Naringin ameliorates H_(2)O_(2)-induced oxidative damage in cells and prolongs the lifespan of female Drosophila melanogaster via the insulin signaling pathway

Naringin exists in a wide range of Chinese herbal medicine and has proven to possess several pharmacological properties.In this study,PC12,HepG2 cells,and female Drosophila melanogaster were used to investigate the antioxidative and anti-aging effects of naringin and explore the underlying mechanisms.The results showed that naringin inhibited H_(2)O_(2)-induced decline in cell viability and decreased,the content of reactive oxygen species in cells.Meanwhile,naringin prolonged the lifespan of flies,enhanced the abilities of climbing and the resistance to stress,improved the activities of antioxidant enzymes,and decreased malondialdehyde content.Naringin also improved intestinal barrier dysfunction and reduced abnormal proliferation of intestinal stem cells.Moreover,naringin down-regulated the mRNA expressions of inr,chico,pi 3k,and akt-1,and up-regulated the mRNA expressions of dilp2,dilp3,dilp5,and foxo,thereby activating autophagy-related genes and increasing the number of lysosomes.Furthermore,the mutant stocks assays and computer molecular simulation results further indicated that naringin delayed aging by inhibiting the insulin signaling(IIS)pathway and activating the autophagy pathway,which was consistent with the result of network pharmacological predictions.

Pomegranate peel polyphenols alleviate insulin resistance through the promotion of insulin signaling pathway in skeletal muscle of metabolic syndrome rats

Insulin resistance(IR) has been considered to be an important causative factor of metabolic syndrome(Met S). The present study investigated whether pomegranate peel polyphenols(PPPs) could prevent the development of Met S by improving IR in rats. Male Sprague-Dawley(SD) rats were fed high fat diet(HFD) to induce Met S and supplemented with different dosages of PPPs for 12 weeks. The results showed that HFD-induced insulin resistant rats had disordered metabolism of blood glucose, blood lipid, and terrible muscle fiber morphology when compared with normal diet-fed rats, but PPPs treatment at a dosage of 300 mg/kg·day significantly reversed these negative effects. Moreover, in skeletal muscle tissue of insulin resistant rats, PPPs treatments significantly increased the protein expressions of insulin receptor(Ins R) and phosphorylated insulin receptor substrate 1(IRS-1), stimulated peroxisome proliferator activated receptor gamma(PPARγ) and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT/PKB) signaling pathway, and aggrandized the protein levels of phosphorylated glycogen synthase kinase-3β(GSK-3β) and glucose transporter 4(GLUT4). Our results suggest that PPPs possess of the beneficial effects on alleviating IR by enhancing insulin sensitivity and regulating glucose metabolism.

Protective effects of Huanglian Wendan Decoction aganist cognitive deficits and neuronal damages in rats with diabetic encephalopathy by inhibiting the release of inflammatory cytokines and repairing insulin signaling pathway in hippocampus

Huanglian Wendan decoction(HLWDD) has been used for the treatment of symptom of "Re", one of major causes in diabetes and metabolic disorders, according to the theory of traditional Chinese medicine. The present study aimed at investigating the cerebral protective effects of HLWDD on diabetic encephalopathy(DE), one of the major diabetic complications. The effects of HLWDD and metformin were analyzed in the streptozocin(STZ) + high-glucose-fat(HGF) diet-induced DE rats by gastric intubation. In the present study, the effects of HLWDD on cognition deficits were investigated after 30-day intervention at two daily dose levels(3 and 6 g·kg^(-1)). To explore the potential mechanisms underlying the effects of HLWDD, we detected the alterations of neuronal damages, inflammatory cytokines, and impaired insulin signaling pathway in hippocampus of the DE rats. Based on our results from the present study, we concluded that the protective effects of HLWDD against the cognitive deficits and neuronal damages through inhibiting the release of inflammatory cytokines and repairing insulin signaling pathway in hippocampus of the DE rats.

Mechanism by which statins influence insulin signaling pathway

Recent studies have shown that statins can influence insulin resistance （IR） in animal models and inhumans.1.2 However, the mechanism by which statins influence the insulin signaling pathway （ISP） remains obscure. It has been proposed that the pleiotropic effects of statins might be involved in regulation of IR.The phosphatidylinositol 3-kinase （PI3K）-Akt/protein kinase B （PKB） pathway is the main ISE Insulin binding to insulin receptor initiates PI3K-Akt pathway by phosphorylates tyrosine residue of IR substrate proteins （IRSs） including IRS-1 and IRS-2. Activation of the PI3K leads to the accumulation of phosphatidylinositol 3,4,5-triphosphate （PIP3）. PIP3 activates serine/ threonine kinase （Akt）. Glucose transporter-4 （GLUT-4） translocates to plasma membrane from cytosol by serine phosphorylation of Akt and directly regulates glucose metabolism in liver, muscle and adipose tissue （Figure 1）. However, an overall mechanism by which statins influence ISP remained obscure.

Effect of glucagon-like peptide-1 agonist on insulin signaling pathway in skeletal muscle of mice with insulin resistance

Objective To study the effect of glucagon-like peptide-1 agonist(exendin-4)on insulin signaling pathway in skeletal muscle of mice with insulin resistance(IR).Methods Thirty male KM mice were divided into normal control group(NC group,n=10)and IR group(n=20).The mice in NC group and IR group were fed

Anti-diabetic effect of aloin via JNK-IRS1/PI3K pathways and regulation of gut microbiota

This research aimed to investigate the antidiabetic activity,underlying mechanisms,and gut microbiota regulation of aloin.The insulin-resistant HepG2(IR-HepG2)cell model and the type 2 diabetic(T2D)mouse model were successfully established using dexamethasone and a high-fat high-sucrose diet with low-dose streptozotocin,respectively.Aloin intervention increased glucose consumption and stimulated the activity of hexokinase and pyruvate dehydrogenase in IR-HepG2 cells.Additionally,it diminished the weight loss,reduced fasting blood glucose levels and hemoglobin A1c activity,and promoted glucose tolerance and fasting serum insulin activity in T2D mice.Histopathological analysis of the liver indicated hepatic protection by aloin.Additionally,aloin treatment inhibited the protein expression of c-Jun N-terminal kinases and activated that of IRS1/PI3K/Akt in the liver.Moreover,aloin modulated the bacterial community in the gut by raising the abundance of Bacteroidota and reducing the richness of Firmicutes,Proteobacteria,and Actinobacteriota.Thus,aloin ameliorated IR via activating IRS1/PI3K/Akt signaling pathway and regulating the gut microbiota,and it may be promising candidate as functional food for diabetic therapy.

Insulin Resistance in Pregnancy Is Correlated with Decreased Insulin Receptor Gene Expression in Omental Adipose: Insulin Sensitivity and Adipose Tissue Gene Expression in Normal Pregnancy

Aims: To determine correlations of insulin sensitivity to gene expression in omental and subcutaneous adipose tissue of non-obese, non-diabetic pregnant women. Methods: Microarray gene profiling was performed on subcutaneous and omental adipose tissue from 14 patients and obtained while fasting during non-laboring Cesarean section, using Illumina HumanHT-12 V4 Expression BeadChips. Findings were validated by real-time PCR. Matusda-Insulin sensitivity index (IS) and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated from glucose and insulin levels obtained from a frequently sampled oral glucose tolerance test, and correlated with gene expression. Results: Of genes differentially expressed in omental vs. subcutaneous adipose, in omentum 12 genes were expressed toward insulin resistance, whereas only 5 genes were expressed toward insulin sensitivity. In particular, expression of the insulin receptor gene (INSR), which initiates the insulin signaling cascade, is strongly positively correlated with IS and negatively with HOMA-IR in omental tissue (r = 0.84). Conclusion: Differential gene expression in omentum relative to subcutaneous adipose showed a pro-insulin resistance profile in omentum. A clinical importance of omental adipose is observed here, as downregulation of insulin receptor in omentum is correlated with increased systemic insulin resistance.

Functional evaluation of the insulin/insulin-like growth factor signaling pathway in determination of wing polyphenism in pea aphid

Wing polyphenism is a common phenomenon that plays key roles in environmental adaptation of insects.Insulin/insulin-like growth factor signaling(IIS)pathway is a highly conserved pathway in regulation of metabolism,development,and growth in metazoans.It has been reported that IS is required for switching of wing morph in brown planthopper via regulating the development of the wing pad.However,it remains elusive whether and how IIS pathway regulates transgenerational wing dimorphism in aphid.In this study,we found that pairing and solitary treatments can induce pea aphids to produce high and low percentage winged offspring,respectively.The expression level of ILP5(insulin-like peptide 5)in maternal head was significantly higher upon solitary treatment in comparison with pairing,while silencing of ILP5 caused no obvious change in the winged offspring ratio.RNA interference-mediated knockdown of FoxO(Forkhead transcription factor subgroup O)in stage 20 embryos significantly increased the winged offspring ratio.The results of pharmacological and quantitative polymerase chain reaction experiments showed that the embryonic insulin receptors may not be involved in wing polyphenism.Additionally,ILP4 and ILP11 exhibited higher expression levels in 1st wingless offspring than in winged offspring.We demonstrate that FoxO negatively regulates the wing morph development in embryos.ILPs may regulate aphid wing polyphenism in a developmental stage-specific manner.However,the regulation may be not mediated by the canonical IIS pathway.The findings advance our understanding of IIS pathway in insect transgenerational wing polyphenism.

Chromium-containing traditional Chinese medicine, Tianmai Xiaoke Tablet improves blood glucose through activating insulin-signaling pathway and inhibiting PTP1B and PCK2 in diabetic rats

OBJECTIVE： Chromium is an essential mineral that is thought to be necessary for normal glucose homeostasis. Numerous studies give evidence that chromium picolinate can modulate blood glucose and insulin resistance. The main ingredient of-13anmai Xiaoke （TMXK） Tablet is chromium picolinate. In China, TMXK Tablet is used to treat type 2 diabetes. This study investigated the effect of TMXK on glucose metabolism in diabetic rats to explore possible underlying molecular mechanisms for its action. METHODS： Diabetes was induced in rats by feeding a high-fat diet and subcutaneously injection with a single dose of streptozotocin （50 mg/kg, tail vein）. One week after streptozotocin-injection, model rats were divided into diabetic group, low dose of TMXK group and high dose of TMXK group. Eight normal rats were used as normal control. After 8 weeks of treatment, skeletal muscle was obtained and was analyzed using Roche NimbleGen mRNA array and quantitative polymerase chain reaction （qPCR）. Fasting blood glucose, oral glucose tolerance test and homeostasis model assessment of insulin resistance （HOMA-IR） index were also measured. RESULTS： The authors found that the administration of TMXK Tablet can reduce the fasting blood glucose and fasting insulin level and HOMA-IR index. The authors also found that 2 223 genes from skeletal muscle of the high-dose TMXK group had significant changes in expression （1 752 increased, 471 decreased）. Based on Kyoto encyclopedia of genes and genomes pathway analysis, the most three significant pathways were ＂insulin signaling pathway＂, ＂glycolysis/ gluconeogenesis＂ and ＂citrate cycle （-ICA）＂. qPCR showed that relative levels of forkhead box 03 （Fox03）, phosphoenolpyruvate carboxykinase 2 （Pck2）, and protein tyrosine phosphatase 1B （Ptplb） were significantly decreased in the high-dose TMXK group, while v-akt murine thymoma viral oncogene homolog 1 （Aktl） and insulin receptor substrate 2 （Its2） were increased. CONCLUSION： Our data show that TMXK Tablet reduces fasting glucose level and improves insulin resistance in diabetic rats. The mechanism may be linked to the inactivation of PTP1B and PCK enzymes, or through intracellular pathways, such as the insulin signaling pathway.

AT1 receptor downregulation:A mechanism for improving glucose homeostasis

There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1receptor could have beneficial effects in treating metabolic syndrome and type 2diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.

Insulin-like signaling pathway functions in integrative response to an olfactory and a gustatory stimuli in Caenorhabditis elegans

Animals integrate various environmental stimuli within the nervous system to generate proper behavioral responses.However,the underlying neural circuits and molecular mechanisms are largely unknown.The insulinlike signaling pathway is known to regulate dauer formation,fat metabolism,and longevity in Caenorhabditis elegans(C.elegans).Here,we show that this highly conserved signaling pathway also functions in the integrative response to an olfactory diacetyl and a gustatory Cu^(2+) stimuli.Worms of wild-type N2 Bristol displayed a strong avoidance to the Cu^(2+) barrier in the migration pathway to the attractive diacetyl.Mutants of daf-2(insulin receptor),daf-18(PTEN lipid phosphatase),pdk-1(phosphoinositide-dependent kinase),akt-1/-2(Akt/PKB kinase)and sgk-1(serum-and glucocorticoidinducible kinase)show severe defects in the elusion from the Cu^(2+) .Mutations in DAF-16,a forkhead-type transcriptional factor,suppress the integrative defects of daf-2 and akt-1/-2 mutants.We further report that neither cGMP nor TGFβpathways,two other dauer formation regulators,likely plays a role in the integrative learning.These results suggest that the insulin-like signaling pathway constitutes an essential component for sensory integration and decision-making behavior plasticity.

What is the gut feeling telling us about physical activity in colorectal carcinogenesis?

In the last decades,more efforts are focused on the prevention and treatment of malignant diseases,given the increase in all cancers incidence A lifestyle change,including healthy eating habits and regular physical activity,has significantly impacted colorectal cancer prevention.The effect of dose-dependent physical activity on mortality and recurrence rates of colorectal carcinoma has been unequivocally demonstrated in observational studies.However,clear recommendations are not available on the frequency,duration,and intensity of exercise in patients with colorectal cancer due to the lack of evidence in randomized clinical trials.Regarding pathophysiological mechanisms,the most plausible explanation appears to be the influence of physical activity on reducing chronic inflammation and insulin resistance with a consequent positive effect on insulin growth factor 1 signaling pathways.

Network pharmacology research and experimental validation of Qishen decoction in the treatment of non-alcoholic fatty liver disease

Objective:To screen the main active components of Qishen decoction by network pharmacology and predict the target of its treatment for nonalcoholic fatty liver disease(NAFLD),and to verify it by experiments.Methods:The main active components of Qishen decoction and the disease target of NAFLD were screened through the database;the drug disease target network and PPI were constructed by the software of Cytoscape and string database;the enrichment of go and KEGG were analyzed by the database of DAVID;HE staining,red oil O staining,serum biochemical index and Western blot were used to verify the effect mechanism of Qishen Decoction on NAFLD.Results:A total of 207 active compounds and 95 drug-disease-targets of Qishen Decoction were selected in this study.The results of KEGG enrichment analysis showed that the mechanism of Qishen decoction in the treatment of NAFLD involved adipocytokines,insulin signaling pathway,fatty acid biosynthesis,etc.The results showed that Qishen decoction could significantly reduce the liver NAS score and oil red O staining area of NAFLD rats(P<0.05).At meanwhile,Qishen decoction significantly reduced the levels of serum glucose,insulin,HOMA-IR,TC,TG,AST and ALT in NAFLD rats(P<0.05).In addition,Qishen decoction can significantly up regulate the expression of p-INSRβin liver tissue,down regulate the expression of SREBP-1c,Fas and p-ACC(P<0.05).Conclusion:Qishen decoction can improve the insulin resistance of NAFLD rats through insulin signaling pathway,so as to improve NAFLD fat deposition and liver injury.In addition,Qishen decoction can also achieve the therapeutic effect of NAFLD through multiple channels and targets.

Ab-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Ab Secretion in Neural Cells

Alzheimer＇s disease（AD） is characterized by amyloid-b（Ab） toxicity,tau pathology,insulin resistance,neuroinflammation,and dysregulation of cholesterol homeostasis,all of which play roles in neurodegeneration.Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes.In this study,we investigated possible relationships among insulin signaling and cholesterol biosynthesis,along with the effects of Ab42 on these pathways in vitro.We found that neuroblastoma 2a（N2a） cells transfected with the human gene encoding amyloid-b protein precursor（Ab PP）（N2aAb PP） produced Ab and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment,and by increased phosphorylation of insulin receptor subunit-1 at serine 612（p-IRS-S612） as compared to parental N2 a cells.Treatment of human neuroblastoma SH-SY5 Y cells with Ab42 also increased p-IRS-S612,suggesting that Ab42 is responsible for insulin resistance.The insulin resistance was alleviated when N2a-Ab PP cells were treated with higher insulin concentrations.Insulin increased Ab release from N2 aAb PP cells,by which it may promote Ab clearance.Insulin increased cholesterol-synthesis gene expression in SHSY5 Y and N2 a cells,including 24-dehydrocholesterol reductase（DHCR24） and 3-hydroxy-3-methyl-glutaryl-Co A reductase（HMGCR） through sterol-regulatory element-binding protein-2（SREBP2）.While Ab42-treated SH-SY5 Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses,they also showed down-regulation of neuro-protective/antiinflammatory DHCR24.These results suggest that Ab42 may cause insulin resistance,activate JNK for c-Jun phosphorylation,and lead to dysregulation of cholesterol homeostasis,and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote Ab release for clearance from neural cells.

SX-fraction:Promise for novel treatment of type 2 diabetes

SX-fraction(SXF)is a bioactive glycoprotein with anti-diabetic and hypoglycemic activities that have been documented in several reports.We have reviewed those studies herein and also explored the possible mechanism of its hypoglycemic activity.The early animal studies of SXF using diabetic mice showed the significant reduction in the three diabetic parameters,serum glucose,insulin,and triglyceride,suggesting its anti-diabetic activity.The limited clinical studies also showed that SXF led to the significant reduction in the fasting blood glucose levels of type 2 diabetic patients within 2 wk or a month,suggesting its hypoglycemic activity.To explore the hypoglycemic mechanism of SXF,its possible effects on the insulin signal transduction pathway was examined in vitro.Particularly,activities of insulin receptor,insulin receptor substrate 1,and protein kinase B,which are essential elements playing a key regulatory role in the signal pathway,were studied using skeletal muscle L6 cells.The status of these three parameters were examined under a high glucose(35 mmol/L)milieu with SXF and assessed using the enzyme-linked immunosorbent assay.Such studies revealed that all three parameters(insulin receptor,insulin receptor substrate 1,and protein kinase B)were inactivated by high glucose,indicating a disruption of the signal pathway.However,such an inactivation was reversed or re-activated by SXF to successfully carry out the sequential signaling events.In fact,a measurement of glucose uptake in cells showed that SXF did increase a glucose uptake while high glucose decreased it.Therefore,SXF has anti-diabetic and hypoglycemic activities through activation of the insulin signal pathway and appears to be a safe,natural agent for lowering the serum glucose levels in type 2 diabetic patents and improving their diabetic conditions.

Potent Therapeutic Effects of Shouwu Jiangqi Decoction(首乌僵芪汤)on Polycystic Ovary Syndrome with Insulin Resistance in Rats

Objective：To investigate the effect of Shouwu Jiangqi Decoction（首乌僵芪汤,SJD） on polycystic ovary syndrome（PCOS） with insulin resistance（IR） in rats and to explore the underlining molecular mechanisms.Methods：A total of 51 female Sprague-Dawley rats were randomly divided into 6 groups：control group（n=7）,model group（n=8）,SJD high-dose group（n=9）,SJD medium-dose group（n=9）,SJD low-dose group（n=9） and DMBG group（n=9）.Radioimmunoassay was used to measure serum follicle-stimulating hormone（FSH）,luteinizing hormone（LH） and testosterone concentrations and qRT-PCR and western blot were used to examine the expression levels of mRNA and protein respectively of insulin receptor substrate 1（IRS-1）and phosphatidylinositide 3-kinases（PI3K） p85α in different groups.Results：FSH level significantly decreased in the model group compared with the normal control（P〈0.01）,and high-dose SJD and DMBG can significantly increase FSH level（P〈0.01）.LH level showed a mild increase without statistic significance in the model group compared with the control and different dosages of SJD had no significance effect on LH level,while DMBG can significantly decrease LH level（P〈0.01）.Testosterone level significantly increased in the model group compared with the control group（P〈0.01）,and high-dose SJD and DMBG can significantly decrease testosterone level（P〈0.01）.The expression of IRS-1 as well as PI3Kp85α were significantly decreased in the model group compared with the normal control group at both mRNA（P〈0.001） and protein（P〈0.01） level,and both high-dose SJD and DMBG can enhance IRS-1 and PI3 K expression（P〈0.05）.Conclusions：SJD has potent therapeutic effects on PCOS with IR in rats.The therapeutic effects of SJD on IR and ovulatory dysfunction are probably achieved through correcting the defective insulin signaling transduction.

Regulation of the PI3K/AKT Pathway and Fuel Utilization During Primate Torpor in the Gray Mouse Lemur, Microcebus murinus

Gray mouse lemurs（Microcebus murinus） from Madagascar present an excellent model for studies of torpor regulation in a primate species. In the present study, we analyzed the response of the insulin signaling pathway as well as controls on carbohydrate sparing in six different tissues of torpid versus aroused gray mouse lemurs. We found that the relative level of phospho-insulin receptor substrate（IRS-1） was significantly increased in muscle, whereas the level of phospho-insulin receptor（IR） was decreased in white adipose tissue（WAT） of torpid animals, both suggesting an inhibition of insulin/insulin-like growth factor-1（IGF-1） signaling during torpor in these tissues. By contrast, the level of phospho-IR was increased in the liver. Interestingly, muscle,WAT, and liver occupy central roles in whole body homeostasis and each displays regulatory controls operating at the plasma membrane. Changes in other tissues included an increase in phosphoglycogen synthase kinase 3a（GSK3a） and decrease in phospho-ribosomal protein S6（RPS6） in the heart, and a decrease in phospho-mammalian target of rapamycin（m TOR） in the kidney. Pyruvate dehydrogenase（PDH） that gates carbohydrate entry into mitochondria is inhibited via phosphorylation by pyruvate dehydrogenase kinase（e.g., PDK4）. In the skeletal muscle, the protein expression of PDK4 and phosphorylated PDH at Ser 300 was increased, suggesting inhibition during torpor. In contrast, there were no changes in levels of PDH expression and phosphorylation in other tissues comparing torpid and aroused animals. Information gained from these studies highlight the molecular controls that help to regulate metabolic rate depression and balance energetics during primate torpor.