Reduce Insulin Resistance Research Articles

Comprehensive machine learning models for predicting therapeutic targets in type 2 diabetes utilizing molecular and biochemical features in rats

IntroductionWith the increasing prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need to discover effective therapeutic targets for this complex condition. Coding and non-coding RNAs, with traditional biochemical parameters, have shown promise as viable targets for therapy. Machine learning (ML) techniques have emerged as powerful tools for predicting drug responses.MethodIn this study, we developed an ML-based model to identify the most influential features for drug response in the treatment of type 2 diabetes using three medicinal plant-based drugs (Rosavin, Caffeic acid, and Isorhamnetin), and a probiotics drug (Z-biotic), at different doses. A hundred rats were randomly assigned to ten groups, including a normal group, a streptozotocin-induced diabetic group, and eight treated groups. Serum samples were collected for biochemical analysis, while liver tissues (L) and adipose tissues (A) underwent histopathological examination and molecular biomarker extraction using quantitative PCR. Utilizing five machine learning algorithms, we integrated 32 molecular features and 12 biochemical features to select the most predictive targets for each model and the combined model.Results and discussionOur results indicated that high doses of the selected drugs effectively mitigated liver inflammation, reduced insulin resistance, and improved lipid profiles and renal function biomarkers. The machine learning model identified 13 molecular features, 10 biochemical features, and 20 combined features with an accuracy of 80% and AUC (0.894, 0.93, and 0.896), respectively. This study presents an ML model that accurately identifies effective therapeutic targets implicated in the molecular pathways associated with T2DM pathogenesis.

Euonymus alatus Extract Reduces Insulin Resistance in db/db Mice by Regulating the PI3K–AKT Pathway

In accordance with the usage of Euonymus alatus (EA) as folk medicine in diabetes, the present study employed water and 70% ethanol twig extract to assess its antidiabetic effects in C57BL/KsJ-db/db mice. These effects were then compared with those observed in normal C57BL/6J Jms Slc mice. After 4 weeks of supplementation with 70% ethanolic EA extract or water EA extract by oral gavage at a dose of 500 mg/kg with distilled water (DW) per day, body weight was measured and compared with the diabetic group (Db). HPLC demonstrated that the maximum flavonoids were extracted in the Et.EA extract rather than in the water EA extract. The supplementation of the Et.EA extract significantly increased liver and muscle glycogen content with respect to the Db group. Additionally, the Et.EA extract modulated the expression of glycogen synthase (GS) in the liver and muscles of Db mice, indicating that it plays a promotive role in glycogen synthesis. Mechanistically, Et.EA extract activates insulin receptor substrate (IRS1/IRS2)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) in the liver and muscles of Db mice. In conclusion, Et.EA extract attenuates insulin resistance by regulating the expression of metabolic enzymes and signaling pathways.

Bioinformatics study of the potential therapeutic effects of ginsenoside Rh3 in reversing insulin resistance

BackgroundIn recent years, the incidence of insulin resistance is increasing, and it can cause a variety of Metabolic syndrome. Ginsenosides have been clinically proven to improve fat metabolism and reduce insulin resistance, but their components and mechanism of action are still unclear.ObjectiveGinsenoside, a bioactive compound derived from ginseng, exhibits significant potential in treating obesity, diabetes, and metabolic disorders. Despite evidence supporting its efficacy in ameliorating insulin resistance (IR) in obesity, the specific bioactive components and underlying mechanisms remain obscure. In this study, we endeavored to elucidate the potential molecular targets and pathways influenced by ginsenoside Rh3 (GRh3) to ameliorate IR in liver tissue. We employed a comprehensive approach that integrates system pharmacology and bioinformatics analysis.Materials and methodsOur methodology involved the identification of candidate targets for GRh3 and the profiling of differentially expressed genes (DEGs) related to IR in individuals with insulin resistance. The coalescence of candidate targets and DEGs facilitated the construction of a “GRh3-targets-disease” network for each tissue type, ultimately yielding 38 shared target genes. Subsequently, we conducted pathway enrichment analysis, established protein-protein interaction (PPI) networks, and identified hub targets among the GRh3 targets and IR-related DEGs. Additionally, we conducted animal experiments to corroborate the role of these hub targets in the context of GRh3.ResultsOur investigation identified a total of 38 overlapping targets as potential candidates. Notably, our analysis revealed crucial hub targets such as EGFR, SRC, ESR1, MAPK1, and CASP3, alongside implicated signaling pathways, including those related to insulin resistance, the FoxO signaling pathway, the PPAR signaling pathway, and the IL-17 signaling pathway. This study establishes a robust foundation for the mechanisms underlying GRh3’s efficacy in mitigating IR. Furthermore, these results suggest that GRh3 may serve as a representative compound within the ginsenoside family.ConclusionThis study elucidates the potential molecular targets and associated pathways through which GRh3 ameliorates IR, showcasing its multifaceted nature, spanning multiple targets, pathways, and mechanisms. These findings establish a robust foundation for subsequent experimental inquiries and clinical applications.

Effectiveness of structured exercise program on insulin resistance and quality of life in type 2 diabetes mellitus-A randomized controlled trial.

Impaired glucose control & Insulin resistance are reported to be risk factors for the development of cardiovascular diseases. To find the effects of a structured exercise program on insulin resistance, glycaemic control, functional capacity, and quality of life in patients with Type 2 diabetes mellitus. Randomized, controlled trial. Diabetic Foot Clinic, Department of Physiotherapy & Department of General Medicine, Kasturba Hospital in Manipal, Karnataka, India. 160 participants aged between 30-65 years with Type 2 diabetes mellitus. A set of structured exercise programs (aerobic, resistance, and combined) along with the standard hospital care was performed 3-5 times weekly for 12 weeks. Fasting Insulin Level, Homa-IR, Six-minute walk test (6MWT), and WHOQOL-BREF questionnaire at baseline and 12th week. Body composition analysis, Fasting Blood Sugar, Postprandial Blood Sugar, Glycated Haemoglobin (HbA1c), and GPAQ questionnaire at baseline and 12th week. Significant differences have been observed in Homeostasis model assessment for insulin resistance (Homa-IR) (F (1, 144) = 89.29, p < 0.001); Fasting insulin (FI) (F (1, 144) = 129.10, p < 0.001); Fasting blood sugar (FBS) (F (1, 144) = 12.193, p< 0.001); Post prandial blood sugar (PPBS) (F (1, 144) = 53.015, p< 0.001); glycated haemoglobin (HbA1c) (F (1, 144) = 80.050, p < 0.001); WHOQOL-Physical health (F (1, 144) = 20.008, p< 0.001), Psychological (F (1, 144) = 77.984, p< 0.001), Social relationship (F (1, 144) = 44.866, p< 0.001); Environmental (F (1, 144) = 69.974, p< 0.001); Six minute walk test (6MWT) (F (1, 144) = 84.135, p< 0.001) in the study group when compared with the control group from baseline to 12th week. The study reveals that a 12-week structured exercise training program effectively reduces insulin resistance, improves quality of life, enhances functional capacity, and improves glycaemic control in type 2 diabetes mellitus.

Data-Driven Patient clusters of Type 2 Diabetes May Help to Identify Patients at Risk and Predict Metabolic Surgery Outcomes on Diabetes Remission and NAFLD Pregression

Abstract Background Precision medicine and customized medicine have gained enormous attention in recent years, especially in the treatment of type 2 diabetes (T2D). Different subgroups of diabetes have been identified by research employing data-driven cluster analysis, each with a unique diabetes progression and complication risk (Ahlqvist et al., Lancet Diabetes Endocrinol. 2018). Aims We aimed to apply the proposed cluster analysis to a patent population post metabolic surgery and investigate the association with T2D remission and presence of NAFLD. Methods We retrospectively linked newly defined clusters to metabolic surgery outcomes in 53 T2D patients. Utilizing k-means and hierarchical clustering, three clusters emerged based on glutamate decarboxylase antibodies, age, BMI, HbA1c, and homoeostatic model assessment estimates of β-cell function (HOMA2-B%) and insulin resistance (HOMA2-IR). Intraoperative liver biopsies assessed nonalcoholic fatty liver disease (NAFLD) presence differentiating between simple steatosis (NAFL) and steatohepatitis (NASH). Clinical and biochemical data were collected over two years, focusing on T2D remission and NAFLD improvement. Results Cluster 1, characterized by the lowest BMI, highest NASH rate, impaired beta-cell function, and increased insulin resistance, displayed a favorable response to surgery, indicating robust regeneration of beta-cells. Despite increased insulin production, T2D remission was surprisingly low at 44.0% after one year, in contrast to 75.00% in Cluster 2 and 100.00% in Cluster 3. Metabolic surgery notably reduced insulin resistance and promoted NASH remission, evidenced by a significant reduction in a non-invasive NASH detection score and liver enzyme levels across all three clusters. Conclusion Our findings suggest that patients in Cluster 1 already show a lack of beta-cell compensation being associated with a higher prevalence of NAFLD and poorer diabetic control and therefore especially might benefit from an earlier intervention. Data-driven classification might help to customize treatment plans and identify patients at higher risk of problems at diagnosis.

Phlorizin from Lithocarpus litseifolius [Hance] Chun ameliorates FFA-induced insulin resistance by regulating AMPK/PI3K/AKT signaling pathway

BackgroundInsulin resistance (IR) is the central pathophysiological feature in the pathogenesis of metabolic syndrome, obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia. As the main active ingredient in Lithocarpus litseifolius [Hance] Chun, previous studies have shown that phlorizin (PHZ) can reduce insulin resistance in the liver. However, the effect of phlorizin on attenuating hepatic insulin resistance has not been fully investigated, and whether this effect is related to AMPK remains unclear. PurposeThe present study aimed to further investigate the effect of phlorizin on attenuating insulin resistance and the potential action mechanism. MethodsFree fatty acids (FFA) were used to induce insulin resistance in HepG2 cells. The effects of phlorizin and FFA on cell viability were detected by MTT analysis. Glucose consumption, glycogen synthesis, intracellular malondialdehyde (MDA), superoxide dismutase (SOD), total cholesterol (TC), and triglyceride (TG) contents were quantified after phlorizin treatment. Glucose uptake and reactive oxygen species (ROS) levels in HepG2 cells were assayed by flow cytometry. Potential targets and signaling pathways for attenuating insulin resistance by phlorizin were predicted by network pharmacological analysis. Moreover, the expression levels of proteins related to the AMPK/PI3K/AKT signaling pathway were detected by western blot. ResultsInsulin resistance was successfully induced in HepG2 cells by co-treatment of 1 mM sodium oleate (OA) and 0.5 mM sodium palmitate (PA) for 24 h. Treatment with phlorizin promoted glucose consumption, glucose uptake, and glycogen synthesis and inhibited gluconeogenesis in IR-HepG2 cells. In addition, phlorizin inhibited oxidative stress and lipid accumulation in IR-HepG2 cells. Network pharmacological analysis showed that AKT1 was the active target of phlorizin, and the PI3K/AKT signaling pathway may be the potential action mechanism of phlorizin. Furthermore, western blot results showed that phlorizin ameliorated FFA-induced insulin resistance by activating the AMPK/PI3K/AKT signaling pathway. ConclusionPhlorizin inhibited oxidative stress and lipid accumulation in IR-HepG2 cells and ameliorated hepatic insulin resistance by activating the AMPK/PI3K/AKT signaling pathway. Our study proved that phlorizin played a role in alleviating hepatic insulin resistance by activating AMPK, which provided experimental evidence for the use of phlorizin as a potential drug to improve insulin resistance.

Biochemical bases of the organoprotective properties of metformin

Metformin is recognized as the "gold standard" for the treatment of type 2 diabetes mellitus (DM2). Its hypoglycemic properties are realized by reducing insulin resistance, contributing to the utilization of glucose in liver cells, muscles and adipose tissue; suppression of gluconeogenesis in the liver. Due to the wide range of biochemical targets of its pharmacological action, the scientific community actively discusses the use of metformin as an organoprotective drug. Now, the beneficial effect of metformin on the course of neuropathy, diseases of the cardiovascular system, normalization of the composition and metabolic activity of the intestinal microbiota, the course of metabolically associated fatty liver disease has already been proven, the nephroprotective effect has also been proven, and the study of the anti-oncogenic properties of metformin continues. The number of publications devoted to research on the positive effects of metformin on various organs and systems is actively increasing, and data on the identification of new effects are regularly published. The purpose of this literature review is to analyze the pleiotropic effects of metformin at the level of biochemical interactions for a more detailed understanding of the principles of their implementation.

FK506-Binding Protein 51 (FKBP51) Suppresses PPARα Activity and Shifts the Insulin Receptor Alternative Splicing Driving Hepatic Insulin Resistance

FK506-binding protein-51 (FKBP51) is a molecular chaperone protein that has great potential to serve as a treatment target for non-alcoholic fatty liver disease (NAFLD) and type II diabetes (T2DM). FKBP51 has been known to regulate nuclear receptors such as glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor γ (PPARγ). However, the connections between FKBP51 and other PPAR family members, such as peroxisome proliferator-activated receptor α (PPARα), are yet to be identified. FKBP51 can also inhibit protein kinase B (AKT) activation, which may impact the insulin receptor signaling pathway. It has been reported that FKBP51 knockout mice presented less adiposity, reduced liver steatosis, and increased insulin sensitivity and insulin clearance, indicating that FKBP51 plays a role in insulin resistance and fatty liver development. However, how FKBP51 regulates insulin resistance, especially in the liver, still needs to be unveiled. It has been shown that insulin receptor (IR) alternative splicing is associated with insulin sensitivity and that PPARα activation is critical in reducing insulin resistance. Thus, we hypothesize that FKBP51 can regulate hepatic insulin resistance through insulin receptor alternative splicing and PPARα suppression. To test this hypothesis, we developed an FKBP51 knockout mouse hepatocyte cell line, 51KO AML12, and treated the cells with insulin for 1hr. We measured RNA and protein expressions in the cells through RT-PCR and western blotting and found that 51KO AML12 had increased phospho-AKT Ser473 (pAKT S473) and IR isoform B (IR-B), indicating increased insulin signaling activity. We also found increased IR isoform A (IR-A) and IR-B expression in 51KO AML12. In addition, we found an increased ratio of IR-B: IR-A in 51KO AML12 treated with insulin. These data indicate a great potential for FKBP51 to be a novel treatment target for hepatic insulin resistance and T2DM. This research is supported by the National Institute of Health R01DK121797 (T.D.H.), R01DA058933 (T.D.H.), and Start-Up funds from the University of Kentucky (T.D.H.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Argyreia nervosa Mitigates Insulin Resistance in Liver via IR/IRS-1 Mediated Signaling in Streptozotocin-Induced Type-2 Diabetic Rats

Argyreia nervosa, commonly known as Hawaiian baby woodrose or wooly morning glory, is a plant native to India and is also found in various parts of the world. It is known for its seeds, which have been used traditionally in Ayurvedic and traditional medicine systems for various diseases. The study was aimed at assessing the effect of Argyreia nervosa on insulin signaling molecules of the liver in streptozotocin (STZ)-induced experimental type-2 diabetic rats. Healthy adult male Wistar albino rats -150-180 days old weighing 180-200g was used for the study and divided as Group I - Normal rats; Group II – type-2 diabetic rats; Group III -Diabetic rats + A. nervosa 500 mg/kg b.wt; Group IV-Normal rats + A. nervosa 500 mg/kg b.wt. Fasting blood glucose, and fasting serum insulin were measured by calorimetric methods. Further mRNA expression analysis of insulin receptor (IR) was measured in control and treated animals by quantitative Ream Time PCR analysis. A. nervosa root extract significantly reduced fasting blood glucose and serum insulin concentrations in STZ-induced rats compared with control. In addition, mRNA expression of IR showed a one-fold increase in the expression which shows that A. nervosa is involved in the regulation of insulin signaling in the liver and thereby reduces insulin resistance and type-2 diabetes. Our study concludes that A. nervosa root extract has a significant role on insulin signaling molecules thereby it reduces hyperglycemia and hyperinsulinemia via insulin receptor-mediated pathways. Hence, A. nervosa may be considered as one of the therapeutic natural antidiabetic drugs.

Analysis of the Correlation Between Visceral Fat Area and Insulin Resistance in Patients with Type 2 Diabetes and Abdominal Obesity

Objective: To analyze the correlation between visceral fat area and insulin resistance index (HOMA-IR) in patients with type 2 diabetes mellitus (T2DM) and abdominal obesity and to provide a reference for screening and related research of such patients. Methods: Two hundred patients with T2DM admitted to Guandu People’s Hospital of Kunming were included. The study was carried out from October 2022 to December 2023. The patients were divided into three groups according to different abdominal visceral fat areas (VFA): Group A (n = 65) was less than 75cm2, Group B (n = 75) was 75–100 cm2, and Group C (n = 60) was greater than 100 cm2. The subjects in the three groups were all tested for glycated hemoglobin (HbA1c), fasting insulin (FINS), and fasting blood glucose (FPG). Height and weight were measured to calculate body mass index (BMI). The HOMA-IR and TYG (fasting triglyceride and glycemic index) were also calculated. Changes in the BMI, VFA, HOMA-IR, and TYG levels were observed in the three groups. Results: The VFA, BMI, HbA1c, FPG, FINS, HOMA-IR, and TYG of the patients all increased, with a more significant increase in the BMI, FINS, HOMA-IR, and TYG levels (P &lt; 0.01). Multiple linear stepwise regression analyses used visceral fat area (VFA) as the dependent variable. The results showed that VFA was closely related to BMI, FINS, HOMA-IR, and TYG. Conclusion: Early reduction of VFA to reduce insulin resistance may be a better treatment and effective method for T2DM, providing powerful measures and new strategies for effective blood sugar control and early prevention in the treatment of metabolic diseases.

An 8-Week study on the effects of high and Moderate-Intensity interval exercises on mitochondrial MOTS-C changes and their relation to metabolic markers in male diabetic sand rats

Mitochondrial dysfunction is a significant feature of type 2 diabetes. MOTS-C, a peptide derived from mitochondria, has positive effects on metabolism and exercise capacity. This study explored the impact of high and moderate-intensity interval exercises on mitochondrial MOTS-C alterations and their correlation with metabolic markers in male diabetic sand rats. Thirty male sand rats were divided into six groups: control, MIIT, DM + HIIT, DM + MIIT, DM, and HIIT (5 rats each). Diabetes was induced using a high-fat diet (HFD) combined with streptozotocin (STZ). The Wistar sand rats in exercise groups underwent 8 weeks of interval training of varying intensities. Post sample collection, protein expressions of PCG-1a, AMPK, and GLUT4 were assessed through Western blot analysis, while MOTS-C protein expression was determined using ELISA. Both exercise intensity and diabetes significantly affected the levels of PCG-1a, MOTS-C, GLUT4 proteins, and insulin resistance (p < 0.001). The combined effect of diabetes status and exercise intensity on these levels was also significant (p < 0.001). However, the diabetes effect varied when comparing high-intensity to moderate-intensity exercise. The moderate-intensity exercise group with diabetes showed higher levels of PCG-1a, MOTS-C, and GLUT4 proteins and reduced insulin resistance levels (p < 0.001). Exercise intensity (p = 0.022) and diabetes (p = 0.008) significantly influenced AMPK protein levels. The interplay between diabetes status and exercise intensity on AMPK protein levels was noteworthy, with the moderate-intensity diabetes group exhibiting higher AMPK levels than the high-intensity diabetes group (p < 0.001). In conclusion, exercise elevates the levels of PCG-1a, MOTS-C, GLUT4, and AMPK proteins, regulating insulin resistance in diabetic sand rats. Given the AMPK-MOTS-C mitochondrial pathway's mechanisms, interval exercises might enhance the metabolic rates and general health of diabetic rodents.

The impact of vitamin D on the etiopathogenesis and the progression of type 1 and type 2 diabetes in children and adults.

Diabetes is a common chronic metabolic disease with complex causes and pathogenesis. As an immunomodulator, vitamin D has recently become a research hotspot in the occurrence and development of diabetes and its complications. Many studies have shown that vitamin D can reduce the occurrence of diabetes and delay the progression of diabetes complications, and vitamin D can reduce oxidative stress, inhibit iron apoptosis, promote Ca2+ influx, promote insulin secretion, and reduce insulin resistance. Therefore, the prevention and correction of vitamin D deficiency is very necessary for diabetic patients, but further research is needed to confirm what serum levels of vitamin D3 are maintained in the body. This article provides a brief review of the relationship between vitamin D and diabetes, including its acute and chronic complications.

Probiotic consumption and hepatic steatosis: results from the NHANES 2011-2016 and Mendelian randomization study.

Recent research showed that probiotics treatment may reduce insulin resistance, regulate lipid metabolism, raise liver enzyme levels, and ameliorate inflammation in individuals with metabolic associated fatty liver disease (MAFLD). However, the possible effects of probiotic use on the progression of hepatic steatosis (HS) have not been identified. The purpose of this study was to investigate this in a large population database. The cross-sectional research was conducted among adults with complete data on probiotic yogurt consumption and HS in the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Probiotic yogurt consumption was assessed using a dietary supplement questionnaire, while HS was evaluated with HS index (HSI). To explore their relationship, weighted univariate regression analysis, subgroup analysis, and interaction analysis were conducted. To evaluate the causal association between yogurt consumption and NAFLD, mendelian randomization analysis (MR) were performed. A restricted cubic spline (RCS) was used to analyze the relationship curve between the leves of yogurt consumption and hepatic steatosis. A total of 7,891 participants were included in the study represented 146.7 million non-institutionalized residents of the United States, of whom 4,322 (54.77%) were diagnosed with HS. Multivariable logistic regression showed probiotic yogurt consumption had significantly inverse relationship for HS (OR = 0.84, 95% CI: 0.72-0.97, p = 0.02) after adjusting for all covariates. Once more, the independent relationship between probiotic yogurt consumption and HS was verified by subgroup analysis and interaction analysis. The MR analysis results indicate that there is no causal relationship between yogurt consumption and NAFLD. The RCS model demonstrated a robust J-shaped link between yogurt consumption and HS, revealing a significant decrease in risk within the lower range of yogurt consumption, which attained the lowest risk close to 0.4 cup. According to the NHANES data, the consumption of probiotics and yogurt has a beneficial effect on HS, whereas the MR results indicated it was not related to NAFLD. The RCS analysis indicates a J-shaped relationship between yogurt consumption and HS, which may account for the inconsistency in the results. Based on these findings, we recommend that adults take half a cup of yogurt daily.

THE EFFECT OF BARIATRIC SURGERY ON BREAST CANCER INCIDENCE AND CHARACTERISTICS: A COMPREHENSIVE SYSTEMATIC REVIEW

Background: Obesity elevates estrogen levels and pro-inflammatory cytokines, increasing breast cancer risk via macrophage migration to breast tissue and stimulating epithelial proliferation. Observational studies suggest that intentional weight loss, such as through bariatric surgery, can mitigate this risk. This study aims to conduct a comprehensive systematic review, focusing on the impact of bariatric surgery on breast cancer incidence and characteristics using recent literature. Methods: The systematic review followed PRISMA 2020 standards and examined full-text English literature published between 2014 and 2024. This review excluded editorials, review papers from the same journal, and submissions without a DOI. Literature was sourced from online platforms such as PubMed, SagePub, and SpringerLink. Result: A total of 1,011 articles s were retrieved from online databases (PubMed, SagePub, and SpringerLink). After three rounds of screening, five articles directly relevant to the systematic review were selected for full-text reading and analysis. Conclusion: Bariatric surgery decreases overall cancer risk in women, especially for breast cancer, by lowering estrogen levels and altering tumor biology. It also improves glucose homeostasis and reduces insulin resistance, both linked to higher cancer risk.

Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ

BackgroundImeglimin is a new anti-diabetic drug which promotes insulin secretion from pancreatic β-cells and reduces insulin resistance in insulin target tissues. However, there have been no reports examining the possible anti-atherosclerotic effects of imeglimin. In this study, we investigated the possible anti-atherosclerotic effects of imeglimin using atherosclerosis model ApoE KO mice treated with streptozotocin (STZ).MethodsApoE KO mice were divided into three groups: the first group was a normoglycemic group without injecting STZ (non-DM group, n = 10). In the second group, mice were injected with STZ and treated with 0.5% carboxymethyl cellulose (CMC) (control group, n = 12). In the third group, mice were injected with STZ and treated with imeglimin (200 mg/kg, twice daily oral gavage, n = 12). We observed the mice in the three groups from 10 to 18 weeks of age. Plaque formation in aortic arch and expression levels of various vascular factors in abdominal aorta were evaluated for each group.ResultsImeglimin showed favorable effects on the development of plaque formation in the aortic arch in STZ-induced hyperglycemic ApoE KO mice which was independent of glycemic and lipid control. Migration and proliferation of vascular smooth muscle cells and infiltration of macrophage were observed in atherosclerotic lesions in STZ-induced hyperglycemic ApoE KO mice, however, which were markedly reduced by imeglimin treatment. In addition, imeglimin reduced oxidative stress, inflammation and inflammasome in hyperglycemic ApoE KO mice. Expression levels of macrophage makers were also significantly reduced by imeglimin treatment.ConclusionsImeglimin exerts favorable effects on the development of plaque formation and progression of atherosclerosis.

Isorhamnetin as a potential therapeutic agent for diabetes mellitus through PGK1/AKT activation.

Type 2 Diabetes Mellitus (T2D) is a significant health concern worldwide, necessitating novel therapeutic approaches beyond conventional treatments. To assess isorhamnetin's potential in improving insulin sensitivity and mitigating T2D characteristics through oxidative and glycative stress modulation. T2D was induced in mice with a high-fat diet and streptozotocin injections. Isorhamnetin was administered at 10 mg/kg for 12 weeks. HepG2 cells were used to examine in vitro effects on stress markers and insulin sensitivity. Molecular effects on the PGK1 and AKT signalling pathway were also analyzed. The administration of isorhamnetin significantly impacted both in vivo and in vitro models. In HepG2 cells, oxidative and glycative stresses were markedly reduced, indicating a direct effect of isorhamnetin on cellular stress pathways, which are implicated in the deterioration of insulin sensitivity. Specifically, treated cells showed a notable decrease in markers of oxidative stress, such as malondialdehyde, and advanced glycation end products, highlighting isorhamnetin's antioxidant and antiglycative properties. In vivo, isorhamnetin-treated mice exhibited substantially lower fasting glucose levels compared to untreated T2D mice, suggesting a strong hypoglycemic effect. Moreover, these mice showed improved insulin responsiveness, evidenced by enhanced glucose tolerance and insulin tolerance tests. The molecular investigation revealed that isorhamnetin activated PGK1, leading to the activation of the AKT signalling pathway, crucial for promoting glucose uptake and reducing insulin resistance. This molecular action underscores the potential mechanism through which isorhamnetin exerts its beneficial effects in T2D management. The study underscores isorhamnetin's multifaceted role in T2D management, emphasizing its impact on oxidative and glycative stress reduction and molecular pathways critical for insulin sensitivity. Isorhamnetin presents a promising avenue for T2D treatment, offering a novel approach to enhancing insulin sensitivity and managing glucose levels through the modulation of key molecular pathways. Further research is needed to translate these findings into clinical practice.

A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes

PurposeBreast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy.MethodsWomen with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks.ResultsWithin the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline.ConclusionWFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes.Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

Testosterone therapy reduces insulin resistance in men with adult-onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open-label phase.

To describe changes in homeostasis model assessment of insulin resistance index (HOMA-IR) following testosterone therapy in men with hypogonadism and metabolic syndrome (MetS). A randomized, placebo-controlled, double-blind randomized controlled trial (RCT) comprising 184 men with MetS and hypogonadism (testosterone undecanoate [TU]: 113 men, placebo: 71 men) was conducted. This was followed by an open-label phase in which all men were given TU. We focused on men who were not receiving antiglycaemic agents (TU: 81 men; placebo: 54 men) as these could affect HOMA-IR. Inter-group comparison of HOMA-IR was restricted to the RCT (30 weeks), whilst intra-group comparison was carried out on men provided TU during the RCT and open-label phases (study cohort) and men given placebo during the RCT and then switched to TU during the open-label phase (confirmatory cohort). Regression analysis was performed to identify factors associated with change in HOMA-IR (∆HOMA-IR). The median HOMA-IR was significantly reduced at almost every time point (after 18 weeks) compared to baseline in men receiving TU in both the study and confirmatory cohorts. There was a significant decrease in median values of fasting glucose (30 weeks: -2.1%; 138 weeks: -4.9%) and insulin (30 weeks: -10.5%; 138 weeks: -35.5%) after TU treatment. Placebo was not associated with significant ∆HOMA-IR. The only consistent predictor of HOMA-IR decrease following TU treatment was baseline HOMA-IR (r2 ≥ 0.64). Baseline HOMA-IR predicted ΔHOMA-IR, with a greater percentage change in insulin than in fasting glucose. In men with MetS/type 2 diabetes (T2DM) not on antiglycaemic therapy, improvements in HOMA-IR may be greater than suggested by change in fasting glucose. Our results suggest that hypogonadism screening be included in the management of men with MetS/T2DM.

Resistance Training in Cardiovascular Diseases: A Review on Its Effectiveness in Controlling Risk Factors.

Cardiovascular Disease (CVD), a term encompassing various disorders affecting the heart and blood vessels, includes coronary artery disease (CAD). CAD is primarily due to the development of atherosclerotic plaques that disrupt blood flow, oxygenation, and nutrient delivery to the myocardium. Risk factors contributing to CAD progression include smoking, hypertension, diabetes mellitus (DM), dyslipidaemia, and obesity. While aerobic exercise (AE) has shown promising results in controlling CVD risk factors, the impact of resistance training (RT) has not been extensively investigated. This review aims to describe the effects of RT on CVD risk factors based on studies retrieved from PubMed and Google Scholar databases. Both isometric and isotonic RT have been found to decrease systolic blood pressure (SBP), diastolic blood pressure, or mean arterial pressure, with SBP showing a more significant reduction. Hypertensive patients engaging in RT alongside a calorie-restricted diet demonstrated significant improvements in blood pressure. RT is associated with increased nitric oxide bioavailability, sympathetic modulation, and enhanced endothelial function. In type-2 DM patients, 8-12 weeks of RT led to improvements in fasting blood glucose levels, insulin secretion, metabolic syndrome risk, and glucose transporter numbers. Combining AE with RT had a more significant impact in reducing insulin resistance and enhancing blood glucose compared to performing exercises separately. It also significantly decreased total cholesterol, triglycerides, and low-density lipoprotein levels while increasing high-density lipoprotein within 12 weeks of application. However, improvements are considered insignificant when lipid levels are already low to normal at baseline. The administration of RT resulted in weight loss and improved body mass index, with more pronounced effects seen when combining AE with RT and a calorie-restricted diet. Considering these results, the administration of RT, either alone or in combination with AE, proves beneficial in rehabilitating CAD patients by improving various risk factors.

Comprehensive Atlas of Alternative Splicing Reveals NSRP1 Promoting Adipogenesis through CCDC18.

Alternative splicing (AS) plays a crucial role in regulating gene expression, function, and diversity. However, limited reports exist on the identification and comparison of AS in Eastern and Western pigs. Here, we analyzed 243 transcriptome data from eight tissues, integrating information on transcription factors (TFs), selection signals, splicing factors (SFs), and quantitative trait loci (QTL) to comprehensively study alternative splicing events (ASEs) in pigs. Five ASE types were identified, with Mutually Exclusive Exon (MXE) and Skipped Exon (SE) ASEs being the most prevalent. A significant portion of genes with ASEs (ASGs) showed conservation across all eight tissues (63.21-76.13% per tissue). Differentially alternative splicing genes (DASGs) and differentially expressed genes (DEGs) exhibited tissue specificity, with blood and adipose tissues having more DASGs. Functional enrichment analysis revealed coDASG_DEGs in adipose were enriched in pathways associated with adipose deposition and immune inflammation, while coDASG_DEGs in blood were enriched in pathways related to immune inflammation and metabolism. Adipose deposition in Eastern pigs might be linked to the down-regulation of immune-inflammation-related pathways and reduced insulin resistance. The TFs, selection signals, and SFs appeared to regulate ASEs. Notably, ARID4A (TF), NSRP1 (SF), ANKRD12, IFT74, KIAA2026, CCDC18, NEXN, PPIG, and ROCK1 genes in adipose tissue showed potential regulatory effects on adipose-deposition traits. NSRP1 could promote adipogenesis by regulating alternative splicing and expression of CCDC18. Conducting an in-depth investigation into AS, this study has successfully identified key marker genes essential for pig genetic breeding and the enhancement of meat quality, which will play important roles in promoting the diversity of pork quality and meeting market demand.