Alleviates Insulin Resistance Research Articles

AGDMP1 alleviates insulin resistance by modulating heat shock protein 60-mediated IRS-1/AKT/GLUT4 pathway and adipose inflammation: A potential therapeutic peptide for gestational diabetes mellitus.

Gestational Diabetes Mellitus (GDM) is the most frequent complication during pregnancy. Pharmacological interventions, such as peptide drugs that focused on improving the insulin sensitivity might be promising in the prevention and treatment of GDM. In this study, we aimed to investigate the role and mechanism of a novel peptide, named AGDMP1 (Anti-GDM peptide 1), which we previously identified lower in the serum of GDM patients using mass spectrometry, on the adipose insulin resistance in GDM. We found that AGDMP1 had a high affinity for adipose tissues invivo. AGDMP1 markedly improved glucose homeostasis and insulin resistance in GDM mice. This was associated with reduced inflammation and upregulated AKT/GLUT4 signaling pathway in white adipose tissue. Invitro, AGDMP1 could increase glucose uptake and insulin sensitivity of adipocytes by activating the IRS-1/AKT/GLUT4 signaling pathway under basal, insulin-stimulated, and insulin-resistant conditions, respectively. Mechanistically, we found that AGDMP1 could bind to HSP60 to dampen its effects on AKT signaling and pro-inflammatory response, which was reversed in the present of recombinant HSP60 protein. AGDMP1 ameliorated adipose insulin resistance and inflammation by targeting HSP60 and activating the IRS-1/AKT/GLUT4 signaling pathway. These data supported AGDMP1 with therapeutic potential in GDM and associated pathologies.

Zingiber striolatum phytochemicals ameliorated hyperglycemia symptoms by modulating gut microbial communities in mice with type 2 diabetes mellitus

IntroductionProlonged hyperglycemia caused by type 2 diabetes mellitus (T2DM) can lead to liver injury and disrupt the community of the gut microbiota that pose significant risks to human health. As a food rich in a variety of active ingredients, Zingiber striolatum (Z. striolatum) exhibits hypoglycemic and hypolipidemic effects. However, the regulatory influence of Z. striolatum ethanol extract (ZSE) on the gut microbiota of T2DM mice or its potential relationship with T2DM pathology remains unexplored.MethodsAfter a one-week acclimation period, 12 mice were randomly selected as the normal group. The remaining 48 mice were employed T2DM model, and then randomly assigned to four groups: the model group, a low-dose ZSE group (ZSE-L, 100 mg/kg/day), a high-dose ZSE group (ZSE-H, 300 mg/kg/day), and a positive control group treated with metformin hydrochloride (MET, 100 mg/kg/day).ResultsAfter a 4-week intervention, the results revealed that ZSE significantly ameliorated fasting blood glucose (FBG), area under the curve of oral glucose tolerance test (AUC of OGTT) and glycated serum protein (GSP) in T2DM mice. Moreover, the high-dose (ZSE-H) treatment increased the relative abundance of beneficial bacteria such as Faecalibaculum, while reducing harmful bacteria such as Bilophila, thereby alleviating insulin resistance. Additionally, ZSE-H demonstrated superior efficacy over low-dose (ZSE-L) in improving FBG, AUC of OGTT, and other hypoglycemic parameters. Predictive analysis of the correlation between gut microbiota and hypoglycemic parameters identified Dubosiella, Bacillus, and Mailhella as potential microbial biomarkers for further investigation into the pathogenesis of T2DM.ConclusionZSE plays a pivotal role in mitigating hyperglycemia in T2DM mice through the modulation of intestinal microbiota communities.

Pro-Arg, The Potential Anti-Diabetes Peptide, Screened from Almond by In-Silico Analysis.

Insulin resistance was considered to be the most important clinical phenotype of type 2 diabetes (T2DM). Almond is a widely-consumed nut and long-term intake was beneficial to alleviating insulin resistance in patients with T2DM. Hence, screening of anti-diabetic peptides from almond proteins was feasible based on the effectiveness of peptides in the treatment of T2DM. Pro-Arg (PR), a potential anti-diabetic peptide screened from almonds proteins using in-silico technology and cell experiment, upregulated the phosphorylation levels of IRS1, PI3K, AKT, and translocation of GLUT4, and showed potential to target AKT1 in molecular simulation, suggesting PR mediated the activation of IRS1/PI3K/AKT/GLUT4 signaling pathway by targeting AKT1 to alleviate insulin resistance. Consequently, PR was the potential anti-diabetes peptide from almond proteins and showed the potential application as a candidate drug for alleviating T2DM.

Hawthorn carbon dots: a novel therapeutic agent for modulating body weight and hepatic lipid profiles in high-fat diet-fed mice.

Obesity, a chronic metabolic disorder characterized by excessive body weight and adipose tissue accumulation, is intricately linked to a spectrum of health complications. It is driven by a confluence of factors, including gut microbiota dysbiosis, inflammation, and oxidative stress, which are pivotal in its pathogenesis. A multifaceted therapeutic strategy that targets these interrelated pathways is essential for effective obesity management. In this context, biomass-derived carbon dots have emerged as a promising avenue due to their diverse biological activities and potential in nanomedicine. Our study presents the synthesis of multi-modal hawthorn carbon dots (HCD), employing a green hydrothermal carbonization method that diverged from traditional stir-frying techniques. This eco-friendly approach facilitates the preparation of HCD, emphasizing the role of sugar compounds as the primary carbon source in their formation. In vitro assays demonstrate that HCD possess potent anti-inflammatory and antioxidant properties, which are crucial in combating the oxidative stress and inflammation associated with obesity. We further investigate the impact of HCD intervention in a high-fat diet (HFD)-induced obesity mouse model, employing both post-modeling and simultaneous modeling administration strategies. Our findings reveal that HCD treatment significantly reduces body weight and hepatic lipid accumulation in HFD mice, concurrently enhancing glucose tolerance and alleviating insulin resistance. Moreover, antibiotic perturbation experiments, complemented by bioinformatics analysis of colon microbiota, indicate that HCD substantially modulate gut microbiota composition. This modulation is associated with the amelioration of obesity-related conditions, suggesting that HCD may exert their beneficial effects through the regulation of gut microbiota, in addition to their anti-inflammatory and antioxidant activities. These multimodal mechanisms of action position HCD as a promising candidate for the prevention and treatment of obesity, offering a novel therapeutic strategy that targets the complex interplay of factors involved in this metabolic disorder.

Citronellal Alleviates Insulin Resistance in High-Fat Diet/Streptozocin Model: Role of Asprosin/Olfactory Receptor Axis.

Ectopic olfactory receptors are expressed in nonolfactory tissues and perform diverse roles including regulation of glucose homeostasis. We explored the effect of citronellal treatment on olfactory receptor 4M1 subtype (OR4M1) signaling in insulin resistance and Type II diabetes in rats. We aimed to validate the anti-diabetic effect of citronellal through Asprosin/OR4M1 modulation. Exploring new antidiabetics and pharmacological targets is important to improve quality of life and limit complications. The model was established in Sprague-Dawley rats by a high-fat diet for 4weeks followed by a single low-dose streptozotocin (STZ) (35 mg/kg/ip). One week after STZ injection, oral citronellal (100mg/kg) was administered for 4weeks. Citronellal lowered serum glucose and triglycerides and ameliorated OGTT and HOMA-IR results. Docking results revealed that citronellal blocked the Asprosin binding site at OR4M1. The hepatic expression of OR4M1 and Asprosin was reduced. Citronellal lowered cAMP levels causing attenuated levels of protein kinase A and downstream gluconeogenic enzymes: glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Citronellal also inhibited the expression of hepatic TLR-4 and inhibited JNK phosphorylation. Citronellal attenuated hepatic levels of NF-κB, p-NF-κB, and downstream proteins MCP-1 and TNF-α. These results suggest that citronellal alleviates insulin resistance by mitigating Asprosin/OR4M1 and Asprosin/TLR4/JNK signaling.

Exploration of the Fasting Hypoglycemic Mechanism of Casein Hydrolysate Enriched with Glu/Gln and Glu/Gln-Containing Peptides in db/db Diabetic-like Mice Using Multiomics Analysis.

The fasting hypoglycemic effect of casein hydrolysate (CH) was investigated in db/db diabetic-like mice using a multiomics integrated analysis of peptidome, transcriptome, and metabolome. Results showed that the oral administration of CH at a dose of 600 mg/kg/day for 4 weeks reduced the fasting blood glucose levels by 14.73 ± 9.77%, alleviated insulin resistance (HOMA-IR index) by 36.91 ± 22.62%, and mitigated hepatic damage in db/db diabetic-like mice. Hepatic differential metabolites after CH treatment were enriched in Glu-related metabolites, which acted as substrates for the TCA cycle, enhancing hepatic glucose consumption. The hepatic transcriptomic results revealed that CH treatment upregulated (p < 0.05) hub gene expressions of pparg and pik3cb, leading to an activation of the PPAR signaling pathway, further improving the insulin/PI3K/AKT signaling pathway. The hub gene expressions were highly correlated with Glu-related metabolites in multiomics integrated analysis. Glx/Glx-containing peptides (Glx represents Glu and Gln) in CH, as a dietary supplement to increase hepatic Glu-related metabolites, might be the key active component responsible for its hypoglycemic effect. Particularly, the supplement of Glx was confirmed to effectively (p < 0.05) enhance glucose consumption in hepatocytes. This provides a basis for the development of CHs as functional food.

Loss of DDB2 in type II diabetes mellitus induces dysregulated ubiquitination of KMT2A in lipid metabolism disorders.

The disorders of glucose and lipid metabolism contribute to severe diseases, including cardiovascular disease, diabetes, and fatty liver. Here, we identified DNA damage-binding protein 2 (DDB2), an E3 ubiquitin ligase, as a pivotal regulator of lipid metabolism disorders in type II diabetes mellitus (T2DM). A mouse model of T2DM and primary mouse hepatocytes with steatosis were induced. DDB2 overexpression alone or in combination with lysine N-methyltransferase 2A (KMT2A) overexpression vectors were delivered into db/db mice and in vitro hepatocytes. DDB2 was expressed highly, while KMT2A was expressed poorly in liver tissues and primary hepatocytes of db/db mice. DDB2 ameliorated glucose intolerance and insulin resistance, decreased liver/body weight ratio, downregulated expression of lipogenesis-associated proteins (SREBP1, FASN, and SCD1) and gluconeogenesis-related proteins (PEPCK and G6Pase) in liver tissues and cells, and decreased triglyceride and total cholesterol levels in steatotic hepatocytes. DDB2 reduced KMT2A expression through ubiquitination modification. Overexpression of KMT2A promoted glucose intolerance, and alleviated insulin resistance, while promoting lipogenesis and lipid deposition, inhibiting glycogen accumulation in the presence of DDB2. Overall, our data demonstrate that DDB2 alleviates hepatic lipogenesis and lipid deposition via degradation of KMT2A, thereby repressing lipid metabolism disorders in T2DM.

Lactiplantibacillus plantarum N1 derived lipoteichoic acid alleviates insulin resistance in association with modulation of the gut microbiota and amino acid metabolism.

This study aimed to investigate the effects of heat-killed Lactiplantibacillus plantarum N1 (HK-N1) and lipoteichoic acid (LTA) derived from it on alleviating insulin resistance by modulating the gut microbiota and amino acid metabolism. High-fat diet (HFD)-fed mice were administered live bacteria or HK-N1, and the results demonstrated that HK-N1 significantly reduced epididymal adipocyte size and serum low density lipoprotein-cholesterol, and improved insulin resistance by increasing the YY peptide and glucagon-like peptide levels. HK-N1 also modulated the gut microbiome composition, enhancing microbiota uniformity and reducing the abundance of Ruminococcus, Oscillospira and norank_f_Mogibacteriaceae. Three main active substances obtained from HK-N1 (membrane protein, peptidoglycan, and lipoteichoic acid) were also used to investigate their potential effects in hyperglycemic zebrafish. Only LTA reduced blood sugar and altered the gut microbiome, particularly reducing Aeromonas, which is positively related to hyperglycemia. Untargeted metabolomics revealed that LTA improved vitamin and amino acid metabolism, thereby alleviating metabolic disorders in zebrafish. Collectively, our findings indicate that HK-N1, primarily through LTA, modulated insulin sensitivity by regulating the gut microbiota and amino acid metabolism, offering a potential therapeutic strategy for insulin resistance and type 2 diabetes mellitus.

Sea cucumber intestinal hydrolysates alleviate insulin resistance through regulating IRS1/PI3K/AKT signaling pathway mediated by glutamine metabolism in high-fat and high-sucrose diet-induced mice

Sea cucumber intestinal hydrolysates alleviate insulin resistance through regulating IRS1/PI3K/AKT signaling pathway mediated by glutamine metabolism in high-fat and high-sucrose diet-induced mice

Camel milk and D-allulose synergistically improved camel dairy flavor and alleviated insulin resistance of human HepG2 cells

Camel milk and D-allulose synergistically improved camel dairy flavor and alleviated insulin resistance of human HepG2 cells

Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives.

Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC50 value of 1.061±0.202μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.

Polyethylene glycol loxenatide modulates lipid metabolism and insulin resistance through lncRNA steroid receptor RNA activator/cellular nucleic acid binding protein/Rho-associated coiled-coil kinase 2 axis in type 2 diabetes mellitus.

Polyethylene glycol loxenatide (PEG-Loxe) is applied in treating type 2 diabetes mellitus. Nevertheless, the effect and mechanism of PEG-Loxe on lipid metabolism disorder and insulin resistance in type 2 diabetes mellitus are not fully understood. Type 2 diabetes mellitus rats developed by high-fat diet/streptozotocin injection were treated with PEG-Loxe (0.3 or 1 mg/kg). Insulin resistance was evaluated by fasting blood glucose (FBG), oral glucose tolerance test, fasting insulin, homeostasis model of assessment for insulin resistance and for insulin sensitivity. Immunohistochemistry, hematoxylin and eosin staining, and biochemistry measurements were performed to assess lipid metabolism. Inflammatory response and oxidative stress were assessed by inflammatory cytokines and reactive oxygen species. Genes' expressions were tested using RT-qPCR, western blot, and in situ hybridization. Relationships of molecules were validated by pull-down assay and RNA immunoprecipitation. mRNA stability was examined by actinomycin D assay. High-PEG-Loxe decreased FBG and ameliorated glucose tolerance, hyperinsulinemia, and insulin resistance. Low-PEG-Loxe partly while high-PEG-Loxe apparently relieved hepatocyte injury, reduced lipase I, triglyceride, total cholesterol and leptin, and increased adiponectin in type 2 diabetes mellitus rats. PEG-Loxe mitigated inflammatory response and oxidative stress. High-PEG-Loxe reduced RhoA and Rho-associated coiled-coil kinase 2 (ROCK2) in liver tissues of type 2 diabetes mellitus rats, while both doses of PEG-Loxe decreased steroid receptor RNA activator (SRA). SRA overexpression reversed the protective functions of high-PEG-Loxe. SRA cooperated with cellular nucleic acid binding protein (CNBP) to enhance ROCK2 mRNA stability. High-PEG-Loxe relieves insulin resistance and lipid metabolism disorder in type 2 diabetes mellitus through SRA/CNBP/ROCK2 axis. This research provides a molecular mechanism of PEG-Loxe for treating type 2 diabetes mellitus.

Single-cell view and a novel protective macrophage subset in perivascular adipose tissue in T2DM

BackgroundVasculopathy underlies diabetic complications, with perivascular adipose tissue (PVAT) playing crucial roles in its development. However, the changes in the cellular composition and function of PVAT, including the specific cell subsets and mechanisms implicated in type 2 diabetes mellitus (T2DM) vasculopathy, remain unclear.MethodsTo address the above issues, we performed single-cell RNA sequencing on the stromal vascular fraction (SVF) of PVAT from normal and T2DM rats. Then, various bioinformatics tools and functional experiments were used to investigate the characteristic changes in the cellular profile of diabetic PVAT SVF, their implications, and the underlying mechanisms.ResultsOur study reveals the single-cell landscape of the SVF of PVAT, demonstrating its considerable heterogeneity and significant alterations in T2DM, including an enhanced inflammatory response and elevated proportions of macrophages and natural killer (NK) cells. Moreover, macrophages are critical hubs for cross-talk among various cell populations. Notably, we identified a decreased Pdpn+ macrophage subpopulation in the PVAT of T2DM rats and confirmed this in mice and humans. In vitro and in vivo studies demonstrated that Pdpn+ macrophages alleviated insulin resistance and modulated adipokine/cytokine expression in adipocytes via the Pla2g2d-DHA/EPA-GPR120 pathway. This subset also enhances the function of vascular endothelial and smooth muscle cells, inhibits vascular inflammation and oxidative stress, and improves vasodilatory function, thereby protecting blood vessels.ConclusionPdpn+ macrophages exhibit significant vascular protective effects by alleviating insulin resistance and modulating adipokine/cytokine expression in PVAT adipocytes. This macrophage subtype may therefore play pivotal roles in mitigating vascular complications in T2DM. Our findings also underscore the critical role of immune-metabolic cross-talk in maintaining tissue homeostasis.Graphical

Study on the mechanism on Yi-guan-jian decoction alleviating cognitive dysfunction in type 2 diabetes mellitus.

Yi-guan-jian decoction (YGJ) is a traditional Chinese medicine prescription commonly used for treating syndromes associated with Yin deficiency in the liver and kidney, as well as Qi-obstructed in liver. YGJ has shown potential alleviating cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the precise mechanisms are not yet fully understood. This study aims to reveal the mechanism by which YGJ alleviates cognitive dysfunction in T2DM. Various doses of YGJ were administered to T2DM rats with cognitive dysfunction for 8 weeks. The positive control group received a combination of metformin and memantine. Cognitive function was assessed in T2DM rats using the Morris water maze test during treatment. Changes in gut microbiota and bile acids in the intestine were evaluated, and their interactions analyzed. Additionally, this study also evaluated the expressions of inflammatory markers (IL-1β,TNF-α, IL-16, IL-18 and CRP protein), Tau protein, neurotransmitter (5-HT and GABA), and bile acid receptor (FXR, PXR, VDR, and TGR5). YGJ significantly alleviated insulin resistance and hyperlipidemia, reduce the levels of inflammatory factors in serum and hippocampus, and decreased mortality in T2DM rats. The Morris water maze test indicated that YGJ reduced the escape latency and increased platform crossing frequency, thereby improving cognitive function in T2DM rats. Furthermore, YGJ regulated the abundance of microorganisms associated with bile acid metabolism, including Romboutsia, Bacteroides, Turicibacter, Blautia, and Ruminococcus, thus regulating bile acid metabolism in T2DM rats. Additionally, YGJ also regulated bile acid metabolism by regulating intestinal FXR, PXR, VDR and TRG5 receptors. YGJ can alleviate glucose homeostasis, insulin sensitivity, lipid metabolism, neuroinflammation, cognitive function, as well as remodel intestinal flora and BA composition in CDT2DM rats, which is a potential complementary and alternative therapy for the prevention and treatment of CDT2DM. These effects may be associated that YGJ regulates the structure of intestinal flora and BA metabolism, and inhibits intestinal BA receptors FXR, PXR, TGR5, and VDR.

Effects of Tangduqing Granules on Insulin Resistance and Their Association with AhR and PPARs Regulation in Type 2 Diabetic Rats Exposed to Persistent Organic Pollutants

Objectives Tang Du Qing granules, a traditional Chinese medicine for diabetes, may alleviate insulin resistance induced by persistent organic pollutant exposure. This study aims to explore the mechanism by which Tang Du Qing granules improve insulin resistance in rats exposed to PCB126. Methods Male ZDF (fa/fa) rats were divided into a PCB126-exposed group and a model control group. Male ZDF (fa/+) rats served as the normal control group. Normal controls received a regular diet with olive oil via gavage, while the model control group received special feed with olive oil. PCB126 group received special feed with PCB126 in olive oil for 8 weeks. Post-exposure, the positive drug treatment group received CH223191, and Tang Du Qing granules were administered at high, medium, and low doses for 4 weeks. Relevant biochemical indicators and molecular signaling changes were assessed. Results PCB126 exposure increased levels of FBG, FINS, HOMA-IR and elevated serum TG, TC, and FFA in ZDF (fa/fa) rats compared to the model control group ( P &lt; .05). The Tang Du Qing-treated group showed decreased FBG, FINS, HOMA-IR levels, and reduced serum TC, TG, and FFA compared to PCB126-exposed control group ( P &lt; .05). Additionally, the Tang Du Qing-treated group downregulated hepatic AhR, CD36, and TNFα expression, while upregulating PPARα, PPARγ, GLUT4, and FGF21 expression ( P &lt; .05). Conclusion Tang Du Qing granules ameliorate glucose and lipid toxicity and insulin resistance induced by PCB126 exposure in ZDF (fa/fa) rats by modulating the imbalance between AhR and PPARs and related molecular signals.

The therapeutic effects of curcumin on polycystic ovary syndrome by upregulating PPAR-γ expression and reducing oxidative stress in a rat model.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder that impacts 8-13% of women in their reproductive years. However, the drugs commonly used to treat PCOS are often prescribed off-label and may carry potential side effects. This study aimed to investigate the therapeutic effects of curcumin in a PCOS rat model. A PCOS rat model was established through daily subcutaneous injection of 60 mg/kg body weight of dehydroepiandrosterone (DHEA) for 21 days. The PCOS rats received a daily intragastric dose of 50 mg/kg body weight of curcumin for another 21 days. Ovarian morphological changes, estrous cycle changes, and hormone level changes were measured to evaluate the therapeutic effectiveness of curcumin in PCOS rats. Oxidative stress markers in the ovaries were analyzed to explore the mechanisms of curcumin in PCOS rats. This study demonstrated that curcumin alleviated insulin resistance and significantly reduced serum levels of estradiol (p = 0.02), luteinizing hormone (p = 0.009), testosterone (p = 0.003), and the LH/FSH ratio (p = 0.008) in PCOS rats. Curcumin also restored normal ovarian morphology and the estrous cycle in these rats. Furthermore, curcumin treatment significantly decreased levels of oxidative stress markers, including malondialdehyde (p = 0.004) and reactive oxygen species (p = 0.005), while increasing antioxidant levels such as superoxide dismutase (p = 0.04), glutathione peroxidase (p = 0.002), and glutathione (p = 0.02) in ovarian tissues. Additionally, curcumin significantly upregulated PPAR-γ in the ovarian tissues of PCOS rats. This study demonstrates that curcumin effectively restores ovarian morphology, hormone levels, and estrous cycles in PCOS rats. These effects may be linked to its ability to reduce oxidative stress in ovaries via the upregulation of PPAR-γ. Curcumin shows promise as a potential drug for the treatment of PCOS.

Improvement effect of insulin resistance in one-day outpatient service by reducing stress adaptation disorders in patients with gestational diabetes mellitus.

Conducted a one-day outpatient service for GDM patients, analyzed the relationship between stress adaptation disorder and insulin resistance in GDM patients after intervention, and tried to provide some new clues for the prevention and treatment of GDM, provide some theoretical basis for the multidisciplinary diagnosis and treatment model of GDM patients. 240 GDM women were included in this study, 120 women were included in one-day diabetes clinic management for GDM women as GDM Intervention Group, and 120 GDM women receiving regular dietary education as GDM Control Group. One-day diabetes clinic management including disease knowledge and dietary education, sports education and blood sugar monitoring and personalized issues and follow-up visits, and intervention time lasting for 1 month. After intervention, the concentration of 2-h postprandial blood glucose, and HOMA-IR were decreased in GDM Intervention Group, while weekly weight gain rate and insulin application rate were significantly lower than GDM Control Group (all p < 0.05). Cortisol and MDA in GDM Intervention Group were significantly lower than GDM Control Group (both p < 0.01). HOMA-IR was positively correlated with weight gain, E, NE and cortisol (r = 0.249, 0.242, 0.663, 0.313, all p < 0.01), E and HOMA-IR were negatively correlated with SOD in GDM Intervention Group (r = -0.306, -0.213, both p < 0.01). The intervention model in our study was based on the one-day outpatient comprehensive management model of diabetes, which improved the insulin resistance of GDM patients. The possible mechanism was related to the implementation of one-day outpatient intervention measures, which reduced the stress adaptation disorder and oxidative stress injury of GDM patients. At the same time, the implementation of intervention measures reduced the rate of weight gain, which can also alleviate insulin resistance to a certain extent. One-day outpatient treatment has a positive effect on improving insulin resistance in GDM women, which can reduce the risk of maternal and fetal complications.

Lactobacillus murinus alleviates insulin resistance via promoting L-citrulline synthesis.

The role of Lactobacillus murinus as a potential probiotic is being explored. Our objectives were to explore the effects of Lactobacillus murinus on insulin resistance and the underlying mechanism. Insulin resistance animal models were applied to study the effect of L. murinus and the underlying mechanism by six weeks of treatment. Metformin was administered in vitro to analyze the growth and metabolites of L. murinus. Serum metabolites were further analyzed after L. murinus administration. The effect of L-citrulline and the underlying mechanism in alleviating insulin resistance were evaluated. L. murinus not only reduced body weight gain and postprandial blood glucose (PBG) but improved impaired glucose tolerance (IGT) and insulin resistance. Moreover, L. murinus inhibited the secretion of pro-inflammatory factors (IL-1β, IL-6 and TNF-α) while promoted the secretion of anti-inflammatory factor (IL-10). Further, L. murinus promoted the expression of carnitine palmitoyl transferase 1 (CPT1) while inhibited phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase (G6Pase). A total of 147 metabolites of L. murinus were identified, in which the content of L-citrulline increased to 7.94 times after metformin regulation. Further, the serum concentration of L-citrulline significantly increased after L. murinus administration. Similarly, L-citrulline reduced body weight gain and PBG, improved IGT and insulin resistance. Additionally, L-citrulline improved inflammation, promoted CPT1 while inhibited PCK and G6Pase. L. murinus mediated by L-citrulline alleviated insulin resistance via promoting fatty acid oxidation and inhibiting gluconeogenesis, suggesting that supplementation of L. murinus could be a potential therapeutic approach for type 2 diabetes related to insulin resistance.

Chaihu Shugan powder restores fatty acid synthesis to alleviate insulin resistance in metabolic syndrome by regulating the LXRα/SREBP-1 signaling pathway.

Metabolic syndrome (MS) is a significant risk factor for cardiovascular and cerebrovascular diseases, primarily driven by insulin resistance (IR). Although the herbal compound Chaihu Shugan powder (CSP) has demonstrated the potential to improve IR in animal models of MS, its mechanism of action remains incompletely understood. Therefore, this study aimed to investigate the biological pathways through which CSP exerts its therapeutic effects on IR in MS using both in vitro and in vivo methods. The primary metabolites of CSP aqueous extract and CSP-containing serum were measured by LC-MS/MS. A mouse model of MS-related IR was induced by a high-fat, high-fructose diet combined with chronic immobilization stress. The CSP's therapeutic potential was evaluated through glucose and insulin tolerance tests and hepatic insulin signaling molecules (p-IRS-1, IRS-1, p-Akt, and Akt). The expression of lipid metabolism-related factors (FFA, DAG, LXRα, SREBP-1, FASN, and ACC) in the liver was also measured. Hepatocyte IR was modeled using high-glucose and high-insulin conditions, and CSP impact was evaluated using 2-NBDG uptake and insulin signaling molecule expression. The specific mechanism of CSP was explored using the LXRα agonist T0901317. The MS-related IR model exhibited a decreased p-Akt/Akt ratio and increased fasting glucose, insulin, homeostatic model assessment of IR, and hepatic lipid metabolism factors. Treatment with CSP mitigated these effects. In the hepatocyte IR model, CSP-containing serum improved glucose uptake and modulated the expression of insulin signaling and lipid metabolism factors. Furthermore, T0901317 reversed the beneficial effects of CSP, indicating the role of LXRα in CSP's therapeutic action. The CSP ameliorated IR in MS by restoring fatty acid metabolism through the regulation of the LXRα/SREBP-1 signaling pathway.

Circ-ADAM9 Knockdown Reduces Insulin Resistance and Placental Injury in Diabetic Mice via MAPK Pathway Inactivation.

Gestational diabetes mellitus (GDM) significantly risks maternal and neonatal health. Circular RNAs (circRNAs) regulate various diseases but their role in GDM is unclear. We investigated the involvement of circ-ADAM9 in GDM. We analyzed circ-ADAM9 expression in GDM-related microarray data (GSE182737) and measured its levels in the blood of GDM patients. In a high-fat diet-induced GDM mouse model, we inhibited circ-ADAM9 expression and tracked blood glucose levels, serum insulin, lipid levels, placental apoptosis, and reactive oxygen species (ROS) levels. Pathological changes in pancreatic tissues and fetal outcomes were also examined. Molecular interactions were explored using bioinformatics tools and validated through luciferase assays, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting in high glucose (HG)-induced human trophoblast cells (HTR-8/SVneo). We further investigated the involvement of circ-ADAM9/miR-375/FPR2 axis in HG-induced injury in HTR-8/SVneo cells by assessing cell viability, apoptosis, ROS production, and antioxidant levels. Both GDM patients and GDM-induced mice exhibited a substantial upregulation of circ-ADAM9. Knockdown of circ-ADAM9 lowered blood glucose, alleviated insulin resistance, improved lipid metabolism, decreased placental apoptosis and ROS levels, and reduced pancreatic lesions in GDM mice. Circ-ADAM9 downregulation also improved fetal viability, weight, and crown-rump length. In HG-induced HTR-8/SVneo cells, circ-ADAM9 overexpression and miR-375 downregulation were evident. Overexpression of miR-375 inhibited circ-ADAM9 activity, substantiating their binding interaction. In GDM mice, circ-ADAM9 deficiency restored miR-375 expression. TargetScanHuman predicted and luciferase assays confirmed the miR-375-FPR2 interaction and elevated FPR2 levels in GDM mice were reduced by circ-ADAM9 silencing. In HG-induced HTR-8/SVneo cells, circ-ADAM9 knockdown restored cell viability, suppressed apoptosis and ROS levels, and enhanced antioxidant enzyme levels. These effects were reversed by miR-375 inhibition or FPR2 overexpression, suggesting circ-ADAM9 upregulates FPR2 expression by sponging miR-375 and modulating the MAPK pathway. This study is the first to demonstrate the expression and function of circ-ADAM9 in the progression of GDM. Circ-ADAM9 downregulation ameliorates insulin resistance and placental injury in GDM by modulating the miR-375/FPR2 axis and inactivating the MAPK pathway, which may offer a novel therapeutic target for the treatment of GDM.