Asiaticoside ameliorates type 2 diabetes mellitus in rats by modulating carbohydrate metabolism and regulating insulin signaling

Objective:To evaluate the effect of asiaticoside on streptozotocin(STZ)and nicotinamide(NAD)-induced carbohydrate metabolism abnormalities and deregulated insulin signaling pathways in rats.Methods:Asiaticoside(50 and 100 mg/kg body weight)was administered to STZ-NAD-induced diabetic rats for 45 days,and its effects on hyperglycaemic,carbohydrate metabolic,and insulin signaling pathway markers were examined.Results:Asiaticoside increased insulin production,lowered blood glucose levels,and enhanced glycolysis by improving hexokinase activity and suppressing glucose-6-phosphatase and fructose-1,6-bisphosphatase activities.Abnormalities in glycogen metabolism were mitigated by increasing glycogen synthase activity and gluconeogenesis was decreased by decreasing glycogen phosphorylase activity.Furthermore,asiaticoside upregulated the mRNA expressions of IRS-1,IRS-2,and GLUT4 in STZ-NAD-induced diabetic rats and restored the beta cell morphology to normal.Conclusions:Asiaticoside has the potential to ameliorate type 2 diabetes by improving glycolysis,gluconeogenesis,and insulin signaling pathways.

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.

Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice

Icariin,a major prenylated flavonoid found in Epimedium spp.,is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease.In this study,we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease.We performed behavioral tests,pathological examination,and western blot assay,and found that memory deficits of the model mice were obviously improved,neuronal and synaptic damage in the cerebral cortex was substantially mitigated,and amyloid-βaccumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day.Furthermore,deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed,including the insulin receptor,insulin receptor substrate 1,phosphatidylinositol-3-kinase,protein kinase B,and glycogen synthase kinase 3β,and the levels of glucose transporter 1 and 3 were markedly increased.These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer’s disease by regulating brain insulin signaling and glucose transporters,which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer’s disease.

LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR

Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.

Micro RNA-185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non-alcoholic fatty liver disease

AIM: To assess the regulatory effect of microRNA-185 (miR-185) on lipid metabolism and the insulin signalling pathway in human HepG2 hepatocytes and a high-fat diet mouse model.

Distinguishing normal brain aging from the development of Alzheimer＇s disease：inflammation,insulin signaling and cognition

As populations age, prevalence of Alzheimer＇s disease（AD） is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.

interrelationships between ghrelin, insulin and glucose homeostasis: physiological relevance

Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated(AG) and unacylated(UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesityrelated disorders. However, due to the complexity ofits biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis.

Defect of insulin signal in peripheral tissues: important role of ceramide

In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions:to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver.Interestingly,dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues.Normally,the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods.Thus,adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides.When the buffering action of adipose tissue to store fatty acids is impaired,fatty acids that build up in othertissues are metabolized as sphingolipid derivatives such as ceramides.Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.

Novel soybean peptide iglycin ameliorates insulin resistance of high-fat diet fed C57BL/6J mice and differentiated 3T3L1 adipocytes with improvement of insulin signaling and mitochondrial function

Soy consumption has been associated with potential health benefits in reducing chronic diseases.These physiological functions have been attributed to soy proteins or more commonly to bioactive peptides.Thus,more studies are required to identify these bioactive peptides,and elucidate their biological mechanisms of action.In the present study,a novel peptide iglycin was purifi ed from soybean seeds with a molecular mass of 3.88 k Da.Thereafter,iglycin reduced fasting blood glucose and restored insulin sensitivity of C57 BL/6 J mice on a high-fat diet with increased phosphorylation of insulin receptor substrate 1(IRS1)and AKT in adipose tissue.Furthermore,it improved glucose uptake,induced translocation of intracellular GLUT4 to plasma membrane and activation of insulin signaling in adipocytes under insulin-resistant condition.In addition,it decreased reactive oxygen species production,lipid peroxidation and inhibited adipocyte apoptosis with improved mitochondrial function as evidenced by up-regulation of succinate dehydrogenase activity,mitochondrial membrane potential and intracellular ATP store.These data suggested that iglycin ameliorated insulin resistance via activation of insulin signaling,which was associated with inhibition of oxidative stress,adipocyte apoptosis,and improvement of mitochondrial function.

Renal gluconeogenesis in insulin resistance:A culprit for hyperglycemia in diabetes

Renal gluconeogenesis is one of the major pathways for endogenous glucose production.Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes.We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes.A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up.Insulin-resistant models exhibit reduced insulin receptor(IR)expression and/or post-receptor signaling in their kidney tissue.Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys,which may increase renal gluconeogenesis in the state of insulin resistance.It is now established that the kidney contributes up to 20%of all glucose production via gluconeogenesis in the post-absorptive phase.However,the rate of renal glucose release excessively increases in diabetes.The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels.Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis.Overall,the available literature suggests that impairment in renal gluconeogenesis in an insulinresistant state may contribute to hyperglycemia in type 2 diabetes.

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.

Chronic Hyperinsulinism Induced Down-regulation of Insulin Post-Receptor Signaling Transduction in Hep G2 Cells

To study the regulatory effect of acute and chronic insulin treatmenton insulin post- re- ceptor signaling transduction pathway in a human hepatom a cell line (Hep G2 ) ,Hep G2 cells were incubated in the presence or absence of insulin with different concentrations in serum free m edia for16 h and then stim ulated with10 0 nmol/ L insulin for1m in.Protein levels of insulin receptor β- subunit(IRβ) ,insulin receptor substrate- 1(IRS- 1) and p85 subunit of phosphatidylinositol3- kinase(PI3- kinase) were determined in total cell lysates by Western- im munoblot.Phosphorylat- ed proteins IRβ,IRS- 1and interaction of PI3- kinase with IRS- 1were determ ined by im munopre- cipitation.Results showed that 1- min insulin stimulation rapidly induced tyrosine phosphorylation of IRβ and IRS- 1,which in turn,resulting in association of PI 3- kinase with IRS- 1.1- 10 0 nm ol/ L chronic insulin treatment induced a dose- dependent decrease in the protein level of IRβ and a slight decrease in the protein level of IRS- 1.There was a m ore marked reduction in the phospho- rylation of IRβ,IRS- 1,reaching a nadir of2 2 % (P<0 .0 1) and15 % (P<0 .0 1) of control lev- els,respectively,after16 h treatment with 10 0 nm ol/ L insulin.The association between IRS- 1 and PI3- kinase was decreased by6 6 % (P<0 .0 1) .There was no significant change in PI3- ki- nase protein levels. These data suggest that chronic insulin treatm ent can induce alterations of IRβ,IRS- 1and PI 3- kinase three early steps in insulin action,which contributes significantly to insulin resistance,and may account for desensitization of insulin action.

Bitter gourd extract improves glucose homeostasis and lipid profile via enhancing insulin signaling in the liver and skeletal muscles of diabetic rats

Objective:To investigate the modulatory effects of bitter gourd extract on the insulin signaling pathway in the liver and skeletal muscle tissues of diabetic rats.Methods:The ethanolic extract of bitter gourd was prepared and its contents of total polyphenols and flavonoids were assayed.A neonatal streptozotocin-induced diabetic rat model was established and the diabetic rats were assigned into different groups and were treated with different doses of bitter gourd extract(100,200,400,or 600 mg/kg)or with glibenclamide(0.1 mg/kg)for 30 d.Fasting blood glucose,insulin,and lipid profile were evaluated and the insulin signaling pathway in the liver and skeletal muscle of rats was investigated.The correlations between homeostasis model assessment(HOMA)and the components of insulin signaling pathway were also evaluated.Results:Different doses of bitter gourd extract significantly ameliorated fasting blood glucose level and HOMA index for insulin resistance.Moreover,bitter gourd extract increased serum insulin and improved disrupted serum lipid profile.The levels of insulin receptor substrate-1(IRS-1),p-insulin receptorβ(p-IR-β),protein kinase C(PKC),GLUT2,and GLUT4 were improved by treatment with bitter gourd extract.The best results were obtained with 400 mg/kg dose of the extract,the effect of which was equivalent to that of glibenclamide.HOMA in the bitter gourd treated rats was negatively correlated with p-IR-β,IRS-1 and PKC in hepatic and skeletal muscle.HOMA was also negatively correlated with skeletal muscle GLUT4.Conclusions:Bitter gourd extract improves glucose homeostasis and lipid profile in diabetic rats via enhancement of insulin secretion and sensitivity.Therefore,bitter gourd can be used as a potential pharmacological agent for the treatment of type 2 diabetes mellitus.

Effects of Omethoate on Liver Insulin Signaling in Mice

According to the report of the International Diabetes Federation, there were 382 million people affected with diabetes in 2013 and it is expected that this number will increase to 592 million by the year 2035;. Diabetes is caused due to the interaction between environmental and genetic factors;.

Effect of puerarin on the P13K pathway for glucose transportation and insulin signal transduction in adipocytes

To explore the effect of puerarin on insulin receptor （IR）, insulin receptor substrate-1 （IRS-1） and protein expression of protein kinase B （PKB） in the P13K pathway of the glucose consumption, transportation and insulin signal transduction in 3T3-L1 adipoeytes with insulin resistance. The insulin resistance 3T3-L1 adipocytes model was established by free fatty acid induction. The model cells were managed with puerarin in different concentrations. Glucose consumption was detected with glucose oxidase method, glucose transportation rate was determined by 2-deoxy-^3H glucose ingesting method, and the IR, IRS-1 and PKB expression were determined by Western blot. Glucose consumption and transportation were significantly decreased in the model adipoeytes, but increased after treated with puerarin （P 〈 0. 01 ）. Moreover, the level of tyrosine phosphorylation of IR subunit β was higher in the puerarin treated groups, and that of IRS-1 was higher in the group treated with low dose puerarin than that in the model group. The 3T3-L1 adipocytes of insulin resistance model could be induced by free fatty acid successfully, puerarin could promote the glucose utilization in them to alleviate the in- sulin resistance, which may be related with the action in advancing the tyrosine phosphorylation of IR and IRS-1.

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.

Partners in diabetes epidemic:A global perspective

There is a recent increase in the worldwide prevalence of both obesity and diabetes.In this review we assessed insulin signaling,genetics,environment,lipid metabolism dysfunction and mitochondria as the major determinants in diabetes and to identify the potential mechanism of gut microbiota in diabetes diseases.We searched relevant articles,which have key information from laboratory experiments,epidemiological evidence,clinical trials,experimental models,metaanalysis and review articles,in PubMed,MEDLINE,EMBASE,Google scholars and Cochrane Controlled Trial Database.We selected 144 full-length articles that met our inclusion and exclusion criteria for complete assessment.We have briefly discussed these associations,challenges,and the need for further research to manage and treat diabetes more efficiently.Diabetes involves the complex network of physiological dysfunction that can be attributed to insulin signaling,genetics,environment,obesity,mitochondria and stress.In recent years,there are intriguing findings regarding gut microbiome as the important regulator of diabetes.Valid approaches are necessary for speeding medical advances but we should find a solution sooner given the burden of the metabolic disorder―What we need is a collaborative venture that may involve laboratories both in academia and industries for the scientific progress and its application for the diabetes control.

Exposure to Electromagnetic Fields from Mobile Phones and Fructose consumption Coalesce to Perturb Metabolic Regulators AMPK/SIRT1-UCP2/FOXO1 in Growing Rats

Objective In this study,the combined effect of two stressors,namely,electromagnetic fields(EMFs)from mobile phones and fructose consumption,on hypothalamic and hepatic master metabolic regulators of the AMPK/SIRT1-UCP2/FOXO1 pathway were elucidated to delineate the underlying molecular mechanisms of insulin resistance.Methods Weaned Wistar rats(28 days old)were divided into 4 groups:Normal,Exposure Only(ExpO),Fructose Only(FruO),and Exposure and Fructose(EF).Each group was provided standard laboratory chow ad libitum for 8 weeks.Additionally,the control groups,namely,the Normal and FruO groups,had unrestricted access to drinking water and fructose solution(15%),respectively.Furthermore,the respective treatment groups,namely,the ExpO and EF groups,received EMF exposure(1,760 MHz,2 h/day x 8 weeks).In early adulthood,mitochondrial function,insulin receptor signaling,and oxidative stress signals in hypothalamic and hepatic tissues were assessed using western blotting and biochemical analysis.Result In the hypothalamic tissue of EF,SIRT1,FOXO 1,p-PI3K,p-AKT,ComplexⅢ,UCP2,MnSOD,and catalase expressions and OXPHOS and GSH activities were significantly decreased(P<0.05)compared to the Normal,ExpO,and FruO groups.In hepatic tissue of EF,the p-AMPKα,SIRT1,FOXO1,IRS1,p-PI3K,ComplexⅠ,Ⅱ,Ⅲ,Ⅳ,Ⅴ,UCP2,and MnSOD expressions and the activity of OXPHOS,SOD,catalase,and GSH were significantly reduced compared to the Normal group(P<0.05).Conclusion The findings suggest that the combination of EMF exposure and fructose consumption during childhood and adolescence in Wistar rats disrupts the closely interlinked and multi-regulated crosstalk of insulin receptor signals,mitochondrial OXPHOS,and the antioxidant defense system in the hypothalamus and liver.

Diabetes and cognitive decline:Challenges and future direction

There is growing evidence that diabetes can induce cognitive decline and dementia.It is a slow,progressive cognitive decline that can occur in any age group,but is seen more frequently in older individuals.Symptoms related to cognitive decline are worsened by chronic metabolic syndrome.Animal models are frequently utilized to elucidate the mechanisms of cognitive decline in diabetes and to assess potential drugs for therapy and prevention.This review addresses the common factors and pathophysiology involved in diabetes-related cognitive decline and outlines the various animal models used to study this condition.

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.