Type 2 Diabetes Mellitus Rats Research Articles

Oridonin attenuates diabetes‑induced renal fibrosis via the inhibition of TXNIP/NLRP3 and NF‑κB pathways by activating PPARγ in rats.

Oridonin possesses remarkable anti-inflammatory, immunoregulatory properties. However, the renoprotective effects of Oridonin and the underlying molecular mechanisms have not been explored in Diabetic Nephropathy (DN). We hypothesized that Oridonin could ameliorate diabetes‑induced renal fibrosis. We used streptozocin (STZ)-induced diabetic rats combined high-fat diet to establish a type 2 diabetes mellitus (T2DM) animal model, and then treated with Oridonin (10,20mg/kg/day) for two weeks. Kidney function and renal fibrosis were assessed. We also treated high glucose-induced human renal proximal tubule epithelial cells (HK-2) with Oridonin. In addition, the expression of inflammatory factors and fibrotic markers were analyzed. Oridonin treatment preserved kidney function and markedly limited the renal fibrosis size in diabetic rats. The renal fibrotic markers were inhibited in the 10mg/kg/day group and 20mg/kg/day group compared to the T2DM group. Moreover, the expression levels of TXNIP/NLRP3 and NF‑κB pathway were decreased and the level of PPARγ were increased in the Oridonin treatment group compared to non-treated group. In vitro, intervention of PPARγ could significantly regulate the effect of Oridonin on the high glucose-induced inflammatory changes in HK-2. Oridonin reduces renal fibrosis and preserves kidney function via the inhibition of TXNIP/NLRP3 and NF‑κB pathway by activating PPARγ in T2DM rat model, which indicates potential therapeutic effect of Oridonin on DN.

Transcriptomics reveals dynamic changes in the “gene profiles” of rat supraspinatus tendon at three different time points after diabetes induction

ObjectiveThere is increasing evidence that type 2 diabetes mellitus (T2DM) is an independent risk factor for the occur of tendinopathy. Therefore, this study is the first to explore the dynamic changes of the “gene profile” of supraspinatus tendon in rats at different time points after T2DM induction through transcriptomics, providing potential molecular markers for exploring the pathogenesis of diabetic tendinopathy.MethodsA total of 40 Sprague-Dawley rats were randomly divided into normal (NG, n = 10) and T2DM groups (T2DM, n = 30) and subdivided into three groups according to the duration of diabetes: T2DM-4w, T2DM-8w, and T2DM-12w groups; the duration was calculated from the time point of T2DM rat model establishment. The three comparison groups were set up in this study, T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG. Differentially expressed genes (DEGs) in 3 comparison groups were screened. The intersection of the three comparison groups’ DEGs was defined as key genes that changed consistently in the supraspinatus tendon after diabetes induction. Cluster analysis, gene ontology (GO) functional annotation analysis and Kyoto encyclopedia of genes and genomes (KEGG) functional annotation and enrichment analysis were performed for DEGs.ResultsT2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG detected 519 (251 up-regulated and 268 down-regulated), 459 (342 up-regulated and 117 down-regulated) and 328 (255 up-regulated and 73 down-regulated) DEGs, respectively. 103 key genes of sustained changes in the supraspinatus tendon following induction of diabetes, which are the first identified biomarkers of the supraspinatus tendon as it progresses through the course of diabetes.The GO analysis results showed that the most significant enrichment in biological processes was calcium ion transmembrane import into cytosol (3 DEGs). The most significant enrichment in cellular component was extracellular matrix (9 DEGs). The most significant enrichment in molecular function was glutamate-gated calcium ion channel activity (3 DEGs). The results of KEGG pathway enrichment analysis showed that there were 17 major pathways (p < 0.05) that diabetes affected supratinusculus tendinopathy, including cAMP signaling pathway and Calcium signaling pathway.ConclusionsTranscriptomics reveals dynamic changes in the“gene profiles”of rat supraspinatus tendon at three different time points after diabetes induction. The 103 DEGs identified in this study may provide potential molecular markers for exploring the pathogenesis of diabetic tendinopathy, and the 17 major pathways enriched in KEGG may provide new ideas for exploring the pathogenesis of diabetic tendinopathy.

Changes of RNA m6A/m5C Modification Regulatory Molecules in Ferroptosis of T2DM Rat Pancreas.

N6-methyladenine (m6A) and 5-methylcytosine (m5C) are two common forms of RNA methylation that play an important role in the epigenetics of type 2 diabetes mellitus (T2DM). One type of cell death, ferroptosis, has been implicated in islet β-cell damage in T2DM. Notably, RNA methylation, an upstream regulatory mechanism of mRNAs, can regulate the expression of ferroptosis signaling molecules, thereby affecting cell proliferation and death. Here, we found that the ferroptosis signaling pathway was activated in pancreas of T2DM rats, followed by significant changes in m6A/m5C modification regulatory molecules. These detection data together with the prediction results that m6A and m5C exist in the mRNAs of ferroptosis molecules, we speculate that m6A and m5C are probably involved in pancreatic cell damage by modifying of ferroptosis signaling molecules. In short, our findings provide a new research idea for future studies on the molecular mechanisms of pancreatic cell damage and point to a new direction for exploring the mechanisms of ferroptosis from the perspective of RNA methylation modification.

Modulation of Glycolipid Metabolism in T2DM Rats by Rubus Irritans Focke Extract: Insights from Metabolic Profiling and ERK/IRS-1 signaling pathway

Ethnopharmacological RelevanceThe extracellular regulated protein kinase (ERK) plays a crucial role in the mitogen-activated protein kinase (MAPK) family, influencing apoptosis, proliferation, and differentiation. It connection to the insulin (INS) signaling cascade and the development of type 2 diabetes mellitus (T2DM) has been established. Rubus irritans Focke, an indispensable herb in Chinese Tibetan medicine for diabetes mellitus treatment, lacks a comprehensive understanding of its effects and pharmacological mechanisms in T2DM. Aim of the studyThis study aimed to elucidate the effects of Rubus irritans Focke extract (Rife) on a T2DM rat model, exploring its impact on glycemic and lipid metabolism, histopathological changes, and its potential targeting of the extracellular regulated protein kinase/insulin receptor substrate-1 (ERK/IRS-1) signaling pathway. Materials and MethodsA T2DM rat model was induced by streptozotocin (STZ) injection (40 mg/kg) in high-fat diet-fed (HFD) male Wistar rats. Rife and metformin (Met) were administered for 4 weeks, and glycemic, lipid metabolism indices, and histopathological changes were assessed. Protein expression of ERK, IRS-1 in rat liver tissues was examined to evaluate the impact on the ERK/IRS-1 pathway. ResultsRife reducing hepatic ERK and IRS-1 protein expression in T2DM rats. Untargeted metabolomics identified 13 potential biomarkers and 4 differential metabolic pathways related to glycolipid metabolism disorders. ConclusionsRife demonstrated improved glycolipid metabolism in T2DM rats by inhibiting the ERK/IRS-1 related signaling pathway and influencing multiple metabolic pathways. This study provides valuable insights into the potential therapeutic mechanisms of Rife in the context of T2DM.

Petroleum ether extract of Schisandra sphenanthera prevents hyperglycemia and insulin resistance in association with modulation of sweet taste receptors and gut microbiota in T2DM rats

Ethnopharmacological relevanceSchisandra sphenanthera (Schisandra sphenanthera Rehd. et Wils.) is the dried mature fruit of Schisandra sphenanthera, a plant in the Magnoliaceae family. It was used in the treatment of diabetes mellitus in the Jade Fluid Decoction and the Xiaoke pills, which were recorded in ancient books. However, its mechanism of action in the treatment of type 2 diabetes mellitus (T2DM) was unclear and needs further study. Aim of the studyThis research aimed to investigate the chemical composition and lignan content of Schisandra sphenanthera petroleum ether parts (SPEP) and to evaluate the effects of SPEP on sweet taste receptors (STRs) and intestinal flora in rats on a high-fat diet (HFD). Additionally, the relationships between SPEP and hyperglycemia and insulin resistance were examined. Materials and methodsGC-MS was used to determine the chemical composition of SPEP, and HPLC was used to determine the lignin content. A combination of the HFD and the administration of streptozotocin (STZ) was employed to generate a rat model of T2DM. Petroleum ether extracts from Schisandra sphenanthera were used as the focus of the research to evaluate the effects of these extracts on the glucolipid metabolism of T2DM rats, as well as the underlying mechanisms. ResultsAnalysis of the GC-MS spectrum of SESP revealed a total of 58 compounds. HPLC analysis revealed that SPEP had the highest concentration of Schisandrin A and the lowest concentration of Schisandrol A. The drug administration intervention resulted in a significant decrease in body weight and pancreatic weight of diabetic rats compared to the Normal group. When compared to the Model group, the body weight of rats in the drug administration group and the Metformin group had a more moderate decrease, while the pancreatic weight and pancreatic-to-body ratio increased. The Model group shown significant increases in FBG, OGTT, GHb, TC, TG, LDL-C, ALT, AST, MDA, FINS, and NEFA, as well as significant decreases in HDL-C and SOD, when compared to the Normal group (P<0.05). The administration of each group was found to be significantly effective in decreasing FBG, OGTT, GHb, TC, TG, LDL-C, ALT, AST, MDA, FINS, NEFA, while increasing HDL-C and SOD when compared to the Model group. The application of SPEP had a positive impact on hepatocyte swelling, hepatocyte degeneration, and necrosis, as well as the morphological structure of pancreatic islet cells. Furthermore, the protein expression levels of T1R2, TRPM5 and GLP-1 in the small intestine of the Model group were reduced. After a period of six weeks, the protein expression levels began to align more closely with those of the Normal group of rats. Analysis of 16S rRNA sequencing revealed that the intestinal microbiota of diabetic rats was significantly disrupted, with a decrease in the abundance of the Firmicutes phylum and an increase in the abundance of the Bacteroidetes phylum. Furthermore, the composition of the dominant genus was distinct from that of the control group. After the drug intervention, the microbiota of diabetic rats was significantly altered, exhibiting a higher abundance and diversity, as well as a significant enrichment of the community. The SPEP treatment resulted in a significant increase in acetic acid, propionic acid, and butyric acid. ConclusionsThe findings of this research indicated that SPEP could be effective in treating T2DM through the regulation of STRs, the adjustment of disturbed metabolite levels, and the alteration of intestinal flora.

Impact of Combined Aerobic Training and Magnesium Supplementation on Serum Biomarkers and microRNA-155 and microRNA-21 Expression in Adipose Tissue of Type 2 Diabetic Rats: An Eight-Week Interventional Study.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance and chronic inflammation. Aerobic training (AT) and magnesium supplementation (Mg) have both been independently shown to have beneficial effects on glucose control and insulin sensitivity in individuals with T2DM. However, the potential synergistic effects of combining AT and Mg supplementation have not been extensively studied. This study aimed to investigate the effects of an 8-week AT and Mg supplementation on serum levels of insulin, glucose, leptin, adiponectin, TNF-α, IL-1β, IL-6, NF-κB, as well as the expression of mir-155 and mir-21 in the visceral adipose tissue (VAT) of rats with T2DM. For this experimental study, 32 male Wistar rats were induced with T2DM by a high-fat diet combined with a low-dose streptozotocin injection. The rats were randomly assigned to four groups: AT and Mg supplementation (AT + Mg), AT (5 days/week for 8 weeks), Mg supplementation (received daily supplementation of Mg chloride), and diabetic control (C). An 8-week AT program was implemented, with gradually increasing the intensity and duration to reach 25m/min and 60min in the 8th week, respectively. The training intensity was set at 50-60% of VO2max. The Mg groups were provided with rat diets containing 1000mg/kg of Mg. The AT + Mg group received both interventions, while the C group served as the untreated control. Serum biomarkers were measured using enzyme-linked immunosorbent assay (ELISA), and VAT samples were collected for gene expression analysis using real-time polymerase chain reaction (PCR). Serum biomarker analysis revealed that the AT + Mg group had a significant decrease in fasting insulin (p = 0.001) and serum glucose (p = 0.001), as well as an increase in adiponectin levels compared to the C group (p = 0.002). Additionally, the AT + Mg group showed a significant reduction in serum leptin, TNF-α, IL-6, IL-1β, and NF-κB, as well as downregulation of mir-155 and mir-21 in the VAT compared to the other groups. The AT group also showed improvements in several parameters, while the Mg group had fewer significant differences compared to the C group. The combination of AT and Mg supplementation provides a synergistic effect that improves serum biomarkers and downregulates pro-inflammatory microRNAs in the VAT of T2DM rats. Meanwhile, Mg supplementation alone does not have a significant effect on pro-inflammatory microRNAs in the VAT. These findings suggest that such combined interventions could be a promising strategy for managing T2DM, potentially ameliorating inflammatory states and improving metabolic health.

Diabetic Rats Induced Using a High-Fat Diet and Low-Dose Streptozotocin Treatment Exhibit Gut Microbiota Dysbiosis and Osteoporotic Bone Pathologies.

Type 2 diabetes mellitus (T2DM) presents a challenge for individuals today, affecting their health and life quality. Besides its known complications, T2DM has been found to contribute to bone/mineral abnormalities, thereby increasing the vulnerability to bone fragility/fractures. However, there is still a need for appropriate diagnostic approaches and targeted medications to address T2DM-associated bone diseases. This study aims to investigate the relationship between changes in gut microbiota, T2DM, and osteoporosis. To explore this, a T2DM rat model was induced by combining a high-fat diet and low-dose streptozotocin treatment. Our findings reveal that T2DM rats have lower bone mass and reduced levels of bone turnover markers compared to control rats. We also observe significant alterations in gut microbiota in T2DM rats, characterized by a higher relative abundance of Firmicutes (F) and Proteobacteria (P), but a lower relative abundance of Bacteroidetes (B) at the phylum level. Further analysis indicates a correlation between the F/B ratio and bone turnover levels, as well as between the B/P ratio and HbA1c levels. Additionally, at the genus level, we observe an inverse correlation in the relative abundance of Lachnospiraceae. These findings show promise for the development of new strategies to diagnose and treat T2DM-associated bone diseases.

Icariin accelerates bone regeneration by inducing osteogenesis-angiogenesis coupling in rats with type 1 diabetes mellitus

BACKGROUND Icariin (ICA), a natural flavonoid compound monomer, has multiple pharmacological activities. However, its effect on bone defect in the context of type 1 diabetes mellitus (T1DM) has not yet been examined. AIM To explore the role and potential mechanism of ICA on bone defect in the context of T1DM. METHODS The effects of ICA on osteogenesis and angiogenesis were evaluated by alkaline phosphatase staining, alizarin red S staining, quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. Angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis. A bone defect model was established in T1DM rats. The model rats were then treated with ICA or placebo and micron-scale computed tomography, histomorphometry, histology, and sequential fluorescent labeling were used to evaluate the effect of ICA on bone formation in the defect area. RESULTS ICA promoted bone marrow mesenchymal stem cell (BMSC) proliferation and osteogenic differentiation. The ICA treated-BMSCs showed higher expression levels of osteogenesis-related markers (alkaline phosphatase and osteocalcin) and angiogenesis-related markers (vascular endothelial growth factor A and platelet endothelial cell adhesion molecule 1) compared to the untreated group. ICA was also found to induce osteogenesis-angiogenesis coupling of BMSCs. In the bone defect model T1DM rats, ICA facilitated bone formation and CD31hiEMCNhi type H-positive capillary formation. Lastly, ICA effectively accelerated the rate of bone formation in the defect area. CONCLUSION ICA was able to accelerate bone regeneration in a T1DM rat model by inducing osteogenesis-angiogenesis coupling of BMSCs.

Serum testosterone levels and oxidative stress in type 1 diabetes, type 2 diabetes, and obesity.

Obesity, type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) are metabolic diseases that continue to be a global problem. Testosterone levels in men are affected by several factors, including obesity and DM. Although the relationship between diabetes and testosterone is not fully understood, oxidative stress is thought to play a major role. The aim of this study was to compare serum testosterone levels and oxidative stress markers [total antioxidant status (TAS), total oxidant capacity (TOS), oxidative stress index (OSI), and ischaemic modified albumin (IMA)] among the control group and experimentally induced obese, T1DM, and T2DM rats. The study included 28 male Sprague-Dawley rats divided into 4 groups: the obesity group were fed a high-fat diet (HFD), the T2DM group received a HFD plus a single dose of streptozocin (STZ), the T1DM group received only STZ, and there was a control group. Serum testosterone, TAS, TOS, OSI, and IMA were analysed. Serum testosterone levels were lower in the T1DM and T2DM groups compared to the control and obesity groups. The TOS levels were highest in the T2DM group, followed by the T1DM group, the obesity group, and finally the control group. No significant difference was found between the obesity group and the control group in terms of TOS levels. Regarding TAS levels, the order observed was control group > obesity group > T2DM > T1DM. Testosterone was positively correlated with TAS and negatively correlated with TOS and OSI. Increased oxidative stress in diabetes may be an important factor that decreases serum testosterone levels.

The preventive and therapeutic consumption of meat enriched with carob fruit extract, rich in phenolic compounds, improves colonic antioxidant status in late-stage T2DM rats

Oxidative stress is prevalent in Type 2 Diabetes Mellitus (T2DM) and has been associated with high meat consumption. Carob Fruit Extract (CFE) contains phenolic compounds, making it a suitable functional ingredient. Current study aims to evaluate the effect of CFE-enriched meat (CFE-meat) consumption on the antioxidant status of proximal and distal colon, and its relationship with fecal phenolic compounds in late-stage T2DM rats. Three groups of eight rats were studied: 1) D, fed control-meat; 2) ED, fed CFE-meat since the beginning of the study; 3) DE, fed CFE-meat after confirming T2DM. CFE-meat consumption reduces colonic oxidative stress mainly in the proximal section and helps to ameliorate glutathione metabolism and antioxidant score. Difference between ED and DE groups were associated with colon homeostasis and T2DM progression suggesting greater fermentation but lower absorption in the DE group. CFE appears as a promising tool to improve the antioxidant status observed in late-stage T2DM.

Liraglutide promotes UCP1 expression and lipolysis of adipocytes by promoting the secretion of irisin from skeletal muscle cells

Although Liraglutide (Lira) increases serum irisin levels in type 2 diabetes mellitus (T2DM), it is unclear whether it induces expression of uncoupling protein 1 (UCP1) of adipocytes via promoting irisin secretion from skeletal muscle. Male T2DM rats were treated with 0.4 mg/kg/d Lira twice a day for 8 weeks, and the protein expression of phosphorylated AMP kinase (p-AMPK), phosphorylated acetyl-CoA carboxylase 1 (p-ACC1) and UCP1 in white adipose tissues were detected. Differentiated C2C12 cells were treated with palmitic acid (PA) and Lira to detect the secretion of irisin. Differentiated 3T3-L1 cells were treated with irisin, supernatant from Lira-treated C2C12 cells, Compound C or siAMPKα1, the triglyceride (TG) content and the related gene expression were measured. The transcriptome in irisin-treated differentiated 3T3-L1 cells was analyzed. Lira elevated serum irisin levels, decreased the adipocyte size and increased the protein expression of UCP1, p-AMPK and p-ACC1 in WAT. Moreover, it promoted the expression of PGC1α and FNDC5, the secretion of irisin in PA-treated differentiated C2C12 cells. The irisin and supernatant decreased TG synthesis and promoted the expression of browning- and lipolysis-related genes in differentiated 3T3-L1 cells. While Compound C and siAMPKα1 blocked AMPK activities and expression, irisin partly reversed the pathway. Finally, the transcriptome analysis indicated that differently expressed genes are mainly involved in browning and lipid metabolism. Overall, our findings showed that Lira modulated muscle-to-adipose signaling pathways in diabetes via irisin-mediated AMPKα/ACC1/UCP1/PPARα pathway. Our results suggest a new mechanism for the treatment of T2DM by Lira.

Cyclooxygenase products contribute to the exaggerated exercise pressor reflex evoked by static muscle contraction in male UCD-type 2 diabetes mellitus rats.

Cyclooxygenase (COX) products of arachidonic acid metabolism, specifically prostaglandins, play a role in evoking and transmitting the exercise pressor reflex in health and disease. Individuals with type 2 diabetes mellitus (T2DM) have an exaggerated exercise pressor reflex; however, the mechanisms for this exaggerated reflex are not fully understood. We aimed to determine the role played by COX products in the exaggerated exercise pressor reflex in T2DM rats. The exercise pressor reflex was evoked by static muscle contraction in unanesthetized, decerebrate, male, adult University of California Davis (UCD)-T2DM (n = 8) and healthy Sprague-Dawley (n = 8) rats. Changes (Δ) in peak mean arterial pressure (MAP) and heart rate (HR) during muscle contraction were compared before and after intra-arterial injection of indomethacin (1 mg/kg) into the contracting hindlimb. Data are presented as means ± SD. Inhibition of COX activity attenuated the exaggerated peak MAP (Before: Δ32 ± 13 mmHg and After: Δ18 ± 8 mmHg; P = 0.004) and blood pressor index (BPi) (Before: Δ683 ± 324 mmHg·s and After: Δ361 ± 222 mmHg·s; P = 0.006), but not HR (Before: Δ23 ± 8 beats/min and After Δ19 ± 10 beats/min; P = 0.452) responses to muscle contraction in T2DM rats. In healthy rats, COX activity inhibition did not affect MAP, HR, or BPi responses to muscle contraction. Inhibition of COX activity significantly reduced local production of prostaglandin E2 in T2DM and healthy rats. We conclude that peripheral inhibition of COX activity attenuates the pressor response to muscle contraction in T2DM rats, suggesting that COX products partially contribute to the exaggerated exercise pressor reflex in those with T2DM.NEW & NOTEWORTHY We compared the pressor and cardioaccelerator responses to static muscle contraction before and after inhibition of cyclooxygenase (COX) activity within the contracting hindlimb in decerebrate, unanesthetized type 2 diabetic mellitus (T2DM) and healthy rats. The pressor responses to muscle contraction were attenuated after peripheral inhibition of COX activity in T2DM but not in healthy rats. We concluded that COX products partially contribute to the exaggerated pressor reflex in those with T2DM.

Artesunate-loaded thermosensitive chitosan hydrogel promotes osteogenesis of maxillary tooth extraction through regulating T lymphocytes in type 2 diabetic rats.

Type 2 diabetes mellitus (T2DM) causes severe bone loss after tooth extraction as a hyperglycemic environment causes aberrant bone homeostasis. Artesunate (ART) is known to possess anti-inflammation and osteogenic properties. However, its osteogenesis property in alveolar bone remains unclear. This study aimed to explore the osteogenic and immunoregulatory effects of artesunate-loaded thermosensitive chitosan hydrogel (ART-loaded TCH) on maxilla tooth extraction in T2DM rats. T2DM rats were induced by a high-fat diet and streptozotocin. Different concentrations of ART-loaded TCH were applied in tooth extraction sockets. Bone loss and the expression of osteogenic regulatory factors (OPG, ALP, RANK) were evaluated. The immunoregulatory effects of ART-loaded TCH were observed through detecting the infiltration of T lymphocytes and their cytokines. The underlying mechanisms were explored. Results showed that the 150mg/ml ART-loaded TCH group significantly ameliorated maxilla bone height and bone mineral density when compared with the T2DM group (p < 0.05). It also improved the expression of OPG, ALP, and RANK. Although the alteration of CD4+ T, CD8+ T, and CD4+:CD8+ T ratio has no significant difference among groups, the release of Th1 and Th2 in the 150mg/ml ART-loaded TCH group has been significantly regulated than in the T2DM group (p < 0.05). Besides, ART-loaded TCH treatment inhibited the expression of p38 MAPK and ERK1 in T2DM maxilla. Therefore, the results indicated that 150mg/ml ART-loaded TCH could be an effective method to prevent bone loss in T2DM tooth extraction rats by modulating the immunoregulation of Th1 and Th2 and the MAPK signaling pathway.

Alleviation of taurine on liver injury of type 2 diabetic rats by improving antioxidant and anti-inflammatory capacity

Type 2 diabetes mellitus (T2DM) is a serious metabolic disease characterized by insulin resistance and reduced insulin production, which causes abnormally elevated blood glucose. It has been reported that T2DM can enhance oxidative stress and inflammatory responses, and stimulate a variety of complications including liver injury. Studies have shown that taurine has antioxidant and anti-inflammatory effects that can not only ameliorate diabetes but also alleviate liver injury caused by various diseases. However, its effect on liver injury in T2DM is not clear. In our study, a high-fat diet and intraperitoneal injection of streptozotocin (STZ) was used to induce liver injury in T2DM rats, and taurine was given as a treatment. Through the use of HE staining on paraffin sections, ELISA, and qRT-PCR, the effects of taurine on liver pathological alterations, antioxidant capacity, and inflammatory response were investigated. We found that: hepatic transaminase levels of rats were reduced significantly following taurine administration; histopathological observations revealed that the morphology of rat hepatocytes was close to normal, and the number of inflammatory cells around liver vessels was significantly reduced; antioxidant-related indicators were significantly increased, including SOD, CAT, GSH-Px and T-AOC, while related factors of the Nrf2 signalling pathway and its downstream HO-1, NQO1 and γ-GCS were significantly increased; the expression of the JAK2-STAT1 signalling pathway, TLR4/NF-κB signalling pathway and NLRP3 inflammatory vesicle-related factors were significantly reduced. Our results suggest taurine can alleviate T2DM-induced liver injury by improving the antioxidant capacity of the liver and inhibiting macrophage M1-type polarization and the inflammatory response mediated thereby.

Nrf-2-dependent antioxidant and anti-inflammatory effects underlie the protective effect of esculeoside A against retinal damage in streptozotocin-induced diabetic rats

Esculeoside A (ESA) is a tomato-derived glycoside with antioxidant and anti-inflammatory properties. The protective effect of ESA against diabetic retinopathy is not well-investigated and was the core objective of this study. In addition, we tested if such protection involves the activation of Nrf2 signaling. Type 1 diabetes mellitus (T1DM) was induced in adult Wistar male rats by an intraperitoneal injection of streptozotocin (65 mg/kg). Non-diabetic and T1DM rats were divided into two subgroup groups given either the vehicle or ESA (100 mg)/kg. An additional T1DM group was given ESA (100 mg/kg) and an Nrf2 inhibitor (2 mg/kg) (n=8 rats/group). Treatments continued for 12 weeks. In this study, according to the histological features, ESA improved the structure of ganglionic cells and increased the number of cells of the inner nuclear and plexiform layers in the retinas of T1DM rats. Concomitantly, it reduced the retina levels of malondialdehyde (lipid peroxides), vascular endothelial growth factor, interleukin-6, tumor necrosis factor-α, Bax, and caspase-3. In the retinas of the control and diabetic rats, ESA boosted the levels of total glutathione, superoxide dismutase, heme-oxygenase-1, and Bcl2, reduced the mRNA levels of REDD1, and enhanced cytoplasmic and nuclear levels of Nrf2. However, ESA failed to alter the mRNA levels of Nrf2 and keap1, protein levels of keap1, plasma glucose, plasma insulin, serum triglycerides, cholesterol, and LDL-c in both the control and T1DM rats. In conclusion, ESA alleviates retinopathy in T1DM rats by suppressing REDD1-associated degradation and inhibiting the Nrf2/antioxidant axis.

Investigating the mechanism of cornel iridoid glycosides on type 2 diabetes mellitus using serum and urine metabolites in rats

Ethnopharmacological relevanceCornel iridoid glycosides (CIG) are extracted from Corni fructus, a herbal medicine used in traditional Chinese medicine to treat diabetes. However, the antidiabetic effects of CIG and the underlying metabolic mechanisms require further exploration. Aim of the studyThis study aimed to assess the antidiabetic effects and metabolic mechanism of CIG by performing metabolomic analyses of serum and urine samples of rats. Materials and methodsA rat model of type 2 diabetes mellitus (T2DM) was established by administering a low dose of streptozotocin (30 mg/kg) intraperitoneally after 4 weeks of feeding a high-fat diet. The model was evaluated based on several parameters, including fasting blood glucose (FBG), random blood glucose (RBG), urine volume, liver index, body weight, histopathological sections, and serum biochemical parameters. Subsequently, serum and urine metabolomics were analyzed using ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS). Data were analyzed using unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA). Differential metabolites were examined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways to explore the underlying mechanisms. ResultsAfter 4 weeks of treatment with different doses of CIG, varying degrees of antidiabetic effects were observed, along with reduced liver and pancreatic injury, and improved oxidative stress levels. Compared with the T2DM group, 19 and 23 differential metabolites were detected in the serum and urine of the CIG treatment group, respectively. The key metabolites involved in pathway regulation include taurine, chenodeoxycholic acid, glycocholic acid, and L-tyrosine in the serum and glycine, hippuric acid, phenylacetylglycine, citric acid, and D-glucuronic acid in the urine, which are related to lipid, amino acid, energy, and carbohydrate metabolism. ConclusionsThis study confirmed the antidiabetic effects of CIG and revealed that CIG effectively controlled metabolic disorders in T2DM rats. This seems to be meaningful for the clinical application of CIG, and can benefit further studies on CIG mechanism.

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.

Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Ameliorates Hyperglycemia in Type 2 Diabetes Mellitus Rats

Introduction: Type 2 diabetes mellitus (T2DM) is a prevalent form of diabetes that affects 90 - 95 % of all diabetic patients. Insulin sensitizers and insulin exogenous supply could temporarily ameliorate hyperglycaemia; however, they are accompanied by side effects. As a result, new approaches are required to address insulin resistance and regenerate beta cells simultaneously. The secretome of hypoxic mesenchymal stem cells (SH-MSCs) contains various growth factors and anti-inflammatory cytokines that could potentially enhance insulin resistance and improve pancreatic function. Objectives: In this study, we performed SH-MSCs infusion to ameliorate HFD-induced hyperglycaemia in T2DM rats. Methods: We created a T2DM rat model using a combination of a high-fat diet (HFD) and streptozotocin (STZ) administration. Then, we administered SH-MSCs injection at doses of 250 and 500 µL and assessed the therapeutic effects of SH-MSCs. We also investigated the potential underlying mechanisms involved. Results: The administration of SH-MSCs improved hyperglycemia in rats with T2DM. Infusion of SH-MSCs at 500 µL dose decreased homeostatic model assessment for insulin resistance (HOMA-IR). Histological analysis revealed that injection of SH-MSCs alleviated morphological damage of pancreas. SH-MSCs administration also inhibit the level of IL-6 and promote the expression of CD163 type 2 macrophage. Conclusion: The results of our study indicate that SH-MSCs have the potential to improve hyperglycemia and exert a protective effect on T2DM rats. HIGHLIGHTS Administration of SH-MSCs effectively improved hyperglycemia and decreased insulin resistance in TD2M rats through modulation of IL-6 levels and promotes the expression of CD163 type 2 macrophage Histological analysis demonstrated the protective effect of SH-MSCs on pancreatic morphology SH-MSCs hold promise for improving hyperglycemia, insulin resistance, and providing a protective effect in TD2M GRAPHICAL ABSTRACT

Nephroprotective and Anti-Diabetic Potential of Beta vulgaris L. Root (Beetroot) Methanolic Extract in a Rat Model of Type 2 Diabetes Mellitus.

Background and Objectives: Diabetes mellitus is a chronic metabolic disease associated with several complications, including that of kidney disease. Plant-based dietary products have shown promise in mitigating these effects to improve kidney function and prevent tissue damage. This study assessed the possible favorable effects of beetroot extract (BE) in improving kidney function and preventing tissue damage in diabetic rats. Materials and Methods: Type 2 diabetes mellitus (T2DM) was induced using a low dose of streptozotocin (STZ). Both control and rats with pre-established T2DM were divided into six groups (each consisting of eight rats). All treatments were given by gavage and continued for 12 weeks. Fasting blood glucose levels, serum fasting insulin levels, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum triglycerides, cholesterol, low-density lipoprotein-cholesterol, serum and urinary albumin, and creatinine and urea levels were measured. Apart from this, glutathione, malondialdehyde, superoxide dismutase, tumor necrosis factor-α, and interleukine-6 in the kidney homogenates of all groups of rats were measured, and the histopathological evaluation of the kidney was also performed. Results: It was observed that treatment with BE increased body weight significantly (p ≤ 0.05) to be similar to that of control groups. Fasting glucose, insulin, HOMA-IR levels, and lipid profile in the plasma of the pre-established T2DM rats groups decreased to p ≤ 0.05 in the BE-treated rats as the BE concentration increased. Treatment with BE also improved the renal levels of oxidative stress and inflammatory markers, urinary albumin, and serum creatinine and urea levels. Unlike all other groups, only the kidney tissues of the T2DM + BE (500 mg/kg) rats group showed normal kidney tissue structure, which appears to be similar to those found in the kidney tissues of the control rats groups. Conclusion: we found that streptozotocin administration disturbed markers of kidney dysfunction. However, Beta vulgaris L. root extract reversed these changes through antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

SIRT3 alleviates high glucose-induced chondrocyte injury through the promotion of autophagy and suppression of apoptosis in osteoarthritis progression

A growing amount of epidemiological evidence proposes diabetes mellitus (DM) to be an independent risk factor for osteoarthritis (OA). Sirtuin 3 (SIRT3), which is mainly located in mitochondria, belongs to the family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases and is involved in the physiological and pathological processes of cell regulation. The aim of this study was to investigate the effects of SIRT3 on diabetic OA and underlying mechanisms in the prevention of type 2 DM (T2DM)-induced articular cartilage damage. High-fat and high-sugar diets combined with streptozotocin (STZ) injection were used for establishing an experimental T2DM rat model. The destabilization of medial meniscus (DMM) surgery was applied to induce the rat OA model. Primary rat chondrocytes were cultivated with a concentration of gradient glucose. Treatment with intra-articular injection of SIRT3 overexpression lentivirus was achieved in vivo, and intervention with SIRT3 knockdown was performed using siRNA transfection in vitro. High glucose content was found to activate inflammatory response, facilitate apoptosis, downregulate autophagy, and exacerbate mitochondrial dysfunction in a dose-dependent manner in rat chondrocytes, which can be deteriorated by SIRT3 knockdown. In addition, articular cartilage damage was found to be more severe in T2DM-OA rats than in DMM-induced OA rats, which can be mitigated by the intra-articular injection of SIRT3 overexpression lentivirus. Targeting SIRT3 is a potential therapeutic strategy for the alleviation of diabetic OA.