Model Of Insulin Resistance Research Articles

Oxalis erythrorhiza Gillies ex Hooker et Arnott (Oxalidaceae): Chemical Analysis, Biological In Vitro and In Vivo Properties and Behavioral Effects

In this work, a decoction (DOe) and a methanolic global extract (MGEOe), obtained with the aerial parts of Oxalis erythrorhiza Gillies ex Hooker et Arnott (Oxalidaceae), were evaluated. The high-resolution liquid chromatography in conjunction with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) analysis showed forty compounds in MGEOe and twenty-nine in DOe, including flavones, C-glycosyl flavones, isoflavones, fatty acids, terpenes, phenolic acids, and sterols. The antioxidant properties were evaluated by DPPH, TEAC, FRAP, and ILP assays. Both DOe and MGEOe showed stronger antioxidant activities. The anti-inflammatory effects were evaluated by COX inhibition method, where DOe demonstrated a significant inhibitory effect. The cytotoxic effects were evaluated in the tumoral HCT-116 and non-tumoral HBL-100 cell lines, revealing a selective action from DOe and MGOe on cancer cells. DOe was evaluated in an animal model of insulin resistance, which is characterized by alterations in glucose and lipid metabolism, as well as cognitive impairments, including anxiety-like behavior and memory deficits. Male SD rats received sucrose (10% w/v, SUC), a half dilution of DOe (5% w/v) with sucrose (HDOeS) or DOe with sucrose (DOeS) from PND21 to PND61. Then, anxiety-like behavior and spatial memory were assessed using the open field (OF), elevated plus maze (EPM) and the novel object location (NOL) tests, respectively. Serum parameters basal glycemia, total cholesterol (TC) and tryglicerides were measured using commercial kits. The lipid peroxidation was determined in homogenates of cerebral cortex, hippocampus and hypothalamus by TBAR assay. Only HDOeS exhibited lower anxiety-like behavior in OF and improved performance in NOL compared to SUC. Furthermore, DOeS showed reduced serum parameters, while HDOeS presented lower TC levels than SUC. No differences were observed on TBAR assay. The beneficial properties of these preparations could be attributed to the identified metabolites. These findings highlighted O. erythrorhiza as a potential source of compounds to improve human health; however, further research is required to elucidate its mechanisms of action.

Flavonoids from Ougan (Citrus suavissima Hort. ex Tanaka) peel exert hypoglycemic potency through inhibiting insulin resistance in HepG2 cells and regulating gut microbiota in diabetic mice

To fully and value-addedly utilize the citrus peel resource, flavonoids were extracted and purified from peel powder of Ougan (Citrus suavissima Hort. ex Tanaka) using an ultrasonic assisted ethanol solution extraction method and AB-8 macroporous resin purification. The obtained flavonoid extract from peel of Ougan (FEPO) was used for the hypoglycemic experiments in vitro and in vivo on glucose consumption in insulin resistance model HepG2 cells and streptozotocin induced diabetes model mice. A significant reduction of glucose consumption in the model cells while a significant increase in the treated were found in a dose-dependent manner, compared to 5.2241 ± 0.2201 mmol/L of the normal cells (P < 0.05). When the FEPO concentration was 80 μg/mL, the cell glucose consumption was 4.4055 ± 0.1772 mmol/L. Compared with those in the model group (diabetic mice), the fasting blood glucose in the FEPO intervened mice was significantly decreased (P < 0.05). FEPO intervention caused decreased levels of TC, TG, LDL-C, and increased HDL-C and insulin contents in the serums as well as ameliorative histopathology of the liver, kidney, and pancreas in diabetic mice. FEPO improved the gut microbiota structure of diabetic mouse by regulating its composition, especially significantly increasing the relative abundance of Lactobacillus, Ileibacterium, unclassified_f_Lachnospiracea, Romboutsia, norank_f_Muribaculaceae, Faecalibaculum and Coriobacteriaceae_UCG-002 (P < 0.05), while decreasing that of norank_f_norank_o_Clostridia_UCG-014, Lachnospiraceae_NK4A136_group and Candidatus_Saccharimonas. In conclusion, FEPO had good hypoglycemic efficacies both in vitro and in vivo as well as gut microbiota regulating effect.

Donepezil improves skeletal muscle insulin resistance in obese mice via the AMPK/FGF21-mediated suppression of inflammation and ferroptosis.

Donepezil has traditionally been used in Alzheimer's disease treatment and is known for its ability to alleviate neural inflammation and apoptosis. However, its impact on insulin signaling remains unexplored. This study sought to elucidate the novel role of donepezil in mitigating skeletal muscle insulin resistance under hyperlipidemic conditions. Western blot analysis was used to assess the expression of various proteins of interest, whereas a glucose uptake assay was performed in skeletal muscle cells via commercially available kits. An in vitro model of obesity was developed using palmitate. These in vitro findings were corroborated in vivo via insulin resistance models established through high-fat diet (HFD) feeding in mice. Intraperitoneal glucose tolerance tests and insulin tolerance tests were performed on the experimental mice. The results revealed that donepezil treatment improved insulin signaling and inflammation in palmitate-treated C2C12 myocytes and the skeletal muscle of HFD-fed mice. Notably, donepezil treatment augmented FGF21 expression and AMPK phosphorylation in the myocytes and skeletal muscle of HFD-fed mice. Knockdown of FGF21 or AMPK via siRNA reversed the effects of donepezil on insulin signaling and inflammation in cultured myocytes. We also found that donepezil ameliorated skeletal muscle insulin resistance via the FGF21-mediated suppression of ferroptosis under hyperlipidemic conditions. These findings suggest that donepezil enhances the FGF21/AMPK axis, thereby mitigating inflammation and insulin resistance in skeletal muscle. This study introduces a novel therapeutic approach for treating Alzheimer's disease patients with insulin resistance.

Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end stage kidney failure worldwide, of which cellular insulin resistance is a major driver. Here, we study key human kidney cell types implicated in DKD (podocytes, glomerular endothelial, mesangial and proximal tubular cells) in insulin sensitive and resistant conditions, and perform simultaneous transcriptomics and proteomics for integrated analysis. Our data is further compared with bulk- and single-cell transcriptomic kidney biopsy data from early- and advanced-stage DKD patient cohorts. We identify several consistent changes (individual genes, proteins, and molecular pathways) occurring across all insulin-resistant kidney cell types, together with cell-line-specific changes occurring in response to insulin resistance, which are replicated in DKD biopsies. This study provides a rich data resource to direct future studies in elucidating underlying kidney signalling pathways and potential therapeutic targets in DKD.

Butyrate-Mediated Modulation of Paraoxonase-1 Alleviates Cardiorenometabolic Abnormalities in a Rat Model of Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) has been associated with cardiovascular risks and comorbid pathologies, particularly cardiorenal disorder. Short-chain fatty acids (SCFAs), especially butyrate, are essential fatty acids that regulate metabolic health and ameliorate granulosa inflammation in PCOS. However, the effect of butyrate on cardiorenal damage associated with PCOS is unknown. This study investigated the impact of SCFA and butyrate on cardiorenal abnormalities in PCOS rat model and the probable involvement of paraoxonase-1 (PON-1). Eight-week-old female Wistar rats were allotted into three groups, n = 5, namely control (CTL), PCOS (LEZ), and LEZ + BUT. Induction of PCOS with letrozole (1mg/kg) lasted for 21days, while treatment with butyrate (200mg/kg) commenced after the induction and lasted for 6weeks uninterruptedly. PCOS rats showed hyperandrogenism, multiple ovarian cysts, disrupted metabolic indices (fasting insulin and homeostatic model of insulin resistance), and increased (p < 0.05) plasma troponin T, urea, and creatinine, as well as increased cardiac/renal stroma cell-derived factor-1/caspase-6, malondialdehyde/nuclear factor-kappaB, transforming growth factor-β1, and renal ϒ-glutamyl transferase, while a significant decrease (p < 0.05) in systemic nitric oxide/endothelial nitric oxide synthase and cardiac/renal hypoxia-inducible factor-1α and nuclear factor erythroid 2-related factor 2, which were accompanied with a decreased level of PON-1. These systemic and cardiorenal derangements were reversed by butyrate administration. The results demonstrate the therapeutic benefits of SCFAs, butyrate, against cardiorenometabolic disorder in a model of PCOS. This beneficial effect is accompanied by an elevated level of PON-1. The present data possibly provides a preclinical relevance for the management of cardiorenal syndrome in PCOS.

Exploring the impact of caloric restriction on molecular mechanisms of liver damage induced by sucrose intake in the drinking water.

A positive association has been demonstrated between consumption of sucrose-sweetened beverages and the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Since the administration of 30 % sucrose in the drinking water (sucrose-rich diet (SRD)) to rats has proven to be a good model of systemic insulin resistance, the aim of our study was to analyse the effect of caloric restriction applied on SRD-treated rats by switching back to a standard diet, on liver morphology, function and metabolism. Consumption of an SRD causes a metabolic shift towards gluconeogenesis and fatty acid synthesis leading to an increase in TAG levels in plasma and in the liver that were associated with a decrease in insulin sensitivity. Moreover, our results show that animals fed an SRD develop steatohepatitis characterised by the generation of oxidative stress, endoplasmic reticulum (ER) stress, inflammation and apoptosis. Although no histological changes were observed after a 2-week caloric restriction, key pathways associated with the progression of MASLD as inflammation, ER stress and apoptosis were slowed down. Notably, this 2-week intervention also increased liver insulin sensitivity (evaluated by AKT activity in this tissue) and drove the lipid metabolic profile towards oxidation, thus lowering circulating TAG levels. In summary, the present study uncovers underlying mechanisms affected, and their metabolic consequences, during the first stages of the phenotypic reversal of steatohepatitis by switching back to a standard diet after receiving sucrose-sweetened water for several weeks.

Linarin Identified as a Bioactive Compound of Lycii Cortex Ameliorates Insulin Resistance and Inflammation Through the c-FOS/ARG2 Signaling Axis.

Insulin resistance (IR) is a central pathophysiological process underlying numerous chronic metabolic disorders, including type 2 diabetes and obesity. Lycii Cortex, a widely used traditional Chinese herb, has demonstrated potential benefits in preventing and managing diabetes and IR. Whereas, the specific bioactive compounds responsible for these protective effects and their underlying mechanisms of action remain elusive. This study aimed to identify the bioactive components within Lycii Cortex that contribute to its anti-diabetic effects and to elucidate the molecular mechanisms underlying its beneficial actions on insulin resistance. Network pharmacology and molecular docking analyses were employed to identify the potential active compounds in Lycii Cortex and their corresponding target proteins. An invitro model of IR was established using palmitic acid (PA)-treated HepG2 cells. Cell viability was assessed using the CCK-8 assay, while glucose uptake was evaluated by 2-NBDG staining and extracellular glucose measurement. To validate the invitro findings, an invivo model of obesity-induced IR was established using high-fat diet (HFD)-fed mice. The network pharmacology analysis preliminarily identified 13 candidate chemicals and 10 hub LyC and IR-related genes (LIRRGs). Molecular docking analysis demonstrates that Linarin as the potential active component exhibits the greatest potential to target c-FOS for preventing obesity-induced IR. Enrichment analysis suggested that Linarin-targeted pathways are correlated with inflammation. Invitro experimental validation demonstrated that Linarin was capable of protecting against PA-induced IR in HepG2 cells evidenced by improving glucose uptake ability and reducing extracellular glucose content. Additionally, we found that Linarin ablated PA-induced increase in the expression of c-FOS and inflammatory cytokines. Furthermore, in PA-treated cells, silencing c-FOS markedly improved glucose consumption, and reduced inflammation and Arginase 2 (ARG2) expression. Similarly, as exposure to PA, silencing ARG2 also ameliorated glucose uptake and inflammation, while not affecting c-FOS expression. Invivo experiments further showed that Linarin administration remarkably improved glucose tolerance and insulin sensitivity, and reduced the fat mass and body weight in HFD-induced obese mice. In this study, Linarin has been identified as the bioactive compound of Lycii Cortex to ameliorate obesity-related IR and inflammation through the c-FOS/ARG2 signaling cascade. These findings underscore the therapeutic potential of Linarin and provide valuable insights into developing novel intervention strategies for type 2 diabetes therapy.

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.

Study on the Mechanism of Raspberry (Rubi fructus)in Treating Type 2 Diabetes Based on UPLC-Q-Exactive Orbitrap MS, Network Pharmacology, and Experimental Validation.

The aim of this study is to analyze the chemical composition of raspberry using liquid chromatography-mass spectrometry (LC-MS) technology, predict the potential effects of raspberry in treating type 2 diabetes through network pharmacology, and conduct preliminary validation through invitro experiments. A Waters CORTECS C18 column (3.0 mm × 100 mm, 2.7 μm) was used; mobile phase A consisted of 0.1% formic acid in water and mobile phase B consisted of 0.1% formic acid in acetonitrile. Gradient elution was performed with full-scan mode in both positive and negative ion modes, covering a mass range of m/z 100-1500. The chemical components of raspberry were analyzed and identified based on secondary spectra from databases and relevant literature. The disease targets related to type 2 diabetes were searched, and protein-protein interaction network analysis as well as gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted on the intersecting targets of the active components of raspberry and the disease. HepG2 cells were used for experimental validation, with high glucose-induced insulin resistance models established. The CCK-8 method was employed to assess the effects of raspberry on cell proliferation, while Western blotting was used to measure the expression of proteins related to the AGE/RAGE signaling pathway. A total of 47 components were identified, including 10 organic acids, 15 flavonoids, 12 phenols, 2 alkaloids, 4 terpenoids, 1 miscellaneous compound, 1 stilbene, 1 steroid and its derivatives, and 1 diterpenoid. Through database screening, seven active components were identified: kaempferol, epicatechin, ellagic acid, crocetin, stigmasterol, fisetin, and isorhamnetin. KEGG and GO results indicated that the therapeutic effects of raspberry on type 2 diabetes may be related to the advanced glycation end product (AGE)- receptor for advanced glycation end product (RAGE) signaling pathway. Establishment of an insulin resistance model in HepG2 cells demonstrated that, compared to the control group, the raspberry treatment group upregulated p53 protein expression while downregulating the expression of RAGE, Akt1, and Caspase-3 proteins. This study preliminarily elucidates that the therapeutic effects of raspberry in treating type 2 diabetes may be mediated through the inhibition of the AGE-RAGE signaling pathway, providing important references for the study of the pharmacological basis and clinical application of raspberry.

Integrating transcriptomics and proteomics to understand the molecular mechanisms underlying the pathogenesis of type 2 diabetes mellitus

The liver plays an important role in glucose regulation, and their dysfunction is closely associated with the development of type 2 diabetes mellitus (T2DM), and insulin resistance (IR) in hepatocyte mediate the pathogenesis of diabetes mellitus. In T2DM rats and their correlated control, we investigated various genes expression at transcriptional and translational level by utilizing transcriptomic using RNA sequencing (RNA-seq) and proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to disclose potential candidates for Type 2 diabetes diagnosis and therapy. We found the lecithin retinol acyltransferase (Lrat) gene regulate hepatocyte IR in T2DM. Furthermore, BRL-3A cells, rat liver cells, worked as the IR model in vitro study. Hence, Lrat gene was overexpressed in BRL-3A cells to explore the role of Lrat gene in IR by measuring the cellular glucose consumption, TCHO, and LDL-C levels. Finally, we found that Lrat gene can improve the level of glycolipid metabolism in BRL-3A cells and reduce the degree of IR in BRL-3A cells. Therefore, further exploration of Lrat gene related molecular mechanism is meaningful.

Study on the Mechanism of Alpinia officinarum Hance in the Improvement of Insulin Resistance through Network Pharmacology, Molecular Docking and in vitro Experimental Verification.

Research has elucidated that the pathophysiological underpinnings of non-alcoholic fatty liver disease and type 2 diabetes mellitus are intrinsically linked to insulin resistance (IR). However, there are currently no pharmacotherapies specifically approved for combating IR. Although Alpinia officinarum Hance (A. officinarum) can ameliorate diabetes, the detailed molecular mechanism through which it influences IR has not been fully clarified. To predict the active components of A. officinarum and determine the mechanism by which A. officinarum affects IR. The active compounds and molecular mechanism underlying the improvement of IR by A. officinarum were predicted via network pharmacology and molecular docking. To further substantiate these predictions, an in vitro model of IR was induced in HepG2 cells using high glucose concentrations. Cytotoxicity and oxidative stress levels were evaluated using Cell Counting Kit-8, reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) assay kits. The putative molecular mechanisms were corroborated through Western blot and RT-PCR analyses. Fourteen principal active components in A. officinarum, 133 potential anti-IR gene targets, and the top five targets with degree values were ALB, AKT1, TNF, IL6, and VEGFA. A. officinarum was posited to exert its pharmacological effects on IR through mechanisms involving lipid and atherosclerosis, the AGE-RAGE signaling pathway in diabetic complications, the PI3K-AKT signaling pathway, fluid shear stress, and atherosclerosis. Intriguingly, network pharmacology analysis highlighted (4E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3- one (A14) as the most active compound. Molecular docking studies further confirmed that A14 has a strong binding affinity for the main targets of PI3K, AKT, and Nrf2. The experiments demonstrated that A14 significantly diminished the ROS and MDA levels while augmenting the SOD activity. Moreover, A14 was found to elevate the protein expression of PI3K, AKT, Nrf2, and HO-1, and increase the mRNA levels of these targets as well as NQO1. A. officinarum could play a therapeutic role in IR through multiple components, targets, and pathways. The most active component of A. officinarum responsible for combating IR is A14, which has the ability to regulate oxidative stress in IR-HepG2 cells by activating the PI3K/AKT/Nrf2 pathway. These findings suggest a potential pharmacological intervention strategy for the treatment of IR.

Insulin Resistance and Impaired Insulin Secretion Predict Incident Diabetes: A Statistical Matching Application to the Two Korean Nationwide, Population-Representative Cohorts.

To evaluate whether insulin resistance and impaired insulin secretion are useful predictors of incident diabetes in Koreans using nationwide population-representative data to enhance data privacy. This study analyzed the data of individuals without diabetes aged >40 years from the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2010 and 2015 and the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). Owing to privacy concerns, these databases cannot be linked using direct identifiers. Therefore, we generated 10 synthetic datasets, followed by statistical matching with the NHIS-HEALS. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were used as indicators of insulin resistance and insulin secretory function, respectively, and diabetes onset was captured in NHIS-HEALS. A median of 4,580 (range, 4,463 to 4,761) adults were included in the analyses after statistical matching of 10 synthetic KNHANES and NHIS-HEALS datasets. During a mean follow-up duration of 5.8 years, a median of 4.7% (range, 4.3% to 5.0%) of the participants developed diabetes. Compared to the reference low-HOMA-IR/high-HOMA-β group, the high-HOMA-IR/low- HOMA-β group had the highest risk of diabetes, followed by high-HOMA-IR/high-HOMA-β group and low-HOMA-IR/low- HOMA-β group (median adjusted hazard ratio [ranges]: 3.36 [1.86 to 6.05], 1.81 [1.01 to 3.22], and 1.68 [0.93 to 3.04], respectively). Insulin resistance and impaired insulin secretion are robust predictors of diabetes in the Korean population. A retrospective cohort constructed by combining cross-sectional synthetic and longitudinal claims-based cohort data through statistical matching may be a reliable resource for studying the natural history of diabetes.

VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signal pathway

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome.MethodsIn this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway.ResultsWe observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis.ConclusionsOur studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor.Graphical

The effect of Helicobacter pylori-derived extracellular vesicles on glucose metabolism and induction of insulin resistance in HepG2 cells.

Helicobacter pylori infection has been associated with the development of insulin resistance (IR). This study aimed to examine the effect of H. pylori-derived extracellular vesicles (EVs) on IR induction. EVs were derived from two H. pylori strains, and characterised by transmission electron microscopy and dynamic light scattering. Different concentrations of insulin were added to HepG2 cells to induce IR model. HepG2 cells were exposed to various concentrations of H. pylori-derived EVs to assess IR development. The gene expression of IRS1, AKT2, GLUT2, IL-6, SOCS3, c-Jun and miR-140 was examined using RT-qPCR. Glucose uptake analysis revealed insulin at 5 × 10 -7 mol/l and EVs at 50 µg/ml induced IR model in HepG2 cells. H. pylori-derived EVs downregulated the expression level of IRS1, AKT2, and GLUT2, and upregulated IL-6, SOCS3, c-Jun, and miR-140 expression in HepG2 cells. In conclusion, our findings propose a novel mechanism by which H. pylori-derived EVs could potentially induce IR.

Insulin Resistance in Hypercalciuric Calcium Kidney Stone Patients

Rational and ObjectiveDiabetes and uric acid kidney stones are strongly associated. Patients with calcium kidney stones also have higher risk of developing diabetes compared to non-kidney stone patients yet this has not been further investigated. We aimed to characterize insulin resistance in calcium kidney stone patients. Study DesignObservational Setting & PopulationThis study was performed in the University of Chicago Clinical Research Center. Kidney stone patients (N=42) were selected for having idiopathic hypercalciuria and calcium stones with no other medical conditions and controls (N=27) were healthy. ExposuresAll participants presented to the Clinical Research Center in a fasting state and at least 2 timed fasting blood and urine were collected prior to a fixed breakfast. Six additional timed blood and urine collections were performed after breakfast. OutcomesWe compared fasting and fed indices of insulin resistance between the groups. Analytic ApproachWe used t-tests and multivariable linear regression models. A sensitivity analysis removing all patients who had ever been on a thiazide diuretic was also performed. ResultsIn separate multivariable linear models, kidney stone patients had higher fasting serum insulin (24 (3 to 46pmol/L), p=0.03) and higher homeostatic model of insulin resistance (HOMA-IR) (1.0 (0.2 to 1.8), p=0.02). In separate multivariable linear models, kidney stone patients had higher fed serum glucose (10 (2 to 18mg/dL), p=0.01). Results were similar in a sensitivity analysis removing all patients who had ever been on a thiazide diuretic. There were no differences in urine composition based on HOMA-IR levels. LimitationsSingle institution. Small sample size limited subanalyses by different calcium stone types. ConclusionsCalcium kidney stone patients without diabetes or other medical conditions demonstrated signs of insulin resistance compared to healthy matched controls.

Berberine Ameliorates High-fat-induced Insulin Resistance in HepG2 Cells by Modulating PPARs Signaling Pathway.

Berberine (BBR), also known as berberine hydrochloride, was isolated from the rhizomes of the Coptis chinensis. Studies have reported that BBR plays an important role in glycolipid metabolism, including insulin (IR). The targets, and molecular mechanisms of BBR against hyperlipid-induced IR is worthy to be further studied. The related targets of BBR were identified via Pharmmapper database and relevant targets of diabetes were obtained through GeneCards and Online Mendelian Inheritance in Man (OMIM) database. The common targets were employed with the STRING database and visualized with the protein-protein interactions (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to explore the biological progress and pathways. In vitro, human hepatocellular carcinomas (HepG2) cell was used as experimental cell line, and an insulin resistant HepG2 cell model (IR-HepG2) was constructed using free fatty acid induction. After intervention with BBR, glucose consumption and uptake in HepG2 cells were observed. Molecular docking was used to test the interaction between BBR and key targets, and real-time fluorescence quantitative PCR was used to detect the regulatory effect of BBR on related targets. 262 overlapped targets were extracted from BBR and diabetes. In the KEGG enrichment analysis, the peroxisome proliferator activated receptor (PPAR) signaling pathway was included. In vitro experiments, BBR can significantly increase sugar consumption and uptake in IR HepG2 cells, while PPAR inhibitors can weaken the effect of BBR on IR-HepG2. The PPAR signaling pathway is one of the important pathways for BBR to improve high-fat-induced insulin resistance in HepG2 cells.

Telerehabilitation Program Impact on Overactive Bladder Symptoms and Metabolic Health in Obese Women: a Randomized Controlled Trial

INTRODUCTION. Overactive bladder syndrome is caused by many factors including obesity, insulin resistance and poor dietary habits. Since it is a chronic disease and needs time to be treated, introducing telepilates in addition to Mediterranean diet would encourage better adherence and results to the treatment program. AIM. To assess the impact of a virtual group-based telerehabilitation program on overactive bladder symptoms and metabolic health in women with obesity. MATERIAL AND METHODS. Eighty obese women (BMI 30.0–34.9 kg/m2) between the ages of 35 and 45 were allocated into two equal groups, 40 for each: (A) supervised telepilates and (B) unsupervised telepilates. The supervised group participated in a 12-week Pilates workout program over videoconference platforms three times a week. Meanwhile, the unsupervised group only received four online meetings. The groups’ diet was the Mediterranean style. The Hemostatic Model of Insulin Resistance (HOMA-IR), body mass index (BMI), waist circumference (WC), Patient Perception of Urgency Scale (PPIUS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and Telehealth Usability Scale (TUS) were measured. RESULTS AND DISCUSSION. The supervised telepilates group exhibited statistically significant amelioration of overactive bladder symptoms and a reduction in HOMA-IR (p 0.001), while the unsupervised telepilates group showed insignificant changes in these measures (p 0.05). Furthermore, the supervised telepilates group showed significantly greater reductions in BMI and WC (p 0.001) than the unsupervised telepilates group (p 0.05). Additionally, the supervised telegroup outperformed the unsupervised telegroup on all parameters of TUS (p 0.001) CONCLUSION. Women with obesity experienced decrease in overactive bladder symptoms and improved metabolic health after completing a 12-week telepilates training program.

7086 Disrupted Mitochondrial Function in Alström Syndrome- A Monogenic Model of Insulin Resistance and Obesity

Abstract Disclosure: S. Ali: None. S. Heising: None. V. Veeranna: None. A. Vincent: None. G.S. Xavier: None. T. Geberhiwot: None. Alström syndrome (ALMS) is a rare monogenic disease typified by severe insulin resistance (IR) and obesity. IR and obesity are cardinal features of metabolic syndrome. The metabolic effects of insulin at key target tissues leads to metabolic haemostasis by promoting glucose and lipid uptake and metabolism to generate energy in cells. Although insulin is a major regulator of fuel metabolism, its effects on mitochondrial ATP production in severe insulin resistance are unclear. RNASeq data from adipose tissue (AT) from patients with ALMS show downregulation of the expression of genes associated with mitochondrial respiratory chain function, pointing towards possible altered mitochondrial function in ALMS. We therefore undertook a detailed assessment of mitochondrial oxidative phosphorylation capacity (OXPHOS) in skeletal muscle (SM) in ALMS. We performed SM biopsy in 10 ALMS and 10 healthy control volunteers that were age, gender and Body Mass Index matched. The SM was subjected to high resolution respirometry, the gold standard method to quantify mitochondrial function ex vivo, using OROBOROS Oxygraph -2k (O2k) system. Overall OXPHOS was higher in control SM compared to ALMS, with maximal respiration of 62.96±19.2 and 44.24 ± 12.53 pmol/(s*mg), respectively (p&amp;lt;0.05).Reduced oxygen influx was observed in ALMS SM in comparison to controls for fatty acid ß oxidation (6.7±5.96 vs 7.87±2.7 pmol/(s*mg);p&amp;lt;0.05, at complex I (19.4 ± 8.98 vs 29.7 ±5.3 pmol/(s*mg);p&amp;lt;0.05, and at complex II (34.98 ±11.75 vs 53.52± 13.2 pmol/(s*mg) ;p&amp;lt;0.05. Mitochondrial membrane integrity was unaffected during these experiments. Therefore, our analysis unveils a consistent reduction in mitochondrial respiration across all the electron transport pathway. This noteworthy finding suggests impairment in respiratory function and the electron transport chain in mitochondria, a crucial aspect of cellular energy metabolism. Several studies have previously linked IR with mitochondrial dysfunction, where insulin-resistant rodents and humans have shown blunted mitochondrial response to ATP generation. Our results align with this body of evidence emphasizing the significance of investigating the underlying mechanism contributing to this phenomenon. These findings could pave the way to exploring potential mitochondrial-targeted therapies to restore mitochondrial function and therefore, improve insulin sensitivity to tackle IR in ALMS. Presentation: 6/2/2024

Effects of probiotics supplementation on glycemic profile in adults with type 2 diabetes mellitus: A grade-assessed systematic review and dose–response meta-analysis of randomized controlled trials

BackgroundDisturbed glycemia and the resulting type 2 diabetes (T2D) are significant health concerns. Various approaches have been examined to improve glycemic control in patients with T2D. Modification of gut microbiome via administering probiotics has been extensively studied. The present study aims to sum up the existing literature which investigated the effect of probiotics on glycemic indices in individuals with T2D in the format of randomized controlled trials (RCTs). MethodsOnline medical databases (PubMed, Scopus, and Web of Science) were searched from inception to January 2024. Eligible studies were included using pre-defined inclusion and exclusion criteria. Outcome variables included fasting blood sugar (FBS), insulin, hemoglobin A1c (HbA1c), and homeostatic model of insulin resistance (HOMA-IR). Weighted mean differences (WMDs) were estimated. Subgroup and dose-response analyses were conducted. P-values <0.05 were considered as statistically significant. ResultsOut of 5,636 records retrieved by the initial search, thirty-two RCTs were included in the final analyses. Supplementation with probiotics was observed to significantly improve indices of glycemic control; including FBS (WMD: -13.27 mg/dl; 95% CI: -18.31, -8.22), HbA1c (WMD: -0.44 %; 95% CI: -0.59, -0.28), insulin (WMD: -1.33 μIU/ml; 95% CI: -2.57, -0.08), and HOMA-IR (WMD: -0.95; 95% CI: -1.71, -0.18). Dose-response analysis revealed that increased duration of intervention results in a larger reduction only in FBS. ConclusionSupplementation with probiotics seems to improve indices of glycemic control. Nonetheless, taken into account the notable heterogeneity (with regard to dosage, duration, and the species/strains used) between the included studies and low quality of evidence, caution must be considered, especially when long-term clinical implications are intended.

Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence.

Beta (β)-cell senescence contributes to type 2 diabetes mellitus (T2DM). While exercise is vital for T2DM management and significantly affects cellular ageing markers, its effect on β-cell senescence remains unexplored. Here, we show that short-term endurance exercise training (treadmill running, 1 h per day for 10 days) in two male and female mouse models of insulin resistance decreases β-cell senescence. In vivo and in vitro experiments revealed that this effect is mediated, at least in part, by training-induced increases in serum glucagon, leading to activation of 5'-AMP-activated protein kinase (AMPK) signalling in β-cells. AMPK activation resulted in the nuclear translocation of NRF2 and decreased expression of senescence markers and effectors. Remarkably, human islets from male and female donors with T2DM treated with serum collected after a 10-week endurance exercise training programme showed a significant decrease in the levels of senescence markers. These findings indicate that exercise training decreases senescence in pancreatic islets, offering promising therapeutic implications for T2DM.