Type 2 Diabetes Mellitus Rats Research Articles

Exploring the Molecular Mechanisms underlying SADI-S Improves Glucose Metabolism in Type 2 Diabetic Rats through Liver Transcriptomics and Proteomics Analysis.

Metabolic surgery could improve or even reverse type 2 diabetes mellitus (T2DM). Single-anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S) is one of the most effective metabolic surgeries for T2DM. However, the molecular mechanisms behind the SADI-S-induced T2DM improvement are not fully understood.Here,T2DM rats received SADI-S and were sacrificed after 8 weeks; the controls received sham surgery; Liver tissues were collected for transcriptomics and proteomics analysis to identify differentially expressed genes (DEGs) and proteins (DEPs). Parallel reaction monitoring (PRM) was performed to validate the accuracy of the proteomics results.SADI-S significantly improved glucose metabolism in T2DM rats.A total of 120 genes/proteins(e.g., phosphoenolpyruvate carboxykinase (Pck1) and pyruvate kinase (Pklr)) exhibited consistent expression trends at both mRNA and protein levels. Among the upregulated genes/proteins involved in glucose metabolic pathways, enrichment was observed in pathways such as the pyruvate metabolic pathway, insulin signaling pathway, glycolysis/gluconeogenesis biological processes, glucagon signaling pathway, and AMPK signaling pathway. Downregulated genes/proteins were enriched in the pyruvate metabolic pathway. The above-mentioned signaling pathways are implicated in glucose metabolism, suggesting a potential mechanism for SADI-S-mediated alleviation of T2DM. The PRM validation results indicated that all selected proteins showed consistent trends between PRM and proteomics data. This consistency suggests the reliability of the proteomics results.

Improving diabetic wound healing: The therapeutic potential of allulose supplement in diabetic skin tissue repair and inflammation modulation

The increasing prevalence of type 2 diabetes mellitus (T2DM) worldwide presents significant challenges in the management of impaired tissue repair in diabetic skin wounds, which has emerged as a critical health concern. Addressing this issue while minimizing adverse effects remains crucial. Allulose has been shown to exhibit hypolipidemic and anti-inflammatory properties, alleviating obesity and atherosclerosis by improving insulin resistance and impaired glucose tolerance. However, its underlying effects and mechanisms in repairing diabetic skin damage remain poorly understood. In this study, we demonstrated that oral administration of allulose remarkably ameliorated T2DM-compromised skin tissue wound associated with the stimulation of skin granulation, surrounding tissue formation, and activated fibroblasts, under high-fat diet (HFD) feeding condition. In addition, administration partially promoted collagen deposition, reduced M1 macrophage polarization, facilitated neovascularization, and mitigated tissue inflammation in the T2DM rats upon HFD feeding. Moreover, allulose could significantly alleviate high glucose stress condition-induced inflammatory response, correlative with modulation of p38/NLRP3/Caspase-1 signaling. In addition, allulose could also ameliorate high glucose stress-compromised cell viability and proliferative capacity, related to stimulation of mTOR pathway in part. Taken together, our study revealed that T2DM compromised some certain factors which are crucial for skin tissue healing and wound repair upon HFD condition. The work highlighted the potential beneficial effects of orally administered allulose for healing diabetic skin wounds and supported a novel strategy for managing diabetes patients adjunctively with allulose dietary supplement.

Effects of moderate-intensity aerobic training on cardiac structure and function in type 2 mellitus diabetic rats: Based on echocardiography and speckle tracking

PurposeThe present study aimed to evaluate the cardiac function changes using Layer-specific Speckle-tracking echocardiography (LS-STE) induced by Moderate-intensity aerobic training (MIAT) in Type 2 diabetes mellitus (T2DM) rats. MethodsTwenty-six rats were divided into four groups: the Control group (Con), the Training control group (CT), the T2DM group (DM), and the T2DM training group (DT). The CT and DT groups underwent an 8 weeks MIAT. Cardiac structure and function were evaluated by echocardiography and LS-STE. ResultsCompared with the Con group, left atrial diameter (LAD), left ventricular end-diastolic diameter(LVEDD), relation wall thickness (RWT), and left ventricular mass (LVM) were significantly higher, and the endo-, mid-, and epi-longitudinal strain (LS), global radial strain (GRS), and endo- and mid-circumferential strain (CS) were significantly lower in DM rats (all p < 0.05). The endo-, mid-, and epi-LS, GRS, endo- and mid-CS were increased in DT rats compared with DM rats (all p < 0.05). Compared with Con rats, CT rats had a significant increase in LVEDD and LVM (all p < 0.05), meanwhile myocardial strains had no significant differences (all p > 0.05). ConclusionLS-STE was a sensitive method to assess subclinical myocardial changes in T2DM rats. MIAT had the benefit of reversing cardiac systolic subclinical dysfunction in T2DM rats.

Swimming training promotes angiogenesis of endothelial progenitor cells by upregulating IGF1 expression and activating the PI3K/AKT pathway in type 2 diabetic rats.

The present study aimed to investigate the effect of swimming training on the angiogenesis of endothelial progenitor cells (EPCs) in type 2 diabetes mellitus (T2DM) rats by upregulating the insulin‑like growth factor 1 (IGF1) expression and to reveal its potential mechanism of action. Male Sprague‑Dawley rats were divided into the Control, Model, Model train, Model train + short interfering (si)‑NC and Model train + si‑IGF1 groups. Serum glucose levels were measured using the oral glucose tolerance test. EPCs were isolated from the bone marrow cavity and identified through morphological observation and immunofluorescence staining. The expression of IGF‑1 mRNA in rat serum and EPCs was analyzed by reverse transcription‑quantitative PCR. The fasting insulin levels in serum were assessed by ELISA. Cell Counting Kit‑8, scratch assay and tube formation assay were used to determine the cell viability, migration and tube formation of rat EPCs, and western blotting was employed to measure the expression levels of IGF1, phosphoinositide 3‑kinase (PI3K), phosphorylated‑PI3K, protein kinase B (AKT) and phosphorylated‑AKT. The present study demonstrated that swimming training significantly decreased the glucose levels and homeostatic model assessment of insulin resistance scores, but increased the fasting insulin levels and IGF1 mRNA expression. Microscopic observation and immunofluorescence identification suggested that EPCs were successfully isolated. In addition, swimming training markedly elevated the levels of IGF1 and promoted cell viability, migration and tube formation in rat EPCs. Furthermore, IGF1 knockdown experiments indicated that swimming training might play a regulatory role by elevating the IGF1 expression to activate the PI3K/AKT pathway. Overall, swimming training promoted the angiogenesis of EPCs in T2DM rats and its potential mechanism may be related to the upregulation of IGF1 expression and the activation of the PI3K/AKT pathway.

Potential roles for eNOS and NrF₂ /HO-1 signaling in the ameliorative effect of lixisenatide on diabetes-induced kidney injury in rats and its amplification by ticagrelor co-administration.

Antioxidant and anti-inflammatory effects of lixisenatide (LX) and ticagrelor (TC) have been previously identified in type 2 diabetes mellitus (T2DM). Diabetic nephropathy is one of the major complications of T2DM. In the current study, we examined the potential protective effects of LX and TC on experimentally induced diabetic nephropathy in T2DM rats and their possible molecular mechanisms. To examine this possibility, rats were fed a high-fat diet (HFD) for 12 weeks, followed by a single injection of 35 mg/kg streptozotocin (STZ) to induce T2DM. 10 μg/kg LX and 25 mg/kg TC were given alone or in combination to T2DM rats for 4 weeks. The kidney examination of T2DM rats showed clear deterioration. T2DM rats exhibited significantly higher body weight, blood glucose, hemostatic model assessment for insulin resistance (HOMA-IR), blood urea nitrogen (BUN), serum creatinine, kidney reactive oxygen species (ROS), nuclear factor-κ B (NF-κ B), and transforming growth factor-β (TGF-β ), and significantly lower serum insulin, urine creatinine, creatinine clearance (CRCL), kidney superoxide dismutase (SOD), glutathione reduced (GSH), nuclear factor erythroid 2 (NrF₂ ), heme oxygenase-1 (HO-1), and endothelial nitric oxide synthase (eNOS) when compared to control rats. Single treatment with LX or TC showed obvious ameliorative effects on kidney complications in T2DM rats, with more ameliorative effects with the combined administration of both drugs. Conclusion: Our investigation found that both LX and TC could significantly ameliorate the development of diabetic nephropathy via stimulating NrF₂ /HO-1 antioxidant pathway in addition to increasing eNOS and decreasing NF-κ B renal tissue concentrations, and these effects were markedly augmented by their combined administration.

Nanocarrier-Assisted Delivery of Berberine Promotes Diabetic Alveolar Bone Regeneration by Scavenging ROS and Improving Mitochondrial Dysfunction.

Oxidative stress and mitochondrial dysfunction are potential contributors to the compromised tissue regeneration capacity of alveolar bone in diabetic patients. Berberine, an active plant alkaloid, exhibits multiple pharmacological effects including antioxidation, blood glucose- and blood lipid-lowering properties. However, it remains uncertain whether berberine can improve impaired osteogenesis in type 2 diabetes mellitus (T2DM), and its poor solubility and oral bioavailability also constrain its applications in bone regeneration. Thus, our study aimed to probe the effects of berberine on bone marrow stem cells (BMSCs) in a diabetic microenvironment, with a greater emphasis on developing a suitable nano-delivery system for berberine and assessing its capability to repair diabetic alveolar bone defects. Firstly, BMSCs were exposed to berberine within a high glucose and palmitate (HG+PA) environment. Reactive oxygen species levels, mitochondrial membrane potential, ATP generation, cell apoptosis, and osteogenic potential were subsequently assessed. Next, we explored the regulatory mechanism of autophagy flux in the positive effects of berberine. Furthermore, a nanocarrier based on emulsion electrospinning for sustained local delivery of berberine (Ber@SF/PCL) was established. We assessed its capacity to enhance bone healing in the alveolar bone defect of T2DM rats through micro-computed tomography and histology analysis. Berberine treatment could inhibit reactive oxygen species overproduction, mitochondrial dysfunction, apoptosis, and improve osteogenesis differentiation by restoring autophagy flux under HG+PA conditions. Notably, Ber@SF/PCL electrospun nanofibrous membrane with excellent physicochemical properties and good biological safety had the potential to promote alveolar bone remodeling in T2DM rats. Our study shed new lights into the protective role of berberine on BMSCs under T2DM microenvironment. Furthermore, berberine-loaded composite electrospun membrane may serve as a promising approach for regenerating alveolar bone in diabetic patients.

Synergistic Effect of Glibenclamide Combining With Vitexin on Type 2 Diabetes Mellitus Rats

Background &amp; objectives: The combination of drugs with herbs is a prevalent treatment for metabolic and chronic diseases. This study combined glibenclamide with vitexin and performed in vivo and in vitro investigations, aiming to evaluate their synergistic effect on type 2 diabetes mellitus (T2DM). Materials and methods: T2DM rat models were established by injecting streptozotocin, and the sham group was injected with a normal saline solution as the control. A single dosage was orally performed with 10 mg/kg glibenclamide, while the co-administrated was conducted by the pre-treatment of 20 mg/kg vitexin for 7 d to avoid potential chemical interactions. The pharmacokinetics of glibenclamide was evaluated in both sham and T2DM rats. The blood glucose of T2DM rats was detected in the presence of different administration strategies. The metabolic stability of glibenclamide was assessed in rat liver microsomes. Results: Glibenclamide showed a significant hypoglycemic effect on T2DM rats, which was enhanced by the co-administration of vitexin. Vitexin significantly affected the pharmacokinetics of glibenclamide in both sham and T2DM rats, where the AUC0-t, Cmax, and t1/2 of glibenclamide significantly increased, and the clearance rate decreased. Moreover, vitexin increased the in vitro half-life and decreased intrinsic clearance of glibenclamide in rat liver microsomes. The previously reported inhibitory effect of vitexin on CYP2C9 activity was hypothesized as the mechanism underlying the interaction. Conclusion: Co-administration of glibenclamide and vitexin would increase the systemic exposure and metabolic stability of glibenclamide and exert a synergistic effect on T2DM.

EFFECT OF DAHLIA TUBER INULIN EXTRACT ON FATTY LIVER IN TYPE 2 DIABETES MELLITUS RATS

Several studies show a correlation between intestinal microbiota disturbances and metabolic disorders, including type 2 diabetes mellitus (T2DM). Fatty liver is one of the complications that occurs due to T2DM. Fatty liver is characterized by the accumulation of lipids in the liver in response to increased triglyceride synthesis in hepatocytes and is thought to be associated with disturbances in the gut microbiota so that changes in the gut microbiota can be a potential target for T2DM treatment. It is known that inulin, a prebiotic, can improve intestinal microbiota disorders. This study aims to analyze the effect of administering inulin from dahlia tubers on fatty liver in T2DM rats.The research design is an experimental study with a post-test-only control group design conducted from June to November 2023. The study used twenty male Rattus norvegicus Wistar strain divided into five groups: a control group, a T2DM-induced group, T2DM groups given inulin extract at doses of 0.5 mg/gBW, 1.0 mg/gBW, and 1.5 mg/gBW. The results showed that the T2DM group had a higher significant percentage of fatty liver (p &lt;0.01) than the control group. Compared to the T2DM group, there was a decrease in the percentage of fatty liver in the T2DM groups given inulin at all doses (p&lt;0.05). This study concluded that inulin administration can reduce fatty liver in T2DM rats. Keywords : Dahlia tubers., fatty liver., inulin., type 2 diabetes mellitus

PDE5 inhibitor potentially improves polyuria and bladder storage and voiding dysfunctions in type 2 diabetic rats.

Bladder dysfunction associated with type 2 diabetes mellitus (T2DM) includes urine storage and voiding disorders. We examined pathological conditions of the bladder wall in a rat T2DM model and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats were used as the T2DM and control groups, respectively. Tadalafil was orally administered for 12 weeks. Micturition behavior was monitored using metabolic cages, and bladder function was evaluated by cystometry. Bladder blood flow was evaluated by laser speckle imaging, and an organ bath bladder distention test was used to measure adenosine triphosphate (ATP) release from the bladder urothelium. The expression levels of vesicular nucleotide transporter (VNUT), hypoxia markers, pro-inflammatory cytokines and growth factors in the bladder wall were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Bladder wall contractions in response to KCl and carbachol were monitored using bladder-strip tests. With aging, OLETF rats had higher micturition frequency and greater urine volume than LETO rats. Although bladder capacity was not significantly different, non-voiding bladder contraction occurred more frequently in OLETF rats than in LETO rats. Bladder blood flow was decreased and ATP release was increased with higher VNUT expression in OLETF rats than in LETO rats. These effects were suppressed by tadalafil administration, with accompanying decreased HIF-1α, 8-OHdG, IL-6, TNF-α, IGF-1, and bFGF expression. The impaired contractile responses of bladder strips to KCl and carbachol in OLETF rats with aging were restored by tadalafil administration. The T2DM rats had polyuria, increased ATP release induced by decreased bladder blood flow and impaired contractile function. PDE5 inhibition improved these changes and may prevent T2DM-associated urinary frequency and bladder storage and voiding dysfunctions.

Carthamus tinctorius L. (Safflower) Flower Extract Attenuates Hepatic Injury and Steatosis in a Rat Model of Type 2 Diabetes Mellitus via Nrf2-Dependent Hypoglycemic, Antioxidant, and Hypolipidemic Effects.

This study aimed to examine the hepatic and anti-steatotic protective effects of methanolic extract from Carthamus tinctorius (safflower) flowers (SFFE), using a rat model of type 2 diabetes mellitus (T2DM), and to examine the molecular mechanisms underlying these effects. Adult male Wistar rats were used for this study. First, T2DM was induced in some rats by feeding them a high-fat diet (HFD) for 4 weeks, followed by a single dose of streptozotocin (STZ) (35 mg/kg, i.p.). Experimental groups included the following five groups (n = 8 in each): control, control + SFFE, T2DM, T2DM + SFFE, and T2DM + SFFE + brusatol (an Nrf2 inhibitor, 2 mg/kg, i.p.). SFFE was administered at a concentration of 300 mg/kg, and all experiments concluded after 8 weeks. Treatments with SFFE significantly reduced fasting blood glucose levels, free fatty acids (FFAs), cholesterol, triglycerides, and low-density lipoprotein cholesterol in both the control and T2DM rats, but they failed to reduce fasting insulin levels in these groups. SFFE treatments also improved the liver structure and reduced hepatocyte vacuolization and hepatic levels of triglycerides and cholesterol in T2DM rats, in addition to increasing the hepatic mRNA levels of keap1 and the cytoplasmic levels and nuclear activities of Nrf2 in both the control and T2DM rats. SFFE also stimulated the expression levels of PPARα and CPT-1 but reduced the malondialdehyde (MDA), mRNA levels of SREBP1, fatty acid synthase, and acetyl CoA carboxylase in both the control and T2DM rats; meanwhile, it reduced hepatic mRNA and the nuclear activities of NF-κB and increased levels of glutathione, superoxide dismutase, and heme oxygenase-1 in the livers of both groups of treated rats. Furthermore, SFFE suppressed the levels of caspase-3, Bax, tumor necrosis factor-α, and interleukin-6 in the T2DM rats. Treatment with brusatol prevented all of these effects of SFFE. In conclusion, SFFE suppresses liver damage and hepatic steatosis in T2DM through Nrf2-dependent hypoglycemic, antioxidant, anti-inflammatory, and hypolipidemic effects.

Farrerol Alleviates Diabetic Cardiomyopathy by Regulating AMPK-Mediated Cardiac Lipid Metabolic Pathways in Type 2 Diabetic Rats.

Diabetic cardiomyopathy (DCM) is a prevalent complication of diabetes mellitus characterized by cardiac dysfunction and myocardial remodeling. Farrerol (FA), an active ingredient in Rhododendron with various pharmacological activities, has an unclear specific role in DCM. Therefore, this study aims to investigate the effects of FA on DCM rats and elucidate its mechanism. The type 2 diabetes mellitus (T2DM) model was induced in adult male Sprague-Dawley rats by administering a high-fat diet for 8 weeks along with STZ injection. Subsequent to successful modeling, FA and the positive drug Dapagliflozin (Dapa) were orally administered via gavage for an additional 8-week period. After administration, the rats' body weight, fasting blood glucose, fasting insulin, and blood lipid profiles were quantified. Cardiac function was assessed through evaluation of cardiac function parameters, histopathological examination and measurement of myocardial enzyme markers were conducted to assess myocardial injury and fibrosis, Oil red O staining was utilized to evaluate myocardial lipid accumulation, wheat germ agglutinin (WGA) staining was used for assessing cardiomyocyte hypertrophy, and Western blot analysis was used to detect the proteins expression level of AMP-activated protein kinase (AMPK) pathway. The rat cardiomyocyte H9c2 were induced with palmitic acid to establish an in vitro cell model of myocardial lipid toxicity. Subsequently, the cells were subjected to treatment with FA and AMPK inhibitor Compound C, followed by assessment of lipid formation and expression levels of proteins related to the AMPK signaling pathway. The findings demonstrated that both FA and Dapa exhibited efficacy in ameliorating diabetic symptoms, cardiac dysfunction, myocardial fibrosis, cardiomyocyte hypertrophy, and lipid accumulation in T2DM rats. Additionally, they were found to enhance AMPK phosphorylation and PPARα expression while down-regulating CD36. Similarly, FA was observed to inhibit lipid formation in H9c2 and activate the AMPK signaling pathway. However, the improved effect of FA on lipotoxic cardiomyocytes induced by palmitic acid was partially reversed by Compound C. Therefore, the activation of the AMPK signaling pathway by FA may enhance cardiac lipid metabolism, thereby improving cardiac dysfunction and myocardial fibrosis in DCM rats.

Effects of Berberis asiatica, Withania somnifera, and Their Combination on Body Weight in Streptozotocin-Nicotinamide-Induced Type 2 Diabetes in Wistar Rats.

Introduction Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, impaired insulin secretion, and beta cell dysfunction, often leading to chronic hyperglycemia and associated complications. Berberis asiatica (BA) and Withania somnifera (WS) are ancient medicinal plants with a reputation for having potential therapeutic effects in diabetes management. The purpose of this study was to look into how body weight (BW) was affected in streptozotocin-nicotinamide (STZ-NIC) induced T2DM in Wistar rats by BA, WS, and their polyherbal combination (PHC). Materials and methods Seventy-eight Wistar rats of both sexes were divided into 13 groups, with six rats in each group, including normal and diabetic controls, and treated with varying doses of BA, WS, and PHC. The rats were under observation over the course of 35 days for any change in BW. The Organization for Economic Co-operation and Development (OECD) rules and guidelines were followed in the conduct of acute toxicity tests. One-way analysis of variance (ANOVA), followed by Tukey-Kramer post hoc tests, was used for statistical analysis. Results The findings indicated that the highest dose of BA (1000 mg/kg) significantly improved BW in diabetic rats, approaching that of the normal control group. The combination of BA and WS also demonstrated significant improvements in BW, suggesting a synergistic effect. The standard antidiabetic drugs, metformin and glimepiride, were effective in increasing BW in diabetic rats. Conclusion The study concludes that BA, WS, and their combination have a positive impact on BW management in T2DM rats, with the combination therapy showing enhanced effects. These findings support the potential utilization of these herbs in managing BW and other T2DM-associated metabolic disturbances and abnormalities.

Evaluation of Lipid Profile Modulation by Berberis asiatica, Withania somnifera, and Their Synergy in Type 2 Diabetic Wistar Rats.

Introduction Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and hyperglycemia, leading to complications such as dyslipidemia, which increases cardiovascular risks. Current treatments for dyslipidemia often have undesirable side effects. This study aims to evaluate the effects ofBerberis asiatica(BA),Withania somnifera(WS), and their combination in the ratio of 1:1 on the lipid profile in T2DM-induced Wistar rats. Additionally, the study investigates the potential synergistic effects of these two herbs. Materials and methods Mature albino Wistar rats of both sexes were employed, weighing 150-250 g. Rats were obtained from the Central Animal House of Krishna Institute of Medical Sciences and kept under standard laboratory conditions. The study was conducted per theguidelines setby the Committee for Control and Supervision of Experiments on Animals (CCSEA). T2DM was induced using streptozotocin (STZ) and nicotinamide (NIC). Thirteen groups of rats were formed, including normal control (NC), diabetic control (DC), and various treatment groups received varying dosages of BA, WS, their polyherbal combination (PHC), and the conventional medications metformin (MET) and glimepiride (GLI). Lipid profiles were measured, and the data were analyzed using one-way ANOVA, followed by the Tukey-Kramer post-hoc test. Results The study revealed that both BA and WS showed statistically significant lipid-lowering effects in diabetic rats. The BA-treated groups displayed a statistically significant and considerable decrease in total cholesterol (TC) and low-density lipoprotein (LDL) levels compared to the DC group. Similarly, WS-treated groups also showed statistically significant reduced levels of TC and LDL, along with an increase in high-density lipoprotein (HDL). The PHCof BA and WS exhibited enhanced lipid-lowering effects compared to individual treatments. No significant differences in triglyceride (TG) levels were observed among the treatment groups. Conclusion BA and WS, individually and in combination,effectively modulate lipid profiles in T2DM rats. Their synergistic effects provide a promising alternative for managing dyslipidemia in diabetic patients. Further research is needed to determine the clinical consequences of these findings.

Mechanism of Takifugu bimaculatus Skin Peptides in Alleviating Hyperglycemia in Rats with Type 2 Diabetic Mellitus Based on Microbiome and Metabolome Analyses.

In this study, we aimed to explore the hypoglycemic effects of a hydrolysate on Takifugu bimaculatus skin (TBSH). The effect of the dipeptidyl peptidase-IV (DPP-IV) inhibitory activities from different TBSH fractions was investigated on basic indexes, gut hormones, blood lipid indexes, viscera, and the gut microbiota and its metabolites in rats with type 2 diabetes mellitus (T2DM). The results showed that the <1 kDa peptide fraction from TBSH (TBP) exhibited a more potent DPP-IV inhibitory effect (IC50 = 0.45 ± 0.01 mg/mL). T2DM rats were induced with streptozocin, followed by the administration of TBP. The 200 mg/kg TBP mitigated weight loss, lowered fasting blood glucose levels, and increased insulin secretion by 20.47%, 25.23%, and 34.55%, respectively, rectified irregular hormonal fluctuations, lipid metabolism, and tissue injuries, and effectively remedied gut microbiota imbalance. In conclusion, TBP exerts a hypoglycemic effect in rats with T2DM. This study offers the potential to develop nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus. It will provide information for developing nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus.

Inhibition of Caspase-1-dependent pyroptosis alleviates myocardial ischemia/reperfusion injury during cardiopulmonary bypass (CPB) in type 2 diabetic rats

Cardiovascular complications pose a significant burden in type 2 diabetes mellitus (T2DM), driven by the intricate interplay of chronic hyperglycemia, insulin resistance, and lipid metabolism disturbances. Myocardial ischemia/reperfusion (MI/R) injury during cardiopulmonary bypass (CPB) exacerbates cardiac vulnerability. This study aims to probe the role of Caspase-1-dependent pyroptosis in global ischemia/reperfusion injury among T2DM rats undergoing CPB, elucidating the mechanisms underlying heightened myocardial injury in T2DM. This study established a rat model of T2DM and compared Mean arterial pressure (MAP), heart rate (HR), and hematocrit (Hct) between T2DM and normal rats. Myocardial cell morphology, infarction area, mitochondrial ROS and caspase-1 levels, NLRP3, pro-caspase-1, caspase-1 p10, GSDMD expressions, plasma CK-MB, cTnI, IL-1β, and IL-18 levels were assessed after reperfusion in both T2DM and normal rats. The role of Caspase-1-dependent pyroptosis in myocardial ischemia/reperfusion injury during CPB in T2DM rats was examined using the caspase-1 inhibitor VX-765 and the ROS scavenger NAC. T2DM rats demonstrated impaired glucose tolerance but stable hemodynamics during CPB, while showing heightened vulnerability to MI/R injury. This was marked by substantial lipid deposition, disrupted myocardial fibers, and intensified cellular apoptosis. The activation of caspase-1-mediated pyroptosis and increased reactive oxygen species (ROS) production further contributed to tissue damage and the ensuing inflammatory response. Notably, myocardial injury was mitigated by inhibiting caspase-1 through VX-765, which also attenuated the inflammatory cascade. Likewise, NAC treatment reduced oxidative stress and partially suppressed ROS-mediated caspase-1 activation, resulting in diminished myocardial injury. This study proved that Caspase-1-dependent pyroptosis significantly contributes to the inflammation and injury stemming from global MI/R in T2DM rats under CPB, which correlate with the surplus ROS generated by oxidative stress during reperfusion.

Intracerebroventricular insulin injection acutely normalizes the augmented exercise pressor reflex in male rats with type 2 diabetes mellitus.

The exercise pressor reflex (EPR) is exaggerated in type 2 diabetes mellitus (T2DM), but the underlying central nervous system aberrations have not been fully delineated. Stimulation of muscle afferents within working skeletal muscle activates the EPR, by sending information to neurons in the brainstem, where it is integrated and results in reflexively increased mean arterial pressure (MAP) and sympathetic nerve activity. Brain insulin is known to regulate neural activity within the brainstem. We hypothesize that brain insulin injection in T2DM rats attenuates the augmented EPR, and that T2DM is associated with decreased brain insulin. Using male Sprague-Dawley rats, T2DM and control rats were generated via an induction protocol with two low doses of streptozotocin (35 and 25mg/kg, i.p.) in combination with a 14-23-week high-fat diet or saline injections and a low-fat diet, respectively. After decerebration, MAP and renal sympathetic nerve activity (RSNA) were evaluated during EPR stimulation, evoked by electrically induced muscle contraction via ventral root stimulation, before and after (1 and 2h post) intracerebroventricular (i.c.v.) insulin microinjections (500mU, 50nl). i.c.v. insulin decreased peak MAP (ΔMAP Pre (36±14mmHg) vs. 1h (21±14mmHg) vs. 2h (11±6mmHg), P<0.05) and RSNA (ΔRSNA Pre (107.5±40%), vs. 1h (75.4±46%) vs. 2h (51±35%), P<0.05) responses in T2DM, but not controls. In T2DM rats, cerebrospinal fluid insulin was decreased (0.41±0.19 vs. 0.11±0.05ng/ml, control (n=14) vs. T2DM (n=4), P<0.01). The results demonstrated that insulin injections into the brain normalized the augmented EPR in brain hypoinsulinaemic T2DM rats, indicating that the EPR can be regulated by brain insulin. KEY POINTS: The reflexive increase in blood pressure and sympathetic nerve activity mediated by the autonomic nervous system during muscle contractions is also known as the exercise pressor reflex. The exercise pressor reflex is dangerously augmented in type 2 diabetes, in both rats and humans. In type 2 diabetic rats both cerebrospinal fluid insulin and phosphoinositide 3-kinase signalling within cardiovascular brainstem neurons decrease in parallel. Brain insulin injections decrease the magnitude of the reflexive pressor and sympathetic responses to hindlimb muscle contraction in type 2 diabetic rats. Partial correction of low insulin within the central nervous system in type 2 diabetes may treat aberrant exercise pressor reflex function.

PCSK9 inhibitor effectively alleviated cognitive dysfunction in a type 2 diabetes mellitus rat model.

The incidence of diabetes-associated cognitive dysfunction (DACD) is increasing; however, few clinical intervention measures are available for the prevention and treatment of this disease. Research has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, particularly SBC-115076, have a protective effect against various neurodegenerative diseases. However, their role in DACD remains unknown. In this study, we aimed to explore the impact of PCSK9 inhibitors on DACD. Male Sprague-Dawley (SD) rats were used to establish an animal model of type 2 diabetes mellitus (T2DM). The rats were randomly divided into three groups: the Control group (Control, healthy rats, n = 8), the Model group (Model, rats with T2DM, n = 8), and the PCSK9 inhibitor-treated group (Treat, T2DM rats treated with PCSK9 inhibitors, n = 8). To assess the spatial learning and memory of the rats in each group, the Morris water maze (MWM) test was conducted. Hematoxylin-eosin staining and Nissl staining procedures were performed to assess the structural characteristics and functional status of the neurons of rats from each group. Transmission electron microscopy was used to examine the morphology and structure of the hippocampal neurons. Determine serum PCSK9 and lipid metabolism indicators in each group of rats. Use qRT-PCR to detect the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in the hippocampal tissues of each group of rats. Western blot was used to detect the expression of PCSK9 and low-density lipoprotein receptor (LDLR) in the hippocampal tissues of rats. In addition, a 4D label-free quantitative proteomics approach was used to analyse protein expression in rat hippocampal tissues. The expression of selected proteins in hippocampal tissues was verified by parallel reaction monitoring (PRM) and immunohistochemistry (IHC). The results showed that the PCSK9 inhibitor alleviated cognitive dysfunction in T2DM rats. PCSK9 inhibitors can reduce PCSK9, total cholesterol (TC), and low-density lipoprotein (LDL) levels in the serum of T2DM rats. Meanwhile, it was found that PCSK9 inhibitors can reduce the expression of PCSK9, IL-1β, IL-6, and TNF-α in the hippocampal tissues of T2DM rats, while increasing the expression of LDLR. Thirteen potential target proteins for the action of PCSK9 inhibitors on DACD rats were identified. PRM and IHC revealed that PCSK9 inhibitors effectively counteracted the downregulation of transthyretin in DACD rats. This study uncovered the target proteins and specific mechanisms of PCSK9 inhibitors in DACD, providing an experimental basis for the clinical application of PCSK9 inhibitors for the potential treatment of DACD.

Effects of Mung Bean Water Supplementation on Modulating Lipid and Glucose Metabolism in a Diabetic Rat Model.

Type 2 diabetes mellitus (T2DM) is often associated with chronic inflammation exacerbated by hyperglycemia and dyslipidemia. Mung beans have a longstanding reputation in traditional medicine for their purported ability to lower blood glucose levels, prompting interest in their pharmacological properties. This study aimed to explore the impact of mung bean water (MBW) on carbohydrate and lipid metabolism in a T2DM rat model induced by nicotinamide/streptozotocin. Normal and DM rats were supplemented with a stock solution of MBW as drinking water ad libitum daily for 8 weeks. MBW supplementation led to significant reductions in plasma total cholesterol, HDL-C, and VLDL-C + LDL-C levels, and decreased malondialdehyde levels in plasma and liver samples, indicating reduced oxidative stress. MBW supplementation lowered plasma glucose levels and upregulated hepatic hexokinase activity, suggesting enhanced glucose utilization. Additionally, MBW decreased hepatic glucose-6-phosphate dehydrogenase and glutathione peroxidase activities, while hepatic levels of glutathione and glutathione disulfide remained unchanged. These findings underscore the potential of MBW to improve plasma glucose and lipid metabolism in DM rats, likely mediated by antioxidant effects and the modulation of hepatic enzyme activities. Further exploration of bioactive components of MBW and its mechanisms could unveil new therapeutic avenues for managing diabetes and its metabolic complications.

Protective effect of Galectin-3 inhibitor against cardiac remodelling in an isoprenaline-induced myocardial infarction in type 2 diabetes

Type 2 Diabetes mellitus (T2DM) has the potential to impair cardiac function and cause heart failure. We aimed to study the cardioprotective influence of Galactin-3 (Gal-3) inhibitor; modified citrus pectin (MCP) in isoprenaline induced myocardial infarction (MI) in T2DM rats. Forty rats were allocated into 4 groups; groups I and II served as control. T2DM was provoked in groups III and IV by serving them high fat diet followed by a single low dose of Streptozotocin (STZ), then group IV were administered MCP in drinking water for 6 weeks. Groups III and IV were then subcutaneously injected isoprenaline hydrochloride once daily on the last 2 successive days to induce MI. MCP restored echocardiographic parameters with significant decline in Gal-3 area % in cardiac tissue alongside protection against cardiac remodelling. our data showed that there is a protective potential for Gal-3 inhibitor (MCP) against cardiac injury in isoprenaline induced MI in T2DM.

Abstract Mo135: Correlation of Leptin Resistance With Attenuation of Cardiac Vagal Activation in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is one of the most prominent diseases impacting individuals worldwide. A leading cause of death for T2DM patients is MI-related ventricular arrhythmia, which is associated with cardiac vagal nerve dysfunction. As T2DM patients exhibit leptin resistance, and leptin signaling has been implicated in heart rate regulation, we set out to characterize changes in cardiac vagal ganglionic neuron activity during development of T2DM and determine leptin signaling’s role in cardiac vagal dysfunction. In this study, T2DM was induced in Sprague-Dawley rats by feeding a high fat diet (HFD) plus a low dose streptozotocin injection. To characterize cardiac dysfunction, we measured arterial baroreflex sensitivity and found that 12 wks post-T2DM induction, rats experienced a diminished baroreflex response (gain max 0.62 ± 0.04 bpm/mm Hg T2DM vs. 2.21 ± 0.14 bpm/mm Hg sham). To determine if the change in baroreflex sensitivity is due to altered cardiac vagal nerve activity, we measured nAChR currents and cell excitability in intracardiac ganglion (ICG) neurons and found that T2DM rat cardiac vagal neurons exhibited reduced nAChR current density (213.9 ± 25.6 pA/pF T2DM vs. 375.5 ± 44.3 pA/pF sham) and action potential frequency (9.1 ± 0.5 spikes/s T2DM vs. 19.9 ± 1.4 spikes/s sham). Furthermore, acetylcholine release from cardiac vagal nerve terminals was attenuated in T2DM rats (0.4 ± 0.16 nM T2DM vs. 1.07 ± 0.12 nM sham). To determine the role of leptin signaling in the decrease of cardiac vagal nerve activity, we examined leptin and leptin receptor levels in ICG at 4, 8, and 12 wks post-T2DM induction. Western blots revealed elevated ICG leptin levels at 4, 8, and 12 wks post-T2DM induction (8.9 ± 0.7, 9.1 ± 1.3, and 11.7 ± 2.1 times sham level, respectively). qRT-PCR revealed reduced levels of leptin receptor transcript at 12 wks post-T2DM induction (48 ± 12% of sham). A reduction of leptin receptor protein in ICG neurons at 12 wks post-T2DM induction was observed using IF microscopy. These data demonstrate that T2DM reduces cardiac vagal nerve activity resulting in diminished control of cardiac functions such as the baroreflex. Furthermore, leptin resistance may play a role in this diminished cardiac function through reductions in leptin receptor levels.