Hypolipidemic Effect of Rice Bran Oil Extract Tocotrienol in High-Fat Diet-Induced Hyperlipidemia Zebrafish (Danio Rerio) Induced by High-Fat Diet.

In recent years, the potent influence of tocotrienol (T3) on diminishing blood glucose and lipid concentrations in both Mus musculus (rats) and Homo sapiens (humans) has been established. However, the comprehensive exploration of tocotrienol's hypolipidemic impact and the corresponding mechanisms in aquatic species remains inadequate. In this study, we established a zebrafish model of a type 2 diabetes mellitus (T2DM) model through high-fat diet administration to zebrafish. In the T2DM zebrafish, the thickness of ocular vascular walls significantly increased compared to the control group, which was mitigated after treatment with T3. Additionally, our findings demonstrate the regulatory effect of T3 on lipid metabolism, leading to the reduced synthesis and storage of adipose tissue in zebrafish. We validated the expression patterns of genes relevant to these processes using RT-qPCR. In the T2DM model, there was an almost two-fold upregulation in pparγ and cyp7a1 mRNA levels, coupled with a significant downregulation in cpt1a mRNA (p < 0.01) compared to the control group. The ELISA revealed that the protein expression levels of Pparγ and Rxrα exhibited a two-fold elevation in the T2DM group relative to the control. In the T3-treated group, Pparγ and Rxrα protein expression levels consistently exhibited a two-fold decrease compared to the model group. Lipid metabolomics showed that T3 could affect the metabolic pathways of zebrafish lipid regulation, including lipid synthesis and decomposition. We provided experimental evidence that T3 could mitigate lipid accumulation in our zebrafish T2DM model. Elucidating the lipid-lowering effects of T3 could help to minimize the detrimental impacts of overfeeding in aquaculture.

Advances in secondary prevention mechanisms of macrovascular complications in type 2 diabetes mellitus patients: a comprehensive review.

Type 2 diabetes mellitus (T2DM) poses a significant global health burden. This is particularly due to its macrovascular complications, such as coronary artery disease, peripheral vascular disease, and cerebrovascular disease, which have emerged as leading contributors to morbidity and mortality. This review comprehensively explores the pathophysiological mechanisms underlying these complications, protective strategies, and both existing and emerging secondary preventive measures. Furthermore, we delve into the applications of experimental models and methodologies in foundational research while also highlighting current research limitations and future directions. Specifically, we focus on the literature published post-2020 concerning the secondary prevention of macrovascular complications in patients with T2DM by conducting a targeted review of studies supported by robust evidence to offer a holistic perspective.

Vitisin B, a resveratrol tetramer from Vitis thunbergii var. taiwaniana, ameliorates impaired glucose regulations in nicotinamide/streptozotocin-induced type 2 diabetic mice.

Background and aim: In Taiwan, Vitis thunbergii var. taiwaniana (VTT) is used in traditional medicine and as a local tea. VTT rich in resveratrol and resveratrol oligomers have been reported to exhibit anti-obesity and anti-hypertensive activities in animal models; however, no studies have investigated type 2 diabetes mellitus (T2DM) treatments. This study aimed to investigate the anti-T2DM effects of resveratrol tetramers isolated from the VTT in nicotinamide/streptozotocin (STZ)-induced Institute of Cancer Research (ICR) mice. Experimental procedure: The oral glucose tolerance test (OGTT) was used to imitate postprandial blood glucose (BG) regulations in mice by pre-treatment with VTT extracts, resveratrol tetramers of vitisin A, vitisin B, and hopeaphenol 30 min before glucose loads. Vitisin B (50 mg/kg) was administered to treat T2DM-ICR mice once daily for 28 days to investigate its hypoglycemic activity. Results and conclusion: Mice pre-treated with VTT-S-95EE, or vitisin B (100 mg/kg) 30-min before glucose loading showed significant reductions (P < 0.001) in the area under the curve at 120-min (BG-AUC0-120) than those without pre-treatment with VTT-S-95 E E or vitisin B. Vitisin B-treated T2DM mice showed hypoglycemic activities via a reduction in plasma dipeptidyl peptidase (DPP)-IV activities to maintain insulin actions and differed significantly than those of untreated T2DM mice (P < 0.05), and also reduced BG-AUC0-120 and insulin-AUC0-120 in the OGTT.These in vivo results showed that VTT containing vitisin B would be beneficial for developing nutraceuticals and/or functional foods for glycemic control in patients with T2DM, which should be investigated further.

Phytoconstituents of Ashwagandha as potential inhibitors of human islet amyloid polypeptide (hIAPP): an in silico investigation.

Amylin or human islet amyloid polypeptide (hIAPP) is a small peptide co-secreted with insulin. Its peripheral aggregation on the lipid bilayer leads to fibril formation. The formation of hIAPP fibrils is hypothesized to rupture the membrane of ß -cells, which culminates in ß-cell death. Following additional studies, amylin fibril formation is a hallmark of T2DM and is also implicitly responsible for Alzheimer's disease. This study reports the virtual screening of 1000 phytoconstituents of traditional Indian medicinal plants to get potential inhibitors of amylin, which will likely restrict and block amyloid aggregation, preventing the progression of T2DM and Alzheimer's illness. The compounds having drug-likeness properties (acquired from ADMET calculations) and highest binding affinities (from molecular docking) are subjected to molecular dynamics (MD) simulation to investigate the temporal stability of the conformations of the complexes. This study discovers that Withaferin A and Withacoagulin have the highest binding affinity for amylin, and their stability with amylin was verified further by parameters such as RMSD, RMSF, number of H-bonds and MMPBSA. Individual principle component analysis (PCA) confirms the stable complex formation of amylin with Withaferin A and Withacoagulin. We strongly believe that wet-lab experiments and clinical trials will help to validate our computational findings.Communicated by Ramaswamy H. Sarma.

Gut-brain axis through the lens of gut microbiota and their relationships with Alzheimer's disease pathology: Review and recommendations.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Growing evidence suggests that the gut microbiome (GM) plays a pivotal role in the pathogenesis of AD through the microbiota-gut-brain axis (MGB). Alterations in GM composition and diversity have been observed in both animal models and in human patients with AD. GM dysbiosis has been implicated in increased intestinal permeability, blood-brain barrier (BBB) impairment, neuroinflammation and the development of hallmarks of AD. Further elucidation of the role of GM in AD could pave way for the development of holistic predictive methods for determining AD risk and progression of disease. Furthermore, accumulating evidence suggests that GM modulation could alleviate adverse symptoms of AD or serve as a preventive measure. In addition, increasing evidence shows that Type 2 Diabetes Mellitus (T2DM) is often comorbid with AD, with common GM alterations and inflammatory response, which could chart the development of GM-related treatment interventions for both diseases. We conclude by exploring the therapeutic potential of GM in alleviating symptoms of AD and in reducing risk. Furthermore, we also propose future directions in AD research, namely fecal microbiota transplantation (FMT) and precision medicine.

Identification of key genes, biological functions, and pathways of empagliflozin by network pharmacology and its significance in the treatment of type 2 diabetes mellitus.

Background: To explore the key genes, biological functions, and pathways of empagliflozin in the treatment of type 2 diabetes mellitus (T2DM) through network pharmacology. Methods: The TCMSP (a traditional Chinese medicine system pharmacology database and analysis platform) was used to screen empagliflozin's active components and targets. The target genes of T2DM were screened according to the GeneCards and OMIM databases, and a Venn diagram was constructed to obtain the target for T2DM treatment. Cytoscape 3.7.2 software was adopted to construct the drug-component-target-disease network. Functional annotation of Gene Ontology (GO) and enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed using R software. Results: Target genes with a probability >0 were selected, among which Compound 012, Compound 060, Compound 093, Compound 111, and Compound 119 Swiss Target Prediction suggested that no similar active substances or predictable target genes were found. A "compound-target gene-disease" network was constructed, in which SLC5A2, SLC5A1, SLC5A4, SLC5A11, ADK, and ADORA2A were the core genes of T2DM. The key factors of the GO summary map included chemical reaction, membrane organelle, protein binding, and so on. The KEGG pathway summary map included the AMPK pathway, insulin resistance, the MAPK pathway, longevity-related pathway regulation, and so on. The top 10 pathways were endocrine resistance, the NF-κB signaling pathway, the HIF-1 signaling pathway, apoptosis, cell senescence, the Ras signaling pathway, the MAPK signaling pathway, the FoxO signaling pathway, the P13K-Akt signaling pathway, and the p53 signaling pathway. The binding of active compounds to key proteins was verified based on the Swiss Dock database, and the molecular docking of 193 bioactive compounds was finally verified. Among them, SLC5A2, SLC5A1, LDHA, KLK1, KLF5, and GSTP1 had better binding to the protein molecules. Conclusions: Empagliflozin may regulate the targets of SLC5A2, SLC5A1, LDHA, KLK1, KLF5, and GSTP1. There are numerous ways of treating T2DM with empagliflozin, including by regulating apoptosis, cell aging, as well as the NF-κB, HIF-1HIF-1, Ras, MAPK, FoxO, P13K-Akt, and p53 pathways.

[Hypoglycemic effect of electroacupuncture at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus based on AMPK].

OBJECTIVE: To observe the hypoglycemic effect of electroacupuncture (EA) at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus (T2DM) as well as its effect on expression of adenosine monophosphate activated protein kinase (AMPK) in liver and pancreas. METHODS: Thirty-six male SD rats were randomly divided into a blank group (6 rats) and a model establishing group (30 rats). The rats in the model establishing group were fed with high-fat diet and treated with intraperitoneal injection of low-dose streptozotocin (STZ) to establish T2DM model. The rats with successful model establishment were randomly divided into a model group, a control group, a metformin group, an EA group and a combination group, 6 rats in each group. The rats in the EA group were treated with EA at "Tianshu" (ST 25), dense-disperse wave, 2 Hz/15 Hz in frequency and 2 mA in current intensity, 20 min each time. The rats in the metformin group were treated with intragastric administration of metformin (190 mg/kg) dissolved in 0.9% sodium chloride solution (2 mL/kg). The rats in the combination group were treated with EA at "Tianshu" (ST 25) and intragastric administration of metformin. The rats in the control group were treated with intragastric administration of 0.9% sodium chloride solution with the same dose. All the treatments were given once a day for 5 weeks. After the intervention, the body mass and random blood glucose were detected; the serum insulin level was detected by ELISA; the expression of AMPK and phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) in liver and pancreas was detected by Western blot method; the expression of protein gene product 9.5 (PGP9.5) was detected by immunofluorescence. RESULTS: ①Compared with the blank group, the body mass in the model group was decreased (P<0.05); compared with the model group, the body mass in the EA group and the combination group was decreased (P<0.05); the body mass in the EA group and the combination group was lower than the metformin group (P<0.05). Compared with the blank group, the random blood glucose in the model group was increased (P<0.01); compared with the model group, the random blood glucose in the metformin group, the EA group and the combination group was decreased (P<0.01). The random blood glucose in the combination group was lower than the metformin group and the EA group (P<0.05). ②Compared with the blank group, the insulin level in the model group was decreased (P<0.05); compared with the model group, the insulin level in the metformin group, the EA group and the combination group was all increased (P<0.05). The insulin level in the combination group was higher than the metformin group and the EA group (P<0.05). ③Compared with the blank group, the protein expression of AMPK and p-AMPK in liver tissue was decreased (P<0.05), and the protein expression of AMPK and p-AMPK in pancreatic tissue was increased (P<0.05) in the model group. Compared with the model group, the protein expression of AMPK and p-AMPK in liver tissue in the metformin group, the EA group and the combination group was increased (P<0.05, P<0.01); the protein expression of AMPK in pancreatic tissue in the metformin group was increased (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was decreased (P<0.05); the protein expression of p-AMPK in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05). The protein expression of AMPK and p-AMPK in liver tissue in the combination group was higher than that in the metformin group and the EA group (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was less than that in the metformin group (P<0.05), and the expression of p-AMPK protein in pancreatic tissue in the combination group was less than that in the metformin group and the EA group (P<0.05). ④Compared with the blank group, the expression of PGP9.5 in pancreatic tissue in the model group was increased (P<0.01); compared with the model group, the expression of PGP9.5 in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05, P<0.01). The expression of PGP9.5 in pancreatic tissue in the EA group was lower than the metformin group and the combination group (P<0.05). CONCLUSION: Electroacupuncture at "Tianshu" (ST 25) could promote the effect of metformin on activating AMPK in liver tissue of T2DM rats, improve the negative effect of metformin on AMPK in pancreatic tissue, and enhance the hypoglycemic effect of metformin. The mechanism may be related to the inhibition of pancreatic intrinsic nervous system.

Hypoglycemic effect of electroacupuncture at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus based on AMPK / 中国针灸

OBJECTIVE@#To observe the hypoglycemic effect of electroacupuncture (EA) at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus (T2DM) as well as its effect on expression of adenosine monophosphate activated protein kinase (AMPK) in liver and pancreas.@*METHODS@#Thirty-six male SD rats were randomly divided into a blank group (6 rats) and a model establishing group (30 rats). The rats in the model establishing group were fed with high-fat diet and treated with intraperitoneal injection of low-dose streptozotocin (STZ) to establish T2DM model. The rats with successful model establishment were randomly divided into a model group, a control group, a metformin group, an EA group and a combination group, 6 rats in each group. The rats in the EA group were treated with EA at "Tianshu" (ST 25), dense-disperse wave, 2 Hz/15 Hz in frequency and 2 mA in current intensity, 20 min each time. The rats in the metformin group were treated with intragastric administration of metformin (190 mg/kg) dissolved in 0.9% sodium chloride solution (2 mL/kg). The rats in the combination group were treated with EA at "Tianshu" (ST 25) and intragastric administration of metformin. The rats in the control group were treated with intragastric administration of 0.9% sodium chloride solution with the same dose. All the treatments were given once a day for 5 weeks. After the intervention, the body mass and random blood glucose were detected; the serum insulin level was detected by ELISA; the expression of AMPK and phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) in liver and pancreas was detected by Western blot method; the expression of protein gene product 9.5 (PGP9.5) was detected by immunofluorescence.@*RESULTS@#①Compared with the blank group, the body mass in the model group was decreased (P<0.05); compared with the model group, the body mass in the EA group and the combination group was decreased (P<0.05); the body mass in the EA group and the combination group was lower than the metformin group (P<0.05). Compared with the blank group, the random blood glucose in the model group was increased (P<0.01); compared with the model group, the random blood glucose in the metformin group, the EA group and the combination group was decreased (P<0.01). The random blood glucose in the combination group was lower than the metformin group and the EA group (P<0.05). ②Compared with the blank group, the insulin level in the model group was decreased (P<0.05); compared with the model group, the insulin level in the metformin group, the EA group and the combination group was all increased (P<0.05). The insulin level in the combination group was higher than the metformin group and the EA group (P<0.05). ③Compared with the blank group, the protein expression of AMPK and p-AMPK in liver tissue was decreased (P<0.05), and the protein expression of AMPK and p-AMPK in pancreatic tissue was increased (P<0.05) in the model group. Compared with the model group, the protein expression of AMPK and p-AMPK in liver tissue in the metformin group, the EA group and the combination group was increased (P<0.05, P<0.01); the protein expression of AMPK in pancreatic tissue in the metformin group was increased (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was decreased (P<0.05); the protein expression of p-AMPK in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05). The protein expression of AMPK and p-AMPK in liver tissue in the combination group was higher than that in the metformin group and the EA group (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was less than that in the metformin group (P<0.05), and the expression of p-AMPK protein in pancreatic tissue in the combination group was less than that in the metformin group and the EA group (P<0.05). ④Compared with the blank group, the expression of PGP9.5 in pancreatic tissue in the model group was increased (P<0.01); compared with the model group, the expression of PGP9.5 in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05, P<0.01). The expression of PGP9.5 in pancreatic tissue in the EA group was lower than the metformin group and the combination group (P<0.05).@*CONCLUSION@#Electroacupuncture at "Tianshu" (ST 25) could promote the effect of metformin on activating AMPK in liver tissue of T2DM rats, improve the negative effect of metformin on AMPK in pancreatic tissue, and enhance the hypoglycemic effect of metformin. The mechanism may be related to the inhibition of pancreatic intrinsic nervous system.

Objective study of the facial parameters of observations in patients with type 2 diabetes mellitus by machine learning.

Background: A predictive model of facial feature data was established by machine learning to screen the objective parameters of risk factors of facial morphological features of type 2 diabetes mellitus (T2DM) following the theory of traditional Chinese medicine (TCM). In TCM, a facial inspection is an important way to diagnose patients. Doctors can judge the health status of their patients by observing their facial features. However, the lack of description of the objective parameters and quantitative indicators hinders the development of TCM testing research. Methods: In this study, the following diagnostic criteria for diabetes developed by the World Health Organization (WHO) in 1999 were used to determine the inclusion and exclusion criteria for T2DM and non-T2DM. T2DM patients and control participants were enrolled in the study, and their facial images were collected. In this study, two facial inspection risk-factor models were constructed, including the "lambda.min" and "lambda.1se" model. Results: A total of 81 key points in the facial images were screened, and 18 facial morphological parameters were measured. The least absolute shrinkage and selection operator (LASSO) regression model was used to construct T2DM facial inspection risk-factor models. The area under the curves (AUCs) of the "lambda.min" model and the "lambda.1se" model were 0.799 and 0.776, respectively. The predictive efficiency of the two T2DM risk models selected by the LASSO regression model was relatively high. Among the eight parameters, the width of the jaw was the most important of the defined facial features. According to the receiver operating characteristic (ROC) curve analysis of the two prediction models constructed, the two models had good predictive efficiency for T2DM. The AUCs of the two models were 0.695 and 0.682, respectively. And the reproducibility is good. The prediction model was available, which showed that the objective parameters of the facial features recognized by machine learning have a certain value in the automatic prediction of T2DM. Conclusions: The influence of facial features is physical factor. Thus, the objective parameters of facial features should be specific to differential diagnosis of T2DM.

Chinese Herbal Medicine for Type 2 Diabetes Mellitus With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Objectives: To evaluate the efficacy and safety of Chinese herbal medicine (CHM) for type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD) with current evidence. Methods: This study was registered in PROSPERO as CRD42021271488. A literature search was conducted in eight electronic databases from inception to December 2021. The primary outcomes were lipid indices and liver functions, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine transaminase (ALT), and aspartate transaminase (AST). Review Manager 5.2 and Stata v14.0 were applied for analysis. Results: The research enrolled 18 RCTs with 1,463 participants. Results showed CHM combined with western medicine (WM) was more effective than WM alone in TG (weighted mean differences (WMD) = -0.35.95% confidence interval (CI) [-0.51, -0.19], p < 0.0001), TC (WMD = -0.58.95%CI [-0.80, -0.36], p < 0.00001), LDL-C (WMD = -0.37, 95%CI [-0.47, -0.26], p < 0.00001), HDL-C (WMD = 0.20, 95%CI [0.10, 0.29], p < 0.0001), ALT (WMD = -4.99, 95%CI [-6.64, -3.33], p < 0.00001), AST (WMD = -4.76, 95%CI [-6.35, -3.16], p < 0.00001), homeostatic model assessment of insulin resistance (WMD = -1.01, 95%CI [-1.22, -0.79], p < 0.00001), fasting blood glucose (WMD = -0.87, 95%CI [-1.13, -0.61], p < 0.00001), 2-h postprandial glucose (WMD = -1.45.95%CI [-2.00, -0.91], p < 0.00001), body mass index (WMD = -0.73.95%CI [-1.35, -0.12], p = 0.02), and overall effective rate (risk ratio (RR) = 1.37.95%CI [1.29, 1.46], p < 0.00001). Conclusion: The CHM in combination with WM seems to be more beneficial in T2DM with NAFLD patients in improving lipid and glucose metabolism, liver function, and insulin resistance as well as improving overall efficiency and reducing body weight. Given the poor quality of reports from these studies and uncertain evidence, these findings should be interpreted cautiously. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021271488, identifier CRD42021271488.

Activation of renal CSE/H2S pathway by alpha-lipoic acid protects against histological and functional changes in the diabetic kidney.

INTRODUCTION: We previously reported that alpha-lipoic acid (ALA) supplementation protects against progression of diabetic kidney disease (DKD). In this study, we aim to investigate whether the mechanism of renal protection by ALA involves renal cystathionine γ-lyase/hydrogen sulfide (CSE/H2S) system in type 2 diabetes mellitus (T2DM). METHODS: Thirty-seven male Sprague-Dawley rats underwent 12 h of overnight fasting. To induce T2DM, 30 of these rats received intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). T2DM rats then received either oral administration of ALA (60 mg/kg/day) or intraperitoneal administration of 40 mg/kg/day DL-propargylglycine (PAG, a CSE inhibitor) or both for 6 weeks after which rats were sacrificed and samples collected for analysis. Untreated diabetic and non-diabetic rats served as diabetic and healthy controls respectively. RESULTS: T2DM was characterized by reduced pancreatic ß-cell function and hyperglycemia. Histologically, untreated diabetic rats showed significantly damaged pancreatic islets, glomerular and tubular injury, with elevated levels of renal function markers compared to healthy control rats (p < 0.001). These pathological changes worsened significantly following PAG administration (p < 0.05). While some renal protection was observed in ALA+PAG rats, ALA administration in untreated diabetic rats provided superior protection comparable to healthy control rats, with improved antioxidant status, lipid profile and reduced inflammation. Mechanistically, ALA significantly activated renal CSE/H2S system in diabetic rats, which was markedly suppressed in PAG-treated rats (p < 0.001). CONCLUSION: Our data suggest that ALA protects against DKD development and progression by activating renal CSE/H2S pathway. Hence, CSE/H2S pathway may represent a therapeutic target in the treatment or prevention of DKD in diabetic patients.

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-ß/Smad Pathway.

Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1ß, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-ß1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-ß1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

Supplementation of conventional anti-diabetic therapy with alpha-lipoic acid prevents early development and progression of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Current pharmacological interventions only retard DN progression. Alpha-lipoic acid (ALA) is a potent antioxidant with beneficial effect in other diabetic complications. This study investigates whether ALA supplementation prevents early development and progression of DN. METHOD: Fifty-eight male Sprague-Dawley rats were randomly assigned to healthy control and diabetic groups and subjected to overnight fasting. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). On day 3 after T2DM induction, diabetic rats received oral daily administration of ALA (60 mg/kg), gliclazide (15 mg/kg), ramipril (10 mg/kg) or drug combinations for 6 weeks. Untreated diabetic rats served as diabetic control. Blood, kidneys and pancreas were harvested for biochemical and histological analyses. RESULT: Induction of T2DM resulted in hypoinsulinemia, hyperglycemia and renal pathology. ALA supplementation maintained ß-cell function, normoinsulinemia and normoglycemia in diabetic rats, and prevented renal pathology (PAS, KIM-1, plasma creatinine, total protein, blood urea nitrogen, uric acid and urine albumin/creatinine ratio) and triglycerides level compared to diabetic control (p < 0.001). Additionally, ALA supplementation significantly prevented elevated serum and tissue malondialdehyde, collagen deposition, α-SMA expression, apoptosis and serum IL-1ß and IL-6 levels while it markedly increased renal glutathione content and plasma HDL-C compared to diabetic control group (p < 0.001). CONCLUSION: ALA supplementation prevents early development and progression of DN by exerting anti-hyperglycemic, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Our findings provide additional option for clinical treatment of DN in T2DM patients.

Antidiabetic potential of Catechu via assays for α-glucosidase, α-amylase, and glucose uptake in adipocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Catechu is the dry water extract of barked branches or stems from Senegalia catechu(L. F.)P. J. H. Hurter & Mabb, which is used as a hypoglycemic regulator in recent researches. Potential anti-hyperglycemic components and the putative mechanisms were evaluated in this investigation. AIM OF THE STUDY: Evaluated the hypoglycemic activity of Catechu via α-glucosidase, α-amylase inhibition assays, and glucose uptake in 3T3-L1 adipocytes. MATERIALS AND METHODS: The effects of Catechu on α-glucosidase, α-amylase inhibition assays and glucose uptake experiment were tested after the ethanol extract of Catechu (EE) was sequentially partitioned with petroleum ether (PEE), ethyl acetate (EAE), and n-butanol fractions (NBE). Next, HPLC-MS and traditional Chinese medicine (TCM) database were used to detect and analyze the primary active ingredients presented in hypoglycemic fraction. In addition, in silico molecular docking study was used to evaluate the candidates' inhibitory activity against α-glucosidase and α-amylase. RESULTS: The results of α-glucosidase and α-amylase inhibition assays indicated that all fractions, with the exception of PEE, presented significant inhibitory effects on α-glucosidase and α-amylase. The inhibitory effect of NBE on α-glucosidase was similar to the positive control (NBE IC50 = 0.3353 ± 0.1215 µg/mL; Acarbose IC50 = 0.1123 ± 0.0023 µg/mL). Furthermore, the inhibitory kinetics of α-glucosidase revealed that all fractions except for PEE belong to uncompetitive type. In silico molecular docking analysis showed that the main compositions of NBE ((-)-epicatechin, cyanidin, and delphinidin) possessed superior binding capacities with α-glucosidase (3WY1 AutoDock score: 4.82 kcal/mol; -5.59 kcal/mol; -5.63 kcal/mol) and α-amylase (4GQR AutoDock score: 4.80 kcal/mol; -5.89 kcal/mol; -4.26 kcal/mol), respectively. The results of glucose uptake experiment indicated that EE, PEE, EAE, and NBE without significant promotion effect on glucose uptake rate of 3T3-L1 adipocytes (P > 0.05). CONCLUSION: This study revealed that the hypoglycemic effect of Catechu might be related to the inhibitory effects of phenols on digestive enzymes (α-glucosidase and α-amylase), and the possible active phenols were (-)-epicatechin, cyanidin, delphinidin and their derivatives, which provided scientific evidences for Catechu's traditional use to treat T2DM.

Habits, Traditions, and Beliefs Associated With the Use of Complementary and Alternative Medicine Among Diabetic Patients in Al-Qassim Region, Saudi Arabia.

Background Since diabetes mellitus (DM) affects every aspect of a person's being, more and more people are using complementary and alternative therapies such as ingesting ginger and cinnamon in addition to conventional medical care and lifestyle changes to manage their condition and enhance their well-being. Although this population uses complementary and alternative medicine (CAM) at a high rate, it is unclear what causes this use. Objective We aim to know the habits, traditions, and beliefs associated with the use of complementary and alternative medicine among type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients in the Al-Qassim region of Saudi Arabia. Methods This is an observational cross-sectional study conducted among diabetes patients in Al-Qassim, Saudi Arabia, in 2022. Participants were selected via a non-probability sampling technique. Patients were interviewed in the diabetic clinics using validated questionnaires. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) software (IBM SPSS Statistics, Armonk, NY, USA). Results A total of 444 validated responses were received in this study. The average age was 50 ± 16.9 years, and females represented the highest proportion (58.6%). Moreover, we found that most of the participants had type 2 diabetes (79.1%) and 93 (20.9%) had type 1 diabetes. Hypertension was the most reported chronic disease. Our results revealed that the prevalence of CAM usage was 29.1%. Regarding the sources of information on herbal medicines, we found that more than half of the respondents (57.4%) obtained information from friends, relatives, and neighbors. Ginger, vitamins and minerals, and cinnamon were the most frequently used herbals among our participants. Our results found that 38% of CAM users used herbal products on a regular basis. As regards the frequency of using herbal products, 29.5% of the respondents used herbal medicine weekly and 21.7% used it daily. In addition, we found that gender, marital status, and monthly income were significantly associated with the use of CAM (P value = 0.008, 0.011, and 0.011, respectively). The significantly higher CAM use was associated with females, married participants, and participants with a monthly income of 10,000-15,000 Saudi riyal (SAR). Conclusion According to our research, CAM use among diabetes patients in the Al-Qassim region was found to be relatively common. The prevalence of type 2 diabetes mellitus was higher (79.1%) in comparison to type 1 diabetes mellitus (20.9%). Also, the most commonly used herb was ginger (47.66%), followed by vitamins and minerals (44.53%), and cinnamon (42.19%). Patients with diabetes need to be informed of the significance of telling their doctors about their use of CAM.

Regulatory Effect of Herbal Pair Astragali Radix-Puerariae Lobatae Radix on PI3K/Akt/FoxO1 Signaling Pathway in Rats with T2DM Based on Network Pharmacology / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of herbal pair Astragali Radix-Puerariae Lobatae Radix （AR-PLR） against type 2 diabetes mellitus （T2DM） based on network pharmacology and experimental verification. MethodThe active ingredients and targets of AR and PLR were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）. The related targets of T2DM were retrieved from disease databases and the common targets of drugs and diseases were extracted. The protein-protein interaction （PPI） network was analyzed and constructed by STRING and the network topology of key targets was analyzed by Cytoscape 3.7.1. Then gene ontology（GO） and Kyoto encyclopedia of genes and genomes（KEGG） enrichment analyses of core targets were carried out by DAVID to explore its possible molecular mechanism. The T2DM model was induced in rats by the high-fat diet combined with tail intravenous injection of streptozocin. The rats were divided into a normal group，a model group，a metformin group，and high-，medium- and low-dose AR-PLR groups. After four weeks of intragastric administration，the serum levels of fasting blood sugar （FBS），fasting insulin（FINS），aspartate aminotransferase（AST），alanine aminotransferase（ALT），triglyceride（TG），total cholesterol（TC），low-density lipoprotein cholesterin（LDL-C），high-density lipoprotein cholesterin （HDL-C），interleukin-6（IL-6）， and tumor necrosis factor-α（TNF-α） of rats in each group were measured. The protein expression of insulin receptor substrate-2（IRS-2），phosphatidylinositol 3-kinase（PI3K），protein kinase B（Akt）， and forkhead box transcription factor O1（FoxO1） in rat liver was detected by Western blot. ResultA total of 131 core targets of AR-PLR in the treatment of T2DM were screened out by network pharmacology， where Akt1，mitogen-activated protein kinase 1 （MAPK1），TNF-α，and IL-6 were critical. As revealed by KEGG enrichment analysis， AR-PLR exerted the hypoglycemic effect mainly through the PI3K/Akt，TNF， and FoxO signaling pathways. Compared with the model group，the high- and medium-dose AR-PLR groups showed reduced FBS and FINS levels and increased glycogen level （P<0.05，P<0.01），all the AR-PLR groups showed decreased levels of AST，ALT，TG， and LDL-C （P<0.05，P<0.01）， the high- and low-dose AR-PLR groups showed decreased TC levels （P<0.05）. Compared with the model group， the high- and medium-dose AR-PLR groups showed reduced levels of IL-6 and TNF-α（P<0.05，P<0.01）， and the high-dose AR-PLR group showed increased expression of IRS-2， Akt， p-Akt， PI3K， and p-PI3K， and decreased expression of FoxO1 protein（P<0.05）. ConclusionAR-PLR has the characteristics of multi-component，Multi-target and multi-pathway in the treatment of T2DM. This herbal pair may regulate the PI3K/Akt/FoxO1 signaling pathway through IL-6， TNF-α， and other targets to affect insulin resistance， glycogen synthesis， gluconeogenesis， glucose transport， inflammation， immune response， and other processes， thereby treating T2DM.

Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial.

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFß-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

Comparative Assessment of the Acute Effects of Whey, Rice and Potato Protein Isolate Intake on Markers of Glycaemic Regulation and Appetite in Healthy Males Using a Randomised Study Design.

Global protein consumption has been increasing for decades due to changes in demographics and consumer shifts towards higher protein intake to gain health benefits in performance nutrition and appetite regulation. Plant-derived proteins may provide a more environmentally sustainable alternative to animal-derived proteins. This study, therefore, aimed to investigate, for the first time, the acute effects on glycaemic indices, gut hormones, and subjective appetite ratings of two high-quality, plant-derived protein isolates (potato and rice), in comparison to a whey protein isolate in a single-blind, triple-crossover design study with nine male participants (30.8 ± 9.3 yrs). Following a 12 h overnight fast, participants consumed an equal volume of the three isocaloric protein shakes on different days, with at least a one-week washout period. Glycaemic indices and gut hormones were measured at baseline, then at 30, 60, 120, 180 min at each visit. Subjective palatability and appetite ratings were measured using visual analogue scales (VAS) over the 3 h, at each visit. This data showed significant differences in insulin secretion with an increase in whey (+141.8 ± 35.1 pmol/L; p = 0.011) and rice (-64.4 ± 20.9 pmol/L; p = 0.046) at 30 min compared to potato protein. A significantly larger total incremental area under the curve (iAUC) was observed with whey versus potato and rice with p < 0.001 and p = 0.010, respectively. There was no significant difference observed in average appetite perception between the different proteins. In conclusion, this study suggests that both plant-derived proteins had a lower insulinaemic response and improved glucose maintenance compared to whey protein.

The Combined Effect of Neuromuscular Electrical Stimulation and Insulin Therapy on Glycated Hemoglobin Concentrations, Lipid Profiles and Hemodynamic Parameters in Patients with Type-2-Diabetes and Hemiplegia Related to Ischemic Stroke: A Pilot Study.

Type-2-diabetes mellitus (T2DM) is a global problem of medical, social and economic consequences. Physical activity is a vital therapy in patients with T2DM, but some of them cannot exercise for various reasons. The purpose of our pilot study was to determine whether a combination of neuromuscular electrostimulation (NMES) and insulin therapy could improve the management of T2DM patients with hemiplegia caused by an ischemic stroke. Fifteen immobile patients with T2DM on insulin therapy were enrolled in the study. NMES was applied to their lower limbs for 60 min, 5 days a week, over a period of 12 weeks. The intervention caused statistically significant reductions in the blood concentrations of glycated hemoglobin, total cholesterol and low-density cholesterol in the participants. Furthermore, systolic and diastolic blood pressure levels were significantly lower. More randomized clinical trials are needed to accurately measure the effect of NMES on T2DM treatment and to determine whether it can be an alternative for physical activity for immobile patients with T2DM.

Magnesium, Little Known But Possibly Relevant: A Link between NASH and Related Comorbidities.

Non-alcoholic steatohepatitis (NASH) is characterized by an abnormal hepatic lipid accumulation accompanied by a necro-inflammatory process and a fibrotic response. It comprises from 10% to 30% of cases of patients with non-alcoholic liver disease, which is a global health problem affecting around a quarter of the worldwide population. Nevertheless, the development of NASH is often surrounded by a pathological context with other comorbidities, such as cardiovascular diseases, obesity, insulin resistance or type 2 diabetes mellitus. Dietary imbalances are increasingly recognized as the root cause of these NASH-related comorbidities. In this context, a growing concern exists about whether magnesium consumption in the general population is sufficient. Hypomagnesemia is a hallmark of the aforementioned NASH comorbidities, and deficiencies in magnesium are also widely related to the triggering of complications that aggravate NASH or derived pathologies. Moreover, the supplementation of this cation has proved to reduce mortality from hepatic complications. In the present review, the role of magnesium in NASH and related comorbidities has been characterized, unraveling the relevance of maintaining the homeostasis of this cation for the correct functioning of the organism.