Ameliorates Insulin Resistance Research Articles

Optogenetic therapeutic strategies for diabetes mellitus.

Diabetes mellitus (DM) is a common chronic disease affecting humans globally. It is characterized by abnormally elevated blood glucose levels due to the failure of insulin production or reduction of insulin sensitivity and functionality. Insulin and glucagon-like peptide (GLP)-1 replenishment or improvement of insulin resistance are the two major strategies to treat diabetes. Recently, optogenetics that uses genetically encoded light-sensitive proteins to precisely control cell functions has been regarded as a novel therapeutic strategy for diabetes. Here, we summarize the latest development of optogenetics and its integration with synthetic biology approaches to produce light-responsive cells for insulin/GLP-1 production, amelioration of insulin resistance and neuromodulation of insulin secretion. In addition, we introduce the development of cell encapsulation and delivery methods and smart bioelectronic devices for the in vivo application of optogenetics-based cell therapy in diabetes. The remaining challenges for optogenetics-based cell therapy in the clinical translational study are also discussed.

Antidiabetic Potential of Tea and Its Active Compounds: From Molecular Mechanism to Clinical Evidence.

Diabetes mellitus (DM) is a chronic endocrine disorder that poses a long-term risk to human health accompanied by serious complications. Common antidiabetic drugs are usually accompanied by side effects such as hepatotoxicity and nephrotoxicity. There is an urgent need for natural dietary alternatives for diabetic treatment. Tea (Camellia sinensis) consumption has been widely investigated to lower the risk of diabetes and its complications through restoring glucose metabolism homeostasis, safeguarding pancreatic β-cells, ameliorating insulin resistance, ameliorating oxidative stresses, inhibiting inflammatory response, and regulating intestinal microbiota. It is indispensable to develop effective strategies to improve the absorption of tea active compounds and exert combinational effects with other natural compounds to broaden its hypoglycemic potential. The advances in clinical trials and population-based investigations are also discussed. This review primarily delves into the antidiabetic potential and underlying mechanisms of tea active compounds, providing a theoretical basis for the practical application of tea and its active compounds against diabetes.

Exercise ameliorates muscular excessive mitochondrial fission, insulin resistance and inflammation in diabetic rats via irisin/AMPK activation

This study aimed to investigate the effects of exercise on excessive mitochondrial fission, insulin resistance, and inflammation in the muscles of diabetic rats. The role of the irisin/AMPK pathway in regulating exercise effects was also determined. Thirty-two 8-week-old male Wistar rats were randomly divided into four groups (n = 8 per group): one control group (Con) and three experimental groups. Type 2 diabetes mellitus (T2DM) was induced in the experimental groups via a high-fat diet followed by a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 30 mg/kg body weight. After T2DM induction, groups were assigned as sedentary (DM), subjected to 8 weeks of treadmill exercise training (Ex), or exercise training combined with 8-week cycloRGDyk treatment (ExRg). Upon completion of the last training session, all rats were euthanized and samples of fasting blood and soleus muscle were collected for analysis using ELISA, immunofluorescence, RT-qPCR, and Western blotting. Statistical differences between groups were analyzed using one-way ANOVA, and differences between two groups were assessed using t-tests. Our findings demonstrate that exercise training markedly ameliorated hyperglycaemia, hyperlipidaemia, and insulin resistance in diabetic rats (p < 0.05). It also mitigated the disarranged morphology and inflammation of skeletal muscle associated with T2DM (p < 0.05). Crucially, exercise training suppressed muscular excessive mitochondrial fission in the soleus muscle of diabetic rats (p < 0.05), and enhanced irisin and p-AMPK levels significantly (p < 0.05). However, exercise-induced irisin and p-AMPK expression were inhibited by cycloRGDyk treatment (p < 0.05). Furthermore, the administration of CycloRGDyk blocked the effects of exercise training in reducing excessive mitochondrial fission and inflammation in the soleus muscle of diabetic rats, as well as the positive effects of exercise training on improving hyperlipidemia and insulin sensitivity in diabetic rats (p < 0.05). These results indicate that regular exercise training effectively ameliorates insulin resistance and glucolipid metabolic dysfunction, and reduces inflammation in skeletal muscle. These benefits are partially mediated by reductions in mitochondrial fission through the irisin/AMPK signalling pathway.

Berberine attenuates obesity-induced insulin resistance by inhibiting miR-27a secretion.

Berberine (BBR) is an alkaloid found in plants. It has neuroprotective, anti-inflammatory and lipid-lowering activity. However, the efficacy of treatment with BBR and the mechanisms through which it acts need further study. This study investigated the therapeutic effects and the mechanism of action of BBR on obesity-induced insulin resistance in peripheral tissues. High-fat-fed C57BL/6J mice and low-fat-fed C57BL/6J mice with miR-27a overexpression were given BBR intervention (100 mg/kg, po), and the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed. Palmitic acid-stimulated hypertrophic adipocyte models were treated with BBR (10 μM). Related indicators and protein expression levels were examined. The AUCs of the OGTT and the ITT in the BBR intervention group were reduced significantly (p < 0.01) (p < 0.05), and the serum biochemical parameters, including FBG, TC, TG and LDL-C were significantly reduced after BBR intervention. In the invitro experiments, the triglyceride level and volume of lipid droplets decreased significantly after BBR intervention (p < 0.01) (p < 0.05). Likewise, BBR ameliorates skeletal muscle and pancreas insulin signalling pathways invivo and invitro. The results showed that BBR significantly ameliorated insulin resistance, reduced body weight and percent body fat and improved serum biochemical parameters in mice. Likewise, BBR reduced triglyceride level and lipid droplet volume in hypertrophic adipocytes, BBR improved obesity effectively. Meanwhile, BBR ameliorated the histomorphology of the pancreas, and skeletal muscle and pancreas insulin related signalling pathways of islets in invitro and invivo experiments. The results further demonstrated that BBR inhibited miR-27a levels in serum from obese mice and supernatant of hypertrophic adipocytes. miR-27a overexpression in low-fat fed mice indicated that miR-27a caused insulin resistance, and BBR intervention significantly improved the miR-27a induced insulin resistance status. This study demonstrates the important role of BBR in obesity-induced peripheral insulin resistance and suggest that the mechanism of its effect may be inhibition of miR-27a secretion.

Fermented dietary fiber from soy sauce residue exerts antidiabetic effects through regulating the PI3K/AKT signaling pathway and gut microbiota-SCFAs-GPRs axis in type 2 diabetic mellitus mice

The gut plays a crucial role in the development and progression of metabolic disorders, particularly in relation to type 2 diabetes mellitus (T2DM). While a high intake of dietary fiber is inversely associated with the risk of T2DM, the specific effects of various dietary fibers on T2DM are not fully understood. This study investigated the anti-diabetic properties of fermented dietary fiber (FDF) derived from soy sauce residue in T2DM mice, demonstrating its ability to lower blood glucose levels and ameliorate insulin resistance. Our findings revealed that FDF could enhance hepatic glucose metabolism via the IRS-1/PI3K/AKT/mTOR pathway. Additionally, the anti-diabetic effect of FDF was correlated with alterations in gut microbiota composition in T2DM mice, promoting a healthier gut environment. Specifically, FDF increased the abundance of beneficial flora such as Dubosiella, Butyricimonas, Lachnospiraceae_NK4A136_group, Lactobacillus and Osillibacter, while reducing harmful bacteria including Bilophila, Parabacteroides and Enterorhabdus. Further analysis of microbial metabolites, including short-chain fatty acids (SCFAs) and bile acids (BAs), provided evidence of FDF's regulatory effects on cecal contents in T2DM mice. Importantly, FDF treatment significantly restored the G-protein-coupled receptors (GPRs) expression in the colon of T2DM mice. In conclusion, our study suggests that the anti-diabetic effects of FDF are associated with the regulation of both the liver-gut axis and the gut microbiota-SCFAs-GPRs axis.

SIRT1 exerts protective effects by inhibiting endoplasmic reticulum stress and NF-κB signaling pathways.

Silent information regulator two homolog 1 (SIRT1), an NAD + -dependent histone deacetylase, plays a pivotal regulatory role in a myriad of physiological processes. A growing body of evidence suggests that SIRT1 can exert protective effects in metabolic disorders and neurodegenerative diseases by inhibiting endoplasmic reticulum (ER) stress and the nuclear factor-κB (NF-κB) inflammatory signaling pathway. This review systematically elucidates the molecular mechanisms and biological significance of SIRT1 in regulating ER stress and the NF-κB pathway. On one hand, SIRT1 can deacetylate key molecules in the ER stress pathway, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), PKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6), thereby alleviating ER stress. On the other hand, SIRT1 can directly or indirectly remove the acetylation modification of the NF-κB p65 subunit, inhibiting its transcriptional activity and thus attenuating inflammatory responses. Through these mechanisms, SIRT1 can ameliorate insulin resistance in metabolic diseases, exert cardioprotective effects in ischemia-reperfusion injury, and reduce neuronal damage in neurodegenerative diseases. However, it is important to note that while these findings are promising, the complex nature of the biological systems involved warrants further investigation to fully unravel the intricacies of SIRT1's regulatory mechanisms. Nevertheless, understanding the regulatory mechanisms of SIRT1 on ER stress and the NF-κB pathway is of great significance for expanding our knowledge of the pathogenesis of related diseases and exploring new preventive and therapeutic strategies targeting SIRT1.

Biochemical Investigation of Therapeutic Efficacy of Berberine-Enriched Extract in Streptozotocin-Induced Metabolic Impairment.

Metabolic disorders pose significant global health challenges, necessitating innovative therapeutic approaches. This study focused on the multifaceted therapeutic potential of berberine-enriched extract (BEE) in mitigating metabolic impairment induced by streptozotocin (STZ) in a rat model and compared the effects of BEE with berberine (BBR) and metformin (MET) to comprehensively evaluate their impact on various biochemical parameters. Our investigation reveals that BEE surpasses the effects of BBR and MET in ameliorating metabolic impairment, making it a promising candidate for managing metabolic disorders. For this, 30 male Wistar rats were divided into five groups (n = 6): control (CN), STZ, STZ + MET, STZ + BBR, and STZ + BEE. The treatment duration was extended over 4 weeks, during which various biochemical parameters were monitored, including fasting blood glucose (FBG), lipid profiles, inflammation, liver and kidney function biomarkers, and gene expressions of various metabolizing enzymes. The induction of metabolic impairment by STZ was evident through an elevated FBG level and disrupted lipid profiles. The enriched extract effectively regulated glucose homeostasis, as evidenced by the restoration of FBG levels, superior to both BBR and MET. Furthermore, BEE demonstrated potent effects on insulin sensitivity, upregulating the key genes involved in carbohydrate metabolism: GCK, IGF-1, and GLUT2. This highlights its potential in enhancing glucose utilization and insulin responsiveness. Dyslipidemia, a common occurrence in metabolic disorders, was effectively managed by BEE. The extract exhibited superior efficacy in regulating lipid profiles. Additionally, BEE exhibited significant anti-inflammatory properties, surpassing the effects of BBR and MET in lowering the levels of inflammatory biomarkers (IL-6 and TNF-α), thereby ameliorating insulin resistance and systemic inflammation. The extract's superior hepatoprotective and nephroprotective effects, indicated by the restoration of liver and kidney function biomarkers, further highlight its potential in maintaining organ health. Moreover, BEE demonstrated potent antioxidant properties, reducing oxidative stress and lipid peroxidation in liver tissue homogenates. Histopathological examination of the pancreas underscored the protective effects of BEE, preserving and recovering pancreatic β-cells damaged by STZ. This collective evidence positions BEE as a promising therapeutic candidate for managing metabolic disorders and offers potential benefits beyond current treatments. In conclusion, our findings emphasize the remarkable therapeutic efficacy of BEE and provide a foundation for further research into its mechanisms, long-term safety, and clinical translation.

KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer's disease.

Epidemiological studies have revealed a correlation between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D). Insulin resistance in the brain is a common feature in patients with T2D and AD. KAT7 is a histone acetyltransferase that participates in the modulation of various genes. To determine the effects of KAT7 on insulin patients with AD. APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes, respectively. An in vitro model of AD was established by Aβ stimulation. Insulin resistance was induced by chronic stimulation with high insulin levels. The expression of microtubule-associated protein 2 (MAP2) was assessed using immunofluorescence. The protein levels of MAP2, Aβ, dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), IRS-1, p-AKT, total AKT, p-GSK3β, total GSK3β, DYRK1A, and KAT7 were measured via western blotting. Accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and SOD activity was measured to determine cellular oxidative stress. Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation, respectively. Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR. A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A. KAT7 expression was suppressed in the AD mice. Overexpression of KAT7 decreased Aβ accumulation and MAP2 expression in AD brains. KAT7 overexpression decreased ROS and MDA levels, elevated SOD activity in brain tissues and neurons, and simultaneously suppressed neuronal apoptosis. KAT7 upregulated levels of p-AKT and p-GSK3β to alleviate insulin resistance, along with elevated expression of DYRK1A. KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A. HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion. We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation. Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.

The effect of Artemisia annua L. aqueous and methanolic extracts on insulin signaling in liver of HFD/STZ diabetic mice.

Many studies have shown the anti-diabetic effects of medicinal plants. But their molecular mechanism has been less studied. Understanding of these mechanisms can help to better manage the treatment of diabetes by using these plants. So, this research examined the effect of Artemisia annua extract on PI3K (phosphatidylinositol 3-kinase)/AKt (serine/threonine kinase protein B) signaling pathway in liver of high-fat diet (HFD)/Streptozotocin (STZ)-induced type 2 diabetic mice. Groups of mice were control, untreated diabetic mice, diabetic mice treated with various doses (400, 200, 100 mg/kg) of methanolic and aqueous extract of A. annua and metformin for four weeks. Type 2 diabetes was produced by feeding high-fat diet following injection of low dose of STZ. After experiment duration all mice were sacrificed and blood glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), index of insulin sensitivity index (ISI) were detected and liver tissues were isolated for to detect m-RNA expression of PI3K and Akt. Extracts of aqueous and methanolic this plant markedly reduced hyperglycemia, hyperinsulinemia, HOMA-IR and elevated ISI in diabetic group in comparison with un-treated diabetic mice. In addition, they could enhance the expression of AKt and PI3K m-RNA in liver tissues in diabetic mice. Artemisia annua extract ameliorated insulin resistance and improved insulin action in liver via the high activity of PI3K/AKt signaling pathway. So, it can be a suitable alternative treatment to synthetic antidiabetic drugs to improve insulin action in condition of type 2 diabetes.

Tangshen formula targets the gut microbiota to treat non-alcoholic fatty liver disease in HFD mice: A 16S rRNA and non-targeted metabolomics analyses

BackgroundTangshen formula (TSF) has an ameliorative effect on hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD), but the role played by the gut microbiota in this process is unknown. MethodWe conducted three batches of experiments to explore the role played by the gut microbiota: TSF administration, antibiotic treatment, and fecal microbial transplantation. NAFLD mice were induced with a high-fat diet to investigate the ameliorative effects of TSF on NAFLD features and intestinal barrier function. 16S rRNA sequencing and serum untargeted metabolomics were performed to further investigate the modulatory effects of TSF on the gut microbiota and metabolic dysregulation in the body. ResultsTSF ameliorated insulin resistance, hypercholesterolemia, lipid metabolism disorders, inflammation, and impairment of intestinal barrier function. 16S rRNA sequencing analysis revealed that TSF regulated the composition of the gut microbiota and increased the abundance of beneficial bacteria. Antibiotic treatment and fecal microbiota transplantation confirmed the importance of the gut microbiota in the treatment of NAFLD with TSF. Subsequently, untargeted metabolomics identified 172 differential metabolites due to the treatment of TSF. Functional predictions suggest that metabolisms of choline, glycerophospholipid, linoleic acid, alpha-linolenic acid, and arachidonic acid are the key metabolic pathways by which TSF ameliorates NAFLD and this may be influenced by the gut microbiota. ConclusionTSF treats the NAFLD phenotype by remodeling the gut microbiota and improving metabolic profile, suggesting that TSF is a functional gut microbial and metabolic modulator for the treatment of NAFLD.

Mitochondria-Associated Membranes as Key Regulators in Cellular Homeostasis and the Potential Impact of Exercise on Insulin Resistance.

The communication between mitochondria and the endoplasmic reticulum (ER) is facilitated by a dynamic membrane structure formed by protein complexes known as mitochondria-associated membranes (MAMs). The structural and functional integrity of MAMs is crucial for insulin signal transduction, relying heavily on their regulation of intracellular calcium homeostasis, lipid homeostasis, mitochondrial quality control, and endoplasmic reticulum stress (ERS). This article reviews recent research findings, suggesting that exercise may promote the remodeling of MAMs structure and function by modulating the expression of molecules associated with their structure and function. This, in turn, restores cellular homeostasis and ultimately contributes to the amelioration of insulin resistance (IR). These insights provide additional possibilities for the study and treatment of insulin resistance-related metabolic disorders such as obesity, diabetes, fatty liver, and atherosclerosis.

Mechanisms by which sheep milk consumption ameliorates insulin resistance in high-fat diet-fed mice

Sheep milk is rich in fat, protein, vitamins and minerals and is also one of the most important sources of natural bioactives. Several biopeptides in sheep milk have been reported to possess antibacterial, antiviral and anti-inflammatory properties, and they may prevent type 2 diabetes (T2D), disease and cancer. However, the precise mechanism(s) underlying the protective role of sheep milk against T2D development remains unclear. Therefore, in the current study, we investigated the effect of sheep milk on insulin resistance and glucose intolerance in high-fat diet (HFD)-fed mice, by conducting intraperitoneal glucose tolerance tests, metabolic cage studies, genomic sequencing, polymerase chain reaction, and biochemical assays. Hyperinsulinemic–euglycemic clamp-based experiments revealed that mice consuming sheep milk exhibited lower hepatic glucose production than mice in the control group. These findings further elucidate the mechanism by which dietary supplementation with sheep milk alleviates HFD-induced systemic glucose intolerance.

Pharmacodynamic material basis and pharmacological mechanisms of Cortex Mori against diabetes mellitus

Ethnopharmacological relevanceThe application of Cortex Mori (CM) in the treatment of diabetes mellitus (DM) has been extensively documented in traditional medicine. In recent years, the chemical composition of CM has been gradually unraveled, and its therapeutic mechanism in treating DM, diabetic nephropathy, diabetic cardiomyopathy, and other related conditions has been highlighted in successive reports. However, there is no systematic study on the treatment of DM based on the chemical composition of CM. Aim of the studyThis study was conducted to systematically explore the hypoglycemic activity mechanism of CM based on its chemical composition. MethodsThe material basis of Cortex Mori extract (CME) was investigated through qualitative analyses based on liquid chromatography-mass spectrometry (LC-MS). The possible acting mechanism was simulated using network pharmacology and validated in streptozotocin (STZ) + high fat diet (HFD)-induced diabetic rats and glucosamine-induced IR-HepG2 model with the assistance of molecular docking techniques. ResultsA total of 39 compounds were identified in CME by the LC-MS-based qualitative analysis. In diabetic rats, it was demonstrated that CME significantly ameliorated insulin resistance, blood lipid levels, and liver injury. The network pharmacology analysis predicted five major targets, including AKT1, PI3K, FoxO1, Gsk-3β, and PPARγ. Additionally, three key compounds (resveratrol, protocatechuic acid, and kaempferol) were selected based on their predicted contributions. The experimental results revealed that CME, resveratrol, protocatechuic acid, and kaempferol could promote the expression of AKT1, PI3K, and PPARγ, while inhibiting the expression of FoxO1 and Gsk-3β. The molecular docking results indicated a strong binding affinity between resveratrol/kaempferol and their respective targets. ConclusionsCME contains a substantial amount of prenylated flavonoids, which may be the focal point of research on the efficacy of CM in the treatment of DM. Besides, CME is effective in controlling blood glucose and insulin resistance, improving lipid levels, and mitigating liver injury in patients with DM. Relevant mechanisms may be associated with the activation of the PI3K/Akt pathway, the inhibition of the expression of FoxO1 and Gsk-3β, and the enhancement of PPARγ activity. This study represents the first report on the role of CME in the treatment of DM through regulating PPARγ, FoxO1, and Gsk-3β.

Vitamin D intervention as a curative measure for glucose intolerance in obese children and adolescents: a systematic review on randomized control trials.

The present review highlights that a significant proportion of the studies incorporated in the analysis demonstrate that the administration of vitamin D may be a preventive measure in ameliorating insulin resistance among pediatric patients with obesity, but it is advisable to implement a prolonged intervention with a substantial sample size and perform micro-level analysis at the gene level to evaluate the impact of vitamin D treatment. • Childhood obesity and its associated metabolic disorder is a concerned global problem. • Several studies showed an association of vitamin D deficiency with adiposity- induced metabolicdisorders which are still controversial. This study focused on finding interlink between vitamin Dsupplementation with obesity induced insulin resistance in children and adolescents. •This study supports that high dosage of Vitamin D in long term may be protective against insulinresistance in obese paediatric individuals. •A new factor is also reported in the study that vitamin D may alter the composition of gut microbiotawhich represents a compelling approach to the therapeutic management of obesity and diabetes.

Impact of Preparative Isolation of C-Glycosylflavones Derived from Dianthus superbus on In Vitro Glucose Metabolism.

Dianthus superbus L. has been extensively studied for its potential medicinal properties in traditional Chinese medicine and is often consumed as a tea by traditional folk. It has the potential to be exploited in the treatment of inflammation, immunological disorders, and diabetic nephropathy. Based on previous studies, this study continued the separation of another subfraction of Dianthus superbus and established reversed-phase/reversed-phase and reversed-phase/hydrophilic (RPLC) two-dimensional (2D) high-performance liquid chromatography (HPLC) modes, quickly separating two C-glycosylflavones, among which 2″-O-rhamnosyllutonarin was a new compound and isomer with 6‴-O-rhamnosyllutonarin. This is the first study to investigate the effects of 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin on cellular glucose metabolism in vitro. First, molecular docking was used to examine the effects of 2″-O-rhamnosyllutonarin and 6″-O-rhamnosyllutonarin on AKT and AMPK; these two compounds exhibited relatively high activity. Following this, based on the HepG2 cell model of insulin resistance, it was proved that both of the 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin demonstrated substantial efficacy in ameliorating insulin resistance and were found to be non-toxic. Simultaneously, it is expected that the methods developed in this study will provide a basis for future studies concerning the separation and pharmacological effects of C-glycosyl flavonoids.

Formononetin‐Vitamin E Conjugate Synergistically Supports Adipogenesis, Attenuates Oxidative Stress, and Restores Insulin Sensitization in Differentiated Preadipocytes

AbstractIn this study, a hybrid conjugate of formononetin (FMN) and vitamin E (VESylated‐FMN) was synthesized through succinic acid linker and investigated for its synergistic effect in diabetes. The conjugate was characterized through Ultra Performance Liquid Chromatography – Mass Spectrometry (UPLC‐MS), High‐Resolution Mass Spectrometry (HRMS), Nuclear Magnetic Resonance (NMR), and Differential Scanning Calorimetry (DSC). The ability of VESylated‐FMN to promote adipogenesis and ameliorate insulin resistance brought on by oxidative stress was evaluated in differentiated preadipocytes. Interestingly, VESylated‐FMN promoted intracellular glucose absorption, which in turn increased lipid and triglyceride accumulation and thereby encouraged adipogenesis. VESylated‐FMN attenuated oxidative stress and promoted cell survival by reducing reactive oxygen species (ROS) generation and reversing apoptosis. Additionally, VESylated‐FMN improved insulin sensitization by upregulating the gene and protein expression of insulin‐sensitizing markers. Overall, FMN in conjugation with vitamin E can effectively augment prior insulin sensitivity by reducing oxidative stress for efficient glycemic control in hyperglycemia.

Xylooligosaccharides ameliorate insulin resistance by increasing Akkermansia muciniphila and improving intestinal barrier dysfunction in gestational diabetes mellitus mice.

Little is known regarding the effects of xylooligosaccharides (XOS) on insulin resistance (IR) in gestational diabetes mellitus (GDM). We aimed to investigate this issue and its mechanism. Sixty female mice were randomly allotted to 4 groups (n = 15): control, high fat diet (HFD), GDM, and GDM + XOS. The control mice were fed an AIN-93 diet, while the mice in the other groups were fed 45% HFD. After pregnancy, mice in GDM and GDM + XOS groups were intraperitoneally injected with 30 mg kg-1 streptozocin for 3 days from the first day of pregnancy. Mice in the GDM + XOS group were then fed an HFD containing 2% XOS. Fasting glucose and insulin levels were monitored. The fecal Akkermansia muciniphila (Akk. muciniphila) and Bifidobacterium were measured by qPCR. The Chiu scores were calculated from hematoxylin-eosin (HE)-stained ileal tissues. Phosphorylated Akt in the liver and occludin and ZO-1 in the intestinal tissues were determined by western blotting. XOS reduced (p < 0.05) fasting blood glucose and insulin and HOMA-IR, and increased (p < 0.05) Akt phosphorylation in the livers of GDM mice. Moreover, XOS decreased (p < 0.05) TNFα, IL-1β, IL-15 and LPS in the serum, increased (p < 0.05) fecal Akk. muciniphila abundance, lowered (p < 0.05) Chiu's scores, and enhanced (p < 0.05) occludin and ZO-1 expression. XOS ameliorate IR by increasing Akk. muciniphila and improving intestinal barrier dysfunction in GDM mice.

Genistein in combination with Chlorogenic acid ameliorates insulin resistance and oxidative stress in skeletal muscle of high-fat diet fed mice

Objectives: Increasing evidence has demonstrated that oxidative stress plays a significant role in the pathogenesis of muscle insulin resistance. The beneficial impacts of genistein (GEN) and chlorogenic acid (CGA) on insulin resistance have already been revealed. However, their combined effects on skeletal muscle oxidative stress and insulin resistance have not been completely understood. The aim of the present study was to determine the effect of GEN in combination with CGA on skeletal muscle insulin resistance in high-fat diet (HFD) fed C57BL/6 mice.&#x0D; Methods: C57BL/6 male mice were fed an HFD for 15 weeks. The mice were then divided into five groups: standard chow diet (SCD), HFD, HFD + GEN, HFD + CGA, and HFD + GEN + CGA for 10 weeks.&#x0D; Results: The findings indicated that single treatment with GEN or CGA, and with a stronger effect of GEN+CGA combined treatment, decreased body weight gain and improved glucose intolerance. Moreover, following treatment with GEN and CGA alone or in combination with further effect, the level of plasma and muscle triglyceride (TG) were reduced. Furthermore, the combination therapy of GEN and CGA with greater efficacy than the single treatments, could decrease several oxidative stress markers in the skeletal muscle. Treatment with GEN and CGA alone or in combination could increase the expression of NF-E2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P): Quinone Oxidoreductase 1 (NQO1).&#x0D; Conclusion: The data of this study suggest that the combination of GEN and CGA might ameliorate insulin resistance and reduce oxidative stress in the skeletal muscle of mice fed HFD.

Baicalin ameliorates insulin resistance and regulates hepatic glucose metabolism via activating insulin signaling pathway in obese pre-diabetic mice

BackgroundDiabetes belongs to the most prevalent metabolic diseases worldwide, which is featured with insulin resistance, closely associated with obesity and urgently needs to be treated. Baicalin, belonging to natural flavonoids, has been reported to inhibit oxidative stress or inflammatoin. PurposeThis study investigated the properties of baicalin on modulating abnormal glucolipid metabolism, as well as the underlying in-vitro and in-vivo mechanisms. MethodsInsulin-resistant (IR)-HepG2 cells were stimulated by dexamethasone (20 µM) and high glucose (50 mM) for 48 h and incubated with or without baicalin or metformin for another 16 h. Male C57BL/6 J mice were fed with a high-fat diet (HFD, 60 % kcal% fat) during the total 14 weeks. Obese mice were then administered with baicalin (50 and 100 mg/kg) or vehicle solution everyday through oral gavage during the last 4-week period. Moreover, baicalin metabolisms in vitro and in vivo were determined using UPLC/MS/MS to study its metabolism situation. ResultsExposure to dexamethasone and high glucose damaged the abilities of glycogen synthesis and glucose uptake with elevated oxidative stress and increased generation levels of advanced glycation end-products (AGEs) in HepG2 cells. These impairments were basically reversed by baicalin treatment. Four-week oral administration with baicalin ameliorated hyperglycemia and dyslipidemia in HFD-induced obese and pre-diabetic mice. Downregulation of IRS/PI3K/Akt signaling pathway accomplished with reduced GLUT4 expression and enhanced GSK-3β activity was observed in insulin resistant HepG2 cells as well as liver tissues from pre-diabetic mice; and such effect was prevented by baicalin. Moreover, baicalin and its matabolites were detected in IR-HepG2 cells and mouse plasma. ConclusionThe study illustrated that baicalin alleviated insulin resistance by activating insulin signaling pathways and inhibiting oxidative stress and AGEs production, revealing the potential of baicalin to be a therapeutic natural flavonoid against hepatic insulin and glucose-lipid metabolic disturbance in pre-diabetes accompanied with obesity.

Combination therapy of metformin and morin attenuates insulin resistance, inflammation, and oxidative stress in skeletal muscle of high-fat diet-fed mice.

Lipid accumulation, inflammation, and oxidative stress are the most important causes of muscle insulin resistance. The aim of this study was to investigate the single and combined treatment effects of metformin (MET) and morin (MOR) on lipid accumulation, inflammation, and oxidative stress in the skeletal muscle of mice fed a high-fat diet. The mice were supplemented with MET (230 mg/kg diet), MOR (100 mg/kg diet), and MET + MOR for 9 weeks. Our results revealed that single treatment with MET or MOR, and with a stronger effect of MET + MOR combined treatment, reduced body weight gain, improved glucose intolerance and enhanced Akt phosphorylation in the muscle tissue. In addition, plasma and muscle triglyceride levels were decreased after treatment with MET and MOR. The expression of genes involved in macrophage infiltration and polarization and pro-inflammatory cytokines showed that MET + MOR combined treatment, significantly reduced inflammation in the muscle. Furthermore, combined treatment of MET + MOR with greater efficacy than the single treatment improved several oxidative stress markers in the muscle. Importantly, combined treatment of MET and MOR could increase the expression of nuclear factor erythroid 2-related factor 2, the master regulator of the antioxidant response. These findings suggest that combination of MET with MOR might ameliorate insulin resistance, inflammation, and oxidative stress in the skeletal muscle of mice fed high-fat diet.