal injection of streptozotocin after 4 weeks of high-fat diet feeding. The T2DM rats were randomly allocated to receive GQD, metformin (Met), or saline for 12 consecutive weeks, and changes in metabolic parameters, intestinal barrier function, and inflammation were investigated. Gut microbiota was analyzed using 16S rRNA gene sequencing from fecal samples, and statistical analyses were performed to correlate microbiota composition with phenotypes of the T2DM rats. GQD administration decreased the levels of blood glucose and inflammatory cytokines, and increased the levels of tight junction proteins. Besides, GQD had a protective effect on islet function, restoring intestinal permeability, and inhibiting inflammation, as evidenced by increases in the levels of serum C-peptide, occludin, and claudin-1 in the colon, and also improved the expression of serum inflammatory factors. In addition, GQD regulated the structure of the gut microbiota by increasing the proportions of short-chain fatty acids-producing and anti-inflammatory bacteria, and decreasing the proportions of conditioned pathogenic bacteria associated with the diabetic phenotype. Overall, these findings suggest that GQD could ameliorate hyperglycemia and protect islet function by regulating the structure of the gut microbiota, thereby restoring intestinal permeability and inhibiting inflammation in T2DM rats. Our study thus suggests that the hypoglycemic mechanism of GQD is mediated by its modulation of the gut microbiota.

Retraction Note to: MiR-34a inhibitor protects mesenchymal stem cells from hyperglycaemic injury through the activation of the SIRT1/FoxO3a autophagy pathway

Mesenchymal stem cells (MSCs) are favourable treatments for ischaemic diseases; however, MSCs from diabetic patients are not useful for this purpose. Recent studies have shown that the expression of miR-34a is significantly increased in patients with hyperglycaemia; the precise role of miR-34a in MSCs in diabetes needs to be clarified. The aim of this study is to determine the precise role of miR-34a in MSCs exposed to hyperglycaemia and in recovery heart function after myocardial infarction (MI) in diabetes mellitus (DM) rats. DM rat models were established by high-fat diet combined with streptozotocin (STZ) injection. MSCs were isolated from the bone marrow of donor rats. Chronic culture of MSCs under high glucose was used to mimic the DM micro-environment. The role of miR-34a in regulating cell viability, senescence and paracrine effects were investigated using a cell counting kit-8 (CCK-8) assay, senescence-associated β-galactosidase (SA-β-gal) staining and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) ELISA, respectively. The expression of autophagy- and senescence-associated proteins in MSCs and silent information regulator 1 (SIRT1) and forkhead box class O 3a (FoxO3a) were analysed by western blotting. Autophagic bodies were analysed by transmission electron microscopy (TEM). The MI model was established by left anterior descending coronary artery (LAD) ligation, and then, the rats were transplanted with differentially treated MSCs intramuscularly at sites around the border zone of the infarcted heart. Thereafter, cardiac function in rats in each group was detected via cardiac ultrasonography at 1 week and 3 weeks after surgery. The infarct size was determined through a 2,3,5-triphenyltetrazolium chloride (TTC) staining assay, while myocardial fibrosis was assessed by Masson staining. The results of the current study showed that miR-34a was significantly increased under chronic hyperglycaemia exposure. Overexpression of miR-34a was significantly associated with impaired cell viability, exacerbated senescence and disrupted cell paracrine capacity. Moreover, we found that the mechanism underlying miR-34a-mediated deterioration of MSCs exposed to high glucose involved the activation of the SIRT1/FoxO3a autophagy pathway. Further analysis showed that miR-34a inhibitor-treated MSC transplantation could improve cardiac function and decrease the scar area in DM rats. Our study demonstrates for the first time that miR-34a mediates the deterioration of MSCs’ functions under hyperglycaemia. The underlying mechanism may involve the SIRT1/FoxO3a autophagy signalling pathway. Thus, inhibition of miR-34a might have important therapeutic implications in MSC-based therapies for myocardial infarction in DM patients.

Effect of irisin on metabolic and platelet functions in type 2 diabetic rats: role of soluble receptor of advanced glycation end products (sRAGE)

BackgroundIrisin is an adipomyokine with a promising potential for the treatment of metabolic disturbances and endothelial dysfunction. This study aimed to explore the effect of irisin on metabolic and platelet functions, and to explore the possible involvement of soluble receptor of advanced glycation end product (sRAGE) in the type 2 diabetes mellitus (T2DM) rat model. Thirty-three adult male albino rats were divided into three groups: normal control, vehicle-treated T2DM group, and irisin-treated T2DM. At the end of the study period, metabolic parameters, platelet count, mean platelet volume, platelet distribution width, plateletcrit, and serum sRAGE were determined.ResultsIrisin significantly improved platelet function and metabolic derangements induced by T2DM and significantly increased sRAGE. sRAGE was significantly negatively associated with platelet function parameters and some glucometabolic parameters. Additionally, mean platelet volume showed a significant predictive value for the change in serum sRAGE.ConclusionsIrisin could have a protective role against diabetes-induced platelet dysfunction by increasing sRAGE levels, indicating the potential beneficial effects of sRAGE in the type 2 diabetic rat model.

Glucose Transporter 4 and Peroxisome Proliferator-Activated Receptor-Alpha Overexpression Association With Cardioprotective Effects of Myoinositol and Metformin Combination in Type 2 Diabetic Rat Model

Background: Type 2 diabetes mellitus (DM) has many complications associated with increased morbidity and mortality. Cardiovascular complications are one of these serious complications. Therefore, there is a need for early and effective management to hamper them. This study aimed to evaluate the cardioprotective efficacy of metformin and myoinositol combination through exploring the associated underlying mechanisms in type 2 DM rat model. Methods: Type 2 DM model was induced in rats by streptozotocin and high-fat diet. Rats were treated with metformin (150 mg/kg) and/or myoinositol (50 mg/kg) by oral gavage once daily for 4 weeks. Immunohistochemistry was used to assess the drugs’ cardioprotective efficacy by estimating troponin T, nuclear factor kappa B (NF-kappaB) and tumor necrosis factor alpha (TNF-alpha). Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to investigate peroxisome proliferator-activated receptor-alpha (PPARalpha) and glucose transporter 4 (GLUT-4) expression levels in the skeletal muscles, respectively. Results: This study found that metformin and myoinositol combination was associated with GLUT-4 and PPARalpha overexpression, together with better lipid profile than metformin alone in diabetic rats. Additionally, the combination of both drugs improved troponin C and decreased creatine kinase MB isoenzyme, NF-kappaB and TNF-alpha cardiac levels. Conclusion: The current study indicated that myoinositol in combination with metformin had better cardioprotective effect than metformin alone in type 2 DM. This favorable effect was exhibited through upregulation of GLUT-4 and PPARalpha receptors expression in skeletal muscles, thus increasing insulin sensitivity and improving lipid profile. J Endocrinol Metab. 2021;11(5):140-151 doi: https://doi.org/10.14740/jem765

PENGARUH DOSIS DAN LAMA PEMBERIAN EKSTRAK DAUN ASAM JAWA (TAMARINDUS INDICA LINN) TERHADAP HOMA-Β PADA TIKUS MODEL DIABETES MELLITUS TIPE 2 The effect of Tamarind Leaf (tamarindus indica linn) Extract on HOMA-β in Rats with Type 2 Diabetes Mellitus Model

Nowadays the epidemiological burden of diabetes increases with long life-threatening symptoms and the effects of antidiabetic drugs. Lack of insulin activity is one of the signs of a drop in diabetes mellitus. The mechanisms in antidiabetic include stimulating β-Langerhans cells which secrete insulin and inhibit enzyme activity. The purpose of this study was to analyze the effect of giving tamarind leaf extract on levels of homa-β in type 2 diabetes mellitus rats. This study used 30 male Wistar rats aged 8-12 weeks with a bodyweight of 150-200 grams and separated into 5 groups. The first group is KN group (DMT2 mice + standard diet), group 2 is KP (DMT2 + Acarbose mice), group 3 is P1 (DMT2 mice + tamarind leaf extract 28 mg / 200gr / day), group 4 is P2 (rat DMT2 + tamarind leaf extract 56 mg/200gr/day), and group 5 is P3 (DMT2 rat + tamarind leaf extract 112 mg / 200gr / day). The measurement method for Homa-β is to use a standardized formula and use the results of blood tests for fasting blood glucose and insulin levels. The results of the inter-variable study using one-way Anova found a significant difference between the levels of homa-β and the administration of tamarind leaves extract in rats with type 2 diabetes mellitus model (p &lt;0.05). There were significant differences in the 5 treatment groups. On the 7th day, there was an increase in homa-β levels in the KP, P1, P2, and P3 groups while in the KN group decreased in homa-β levels. The P3 group was seen to have the highest increase in homa-β levels in the 14th day, but on the 14th day there was no significant difference between the acarbose drug group (99.57 ± 6.41) and the P3 group (15.09 ± 1, 71). The conclusion was the administration of tamarind extract at a dose of 28.56, and 112 mg/kgBW/day significantly increased levels of HOMA-β for 7 and 14 days in rats with type 2 diabetes mellitus.

Blood glucose control contributes to protein stability of Ski-related novel protein N in a rat model of diabetes.

Ski-related novel protein N (SnoN) negatively regulates the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway and is present at a low level during diabetic nephropathy (DN), but its underlying regulatory mechanism is currently unknown. The present study aimed to assess the effects of insulin-controlled blood glucose on renal SnoN expression and fibrosis in rats with diabetes mellitus (DM). Streptozotocin-induced DM rats were treated with insulin glargine (INS group) following successful model establishment. Blood samples were collected and centrifuged for biochemical indexes and the kidneys were collected for morphological analysis. In vitro, rat renal proximal tubular epithelial cells were treated with high-glucose medium for 24 h and transferred to normal glucose medium for 24 h. The expression levels of TGF-β1, SnoN, Smad ubiquitin regulatory factor 2 (Smurf2), Arkadia, Smads, E-cadherin, α-smooth muscle actin and collagen III were assessed by western blotting and immunohistochemistry. The ubiquitylation of SnoN was detected by immunoprecipitation, and the expression levels of SnoN mRNA were evaluated by reverse transcription-quantitative PCR. The biochemical parameters and morphology indicated that renal fibrosis was notable in the DM group and mitigated in the INS group. Compared with the control group, TGF-β1, phosphor (p)-Smad2, p-Smad3, Smurf2 and Arkadia levels were enhanced in the DM group, and the levels of SnoN protein were decreased, whereas the levels of SnoN mRNA and ubiquitylation were increased in renal tissues. Notably, treatment with insulin reversed this trend. Furthermore, changing the glucose levels in the medium from high to normal glucose suppressed the epithelial-mesenchymal transition of NRK-52E cells by restoring the SnoN protein levels, and this phenomenon was impaired by the knockout of SnoN. SnoN protein levels were likely reduced through a mechanism enhanced by the ubiquitin proteasome system, which reversed the transcriptional activation of SnoN during DN progression. In addition, controlling blood glucose may delay DN fibrosis by rescuing the protein stability of SnoN.

The pharmacokinetic profiles of mogrosides in T2DM rats

Ethnopharmacological relevanceLuohanguo (LHG) extract major contenting mogrosides, as a nonnutritive sweetener, has been reported to exert a hypoglycemic effect on diabetic patients and animals. As the pharmacokinetics and pharmacodynamics of drugs were changed with diabetes, it may lead to the different pharmacological of mogrosides between diabetic and normal subjects. Aims of the studyTo characterise the pharmacokinetic profiles of mogrosides in T2DM rats. Study design and methodsHigh-fat diet and streptozocin induced type 2 diabetic mellitus rats were used to investigate the pharmacokinetic behavior of mogroside V and mogrosides IIIA1, IIA1, and IA1 after T2DM rats orally administrated with mogroside V and 1–3 glucose residues’ mogrosides, respectively. The validated convenient UPLC-QTOF/MS and UPLC-MS/MS methods were established to use in the pharmacokinetic studies of mogrosides in normal and T2DM rats. Additionally, the expression of the intestinal tight junction protein zonula occludens-1 (ZO-1) was also detected by immunohistochemical analysis, which assessed the function of passive intestinal permeability in T2DM rats. ResultsThe results showed that for rats treated with mogroside V, its metabolite mogroside IIIA1 has a significant increase (p < 0.05) in maximum plasma concentration (Cmax, 163.80 ± 25.56 ng/mL) and area under the plasma concentration (AUC0-t, 2327.44 ± 474.63 h·ng/mL) in T2DM rats compared with in normal rats. The mean residence time (MRT0-t, 12.04 ± 0.97 h) of mogroside V showed a significant decrease (p < 0.05) in T2DM rats. However, the mogrosides IIIA1, IIA1and IA1 showed no statistical differences in the normal and T2DM rats after administered with 1–3 glucose residues’ mogrosides. Furthermore, the expression level of ZO-1 in the duodenum and colon of T2DM rats were downregulated. ConclusionThe pharmacokinetic profiles of mogroside V and its metabolite mogroside IIIA1 in T2DM rats and normal rats showed some difference, it might be affected by the metabolic changes in the pathological state of T2DM.

Activation of Silent Information Regulator 6 Signaling Attenuates Myocardial Fibrosis by Reducing TGFβ1-Smad2/3 Signaling in a Type 2 Diabetic Animal Model

Abstract Objective: Long-term diabetes can result in ventricular hypertrophic remodeling, tissue fibrosis, myocardial metabolic defection, and eventually, heart failure. Silent information regulator 6 (SIRT6) exerts beneficial effects against cardiovascular diseases. This study is aimed to investigate whether the direct regulation of myocardial SIRT6 signaling affects cardiac performance in the case of diabetes. Meanwhile, we sought to explore the underlying mechanisms. Methods: Sprague Dawley (SD) rats were used in this experiment. Briefly, type 2 diabetic animal model was generated by streptozotocin administration along with feeding a high-fat diet. The SD rats were randomly assigned to non-diabetic group, diabetic group, diabetic injected with empty adenoviral vectors group and diabetic injected with adenoviral vectors expressing SIRT6 group (n = 10, respectively). The animals were kept for another 4 weeks before sacrifice. Cardiac performance was evaluated by echocardiography. Myocardial fibrosis was determined by Masson's trichrome staining. Myocardial SIRT6 signaling and fibrosis related molecules were measured by western blotting. Results: The diabetic myocardium exhibited markedly enhanced TGFβ1-Smad2/3-induced myocardial fibrosis and reduced SIRT6 and AMP-activated protein kinase (AMPK) signaling. After 4 weeks of SIRT6 adenoviral vector infection, myocardial tissues exhibited markedly enhanced SIRT6 and AMPK signaling. Additionally, myocardial fibrosis and TGFβ1-Smad2/3 signaling were both attenuated in the diabetic injected with adenoviral vectors expressing SIRT6 group. Conclusions: SIRT6-AMPK signaling suppressed the progression of tissue fibrosis in diabetes mellitus rats by inhibiting TGFβ1 and its downstream effector Smad2/3. SIRT6 might serve as an alternative therapeutic target for diabetes-related cardiovascular diseases.

Anti-diabetic Activity of the Red Dragon Fruit Peel (Hylocereus polyrhizus) in Ethanol Extract against Diabetic Rats

Background: The red dragon fruit peel, which is rarely used in general, contains higher antioxidant properties compared to the flesh parts and has various secondary metabolites utilised in medicines. Objectives: This study was aimed to determine the effects of ethanol extract administration of the red dragon fruit peel (Hylocereus polyrhizus) against the decline of blood glucose levels in diabetes mellitus rats. Methods: In this study, the total of 24 male white Wistar rats (Rattus novergicus) were divided into 4 groups. All experimental animals were induced to diabetic conditions by the administration of streptozotocin and nicotinamide dosages at 45 mg/kg body weight and 110 mg/kg body weight, respectively. For 14 days, each group was treated accordingly. The first group or negative control (NC) was treated with the administration of CMC-Na 0.5% dose 2 ml/200 g body weight; the second group or positive control (PC) was administrated with glibenclamide dose 0.09 mg/200 g body weight; the third (E1) and fourth (E2) groups were administered with the ethanol extracts of the red dragon fruit peels at dosages of 37.44 mg/200 g body weight and 74.88 mg/200 g body weight, respectively. Results: After the 14-day trial, the average levels of blood glucose on the negative control group (382.92 mg/dl) experienced no decline, and the blood glucose levels amongst groups were statistically different (p<0.05). Conclusion: The anti-diabetic activity of the red dragon fruit peel in the ethanol extract dose 74.88 mg/200 g body weight is statistically equal to the glibenclamide dose 0.09 mg/200 g body weight.