High Glucose Diet Research Articles

Changes of insulin receptors in high fat and high glucose diet mice with insulin resistance

ABSTRACT This study aimed to observe the expression of insulin-signaling molecules in different organs of mice with insulin resistance (IR). Firstly, mice were fed a high-fat and high-sugar diet (HF group) to establish an IR model, and the controls (NF group) were fed with a normal diet. Next, the weight, fasting blood glucose (FBG), serum insulin and insulin tolerance were detected. Pathological changes of liver tissues were observed by H&E staining. The expressions of INSR, IRS-1 and IRS-2 in the liver, skeletal muscle and ovary were measured by qRT-PCR and western blotting. As a result, compared with the NF group, the HF group mice had increased weight, FBG, insulin and IR index after 6-week of feeding as well as a worse performance in the insulin tolerance test and H&E staining showed fatty liver-like changes after 12-week of feeding, exhibited lower expression of INSR, IRS-1 and IRS-2 in the liver of mice at 6 and 12 weeks. The expression of INSR and IRS-1 in skeletal muscle tissues exhibited the same trend, while those in ovary organs showed the opposite trend. These results suggested that the insulin signaling alters in the liver, skeletal muscle and ovary organs with the progress of IR.

The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging

While disorders in lipid metabolism have been associated with aging and age-related diseases, how lipid metabolism is regulated during aging is poorly understood. Here, we characterize the Drosophila endoribonuclease CG2145, an ortholog of mammalian EndoU that we named Age-related lipid regulator (Arlr), as a regulator of lipid homeostasis during aging. In adult adipose tissues, Arlr is necessary for maintenance of lipid storage in lipid droplets (LDs) as flies age, a phenotype that can be rescued by either high-fat or high-glucose diet. Interestingly, RNA-seq of arlr mutant adipose tissues and RIP-seq suggest that Arlr affects lipid metabolism through the degradation of the mRNAs of lipolysis genes – a model further supported by the observation that knockdown of Lsd-1, regucalcin, yip2 or CG5162, which encode genes involved in lipolysis, rescue the LD defects of arlr mutants. In addition, we characterize DendoU as a functional paralog of Arlr and show that human ENDOU can rescue arlr mutants. Altogether, our study reveals a role of ENDOU-like endonucleases as negative regulator of lipolysis.

Dangua Fang regulating tricarboxylic acid cycle and respiratory chain and its mechanism in diabetic rats.

To investigate the influence and possible targets of Dangua Fang on tricarboxylic acid (TCA) cycle and respiratory chain to enrich the prescription's mechanism of effective intervention on glycolipid metabolic diseases such as type 2 diabetes. After interventional rats were fed with high glucose and high fat diet ad libitum for 4 weeks, intraperitoneally injected streptozotocin to induce diabetic model. According to blood glucose level,28 diabetic rats were selected and continued to be fed with high glucose and high fat diet, were stratified by body weight, and divided randomly by blood glucose into Model group (was given sterile water by gastric perfusion and injected aquae pro injection intraperitoneally), Dangua group [Dangua liquor 20.5 g·kg-1·d-1 by perfusion and aquae pro injection intraperitoneally], Inhibitor group [sterile water by perfusion and nicotinamide phosphoribosyl transferase (Nampt) specific blocker GEN-617 1.25 mg/kg intraperitoneally], DanInhit group (Dangua liquor and GEN-617 synchronously). Control group were continuously fed with ordinary diet. The intervention was last for 10 weeks. Body weight (BW), liver index (LI), glycosylated hemoglobin (HbA1c), TC, TG, free fatty acids (FFA), creatinine (Cr), and A-ketoglutarate (α-KG), Iso-citric acid (ICA), oxaloacetic acid (OAA) were tested. The cytochrome C oxidase (COX) and Succinate dehydrogenase (SDH) were evaluated by Colorimetry; Nampt protein, Adenosine triphosphate (ATP) synthase (ATPs), Nicotinamide adenine dinucleotide (NAD+)and its reduced (NADH) in liver were measured by enzyme linked immunosorbent assay. The expressions of Nampt and mitochondrialnadhdehydrogenase-1 (mt-ND1) gene in liver was assessed by real-time polymerase chain reaction. Hepatic tissue staining was also completed. The levels of BW, ICA, α-KG and Nampt-mRNA in the Model group are lower than that in the Normal group (P < 0.05), conversely, liver weight, LI, TC, HbA1c, SDH and ATPs, mt-ND1-mRNA, and Nampt protein in the Model group are higher (P < 0.01, P < 0.05). Compared with Model group, the levels of ICA, Nampt-mRNA and Nampt in Dangua group are significantly increased, and FFA obviously raised (P < 0.01 and P < 0.05); liver weight, BW, SDH are obviously lower, and HbA1c decreased significantly (P < 0.01, P < 0.05). TG, FFA and Nampt protein increased in the DanInhit group, TC, TG, BW obviously increased in the Inhibitor group, but SDH is decreased in both the two groups (P < 0.05, P < 0.01). Compared with Dangua group, DanInhib group has the lower levels of ICA, mt-ND1-mRNA, Nampt-mRNA, and the higher level of BW, LI and HbA1c. In the Inhibitor group, ICA and Nampt protein decreased, BW and LI, HbA1c and TG increased (P < 0.01 or P < 0.05). Tissue staining display that, in the model group there is obvious pathologic changes ie: fibrosis, steatosis and inflammatory cell infiltration. Lesions in the Dangua group are mild, and those of Inhibitor group are more obvious than the Model group, and DanInhit group is intermediately affected compared to Dangua group and Inhibitor group. Dangua Fang increases the metabolic flux of TCA cycle and optimizes respiratory chain function by up-regulating Nampt expression.

Intestinal GPDH-1 regulates high glucose diet induced lifespan extension in aged worms.

A high glucose diet (HGD) is associated with many metabolic diseases including type 2 diabetes, and cardiovascular diseases. Additionally, a HGD increases the oxidative stress resistance of young animals but shortens their lifespan. To investigate the role of HGD feeding on the aging of aged animals, we tested for oxidative stress resistance and changes in lifespan using C. elegans. We showed that a HGD extends the lifespan of aged worms that are dependent on oxidative stress resistance. Furthermore, we measured the lifespan of oxidative stress responding genes of HGD-fed worms. We found that gpdh-1 and col-92 are highly expressed in HGD and paraquat (PQ) treated worms. Further experiments indicated that intestinal gpdh-1 is essential for the HGD induced lifespan extension of aged worms. Our studies provide new insights into understanding the correlation between glucose metabolism, oxidative stress resistance, and aging.

Neuroprotective role of plumbagin on eye damage induced by high-sucrose diet in adult fruit fly Drosophila melanogaster

The natural compound plumbagin has a wide range of pharmacological and potential therapeutic activities, although its role in neuroretina degeneration is unknown. Here we evaluated the effects of plumbagin on retina homeostasis of the fruit fly Drosophila melanogaster fed with high glucose diet, a model of hyperglycemia-induced eye impairment to study the pathophysiology of diabetic retinopathy at the early stages. To this aim, the visual system of flies orally administered with plumbagin has been analyzed at structural, functional, and molecular/cellular level as for instance neuronal apoptosis/autophagy dysregulation and oxidative stress-related signals. Our results demonstrated that plumbagin ameliorates the visual performance of hyperglycemic flies. Drosophila eye-structure, clearly altered by hyperglycemia, i.e. defects of the pattern of ommatidia, irregular rhabdomeres, vacuoles, damaged mitochondria, and abnormal phototransduction units were rescued, at least in part, by plumbagin. In addition, it reactivated autophagy, decreased the presence of cell death/apoptotic features, and exerted antioxidant effects in the retina. In terms of mechanisms favoring death/survival ratio, Nrf2 signaling activation may be one of the strategies by which plumbagin reduced redox unbalance mainly increasing the levels of glutathione-S-transferase. Likewise, plumbagin may act additively and/or synergistically inhibiting the mitochondrial-endoplasmic reticulum stress and unfolded protein response pathways, which prevented neuronal impairment and eye damage induced by reactive oxygen species. These results provide an avenue for further studies, which may be helpful to develop novel therapeutic candidates and drug targets against eye neurotoxicity by high glucose, a key aspect in retinal complications of diabetes.

Total flavonoids of Hippophae rhamnoides L. improves type 2 diabetes symptoms in rats through down-regulating of the DAG/PRKCA/MAPK10/p65/TNF-α signalling pathway

Ethnopharmacological relevanceDry mature fruits of Hippophae rhamnoides L. (HRL), Elaeagnaceae, have traditional functions of invigorating spleen and improving spleen insufficiency. Traditional Chinese medicine (TCM) clinics have been proved that HRL is in favor of diabetes treatment. Modern pharmacological studies demonstrated that total flavones of Hippophae rhamnoides (TFH) are the main substance for HRL to develop anti-inflammation and anti-diabetes functions. However, chemical features, active ingredients and anti-diabetes pharmacological mechanism of HRL still remain unclear. Aim of the studyKey targets and metabolites in anti-type-II diabetes mellitus (T2DM) of TFH have been explored based on AGE-RAGE signaling pathway in diabetic complications. The anti-T2DM mechanism of TFH has been elaborated from comprehensive perspectives, including target prediction, metabolites, potential metabolic pathways, and so on. Materials and methodsIn this study, a qualitative test of chemical composition of HRL was carried out based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The anti-T2DM targets and pathways of HRL were predicted through network pharmacological approach. The T2DM rat model was induced by high-fat and high-glucose diet combined with streptozotocin (STZ). The T2DM model was evaluated through fasting blood glucose level, body weight, serum biochemical indicators, insulin levels and homeostatic model assessment of insulin resistance. The key metabolic pathways were screened through the correlation between metabolites and key targets. Finally, the quantitative analysis of key targets and metabolites was verified through experiments. ResultsAfter TFH intervention, the fasting blood-glucose level of T2DM rats induced by high-fat and high-glucose diet combined with streptozotocin (STZ) was downregulated significantly, while body weight, serum liquid level, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) were improved. According to ELISA, Western blotting (WB) and reverse transcriptase polymerase chain reaction (RT-PCR), TFH significantly downregulates expression levels of diglyceride (DAG)-activated protein kinase C (PRKCA), mitogen activated protein kinase 10 (MAPK10), human nuclear factor κB subunit p65 (NF-κB p65) and tumor necrosis factor-α (TNF-α) in pancreas of STZ-induced rats. ConclusionsTFH downregulates expressions of PRKCA, MAPK10 and p65 TNF-α as well as level of the key metabolite DA in the DAG/PRKCA/MAPK10/TNF-α/p65 pathways, improves lipid metabolism disorder, inhibits inflammatory response and thereby relieves symptoms of T2DM.

The impact of high-glucose or high-fat diets on the metabolomic profiling of mice.

Diets high in glucose or fat contribute to an increased prevalence of the diseases. Therefore, the objective of the current research was to observe and evaluate the impact of dietary components on different metabolomic profiles in primary tissues of mice. For 8 weeks, diet with high-glucose or-fat was given to C57BL/6 J mice. The levels of metabolites in the primary tissues of mice were studied using gas chromatography-mass spectrometry (GC-MS) and analyzed using multivariate statistics. By comparing the metabolic profiles between the two diet groups and control group in mice main tissues, our study revealed 32 metabolites in the high-glucose diet (HGD) group and 28 metabolites in the high-fat diet (HFD) group. The most significantly altered metabolites were amino acids (AAs; L-alanine, L-valine, glycine, L-aspartic acid, L-isoleucine, L-leucine, L-threonine, L-glutamic acid, phenylalanine, tyrosine, serine, proline, and lysine), fatty acids (FAs; propanoic acid, 9,12-octadecadienoic acid, pentadecanoic acid, hexanoic acid, and myristic acid), and organic compounds (succinic acid, malic acid, citric acid, L-(+)-lactic acid, myo-inositol, and urea). These metabolites are implicated in many metabolic pathways related to energy, AAs, and lipids metabolism. We systematically analyzed the metabolic changes underlying high-glucose or high-fat diet. The two divergent diets induced patent changes in AA and lipid metabolism in the main tissues, and helped identify metabolic pathways in a mouse model.

Tissue regeneration and gut microbiota-skeletal muscle axis via microRNAs and nutrition: a systematic review

Introduction: In the scenario of muscle regeneration in athletes, maintenance of skeletal muscle function is the prerequisite for tissue homeostasis and increased performance. MicroRNAs play a positive role in expanding our understanding of the controlling factors for skeletal muscle function. Recent progress has been made regarding gut microbiota, regenerative nutrition, and skeletal muscle metabolism. Objective: It was to carry out a systematic review of the main relations of regeneration of skeletal muscle-gut microbiota through nutrological functions, cells, and microRNAs. Methods: The systematic review rules of the PRISMA Platform were followed. The research was carried out from February to April 2023 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 217 articles were found. A total of 97 articles were fully evaluated and 49 were included and developed in the present systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 54 studies at high risk of bias and 34 studies that did not meet the GRADE. It was concluded that miRNAs are widely present in skeletal muscle and play an irreplaceable tuning role in the proliferation, differentiation, apoptosis, development, and other physiological processes of skeletal muscle cells. The proposal that miRNAs are primarily involved in the cell's stress response makes miRNAs ideal for mediating the skeletal muscle response to changes in contractile activity. Research has accumulated evidence that confirms that miRNAs have played an important regulatory role in cell proliferation and differentiation, thus regulating skeletal muscle growth as highlighted in the small intestine by intestinal stem cells (LGR5+). The ketogenic or high-glucose diet regulates the self-renewal balance of LGR5+. Self-renewal and HSC differentiation can be regulated by manipulating vitamin C, A, or D levels and valine restriction. The composition of each athlete's microbiome influences sports performance.

Regulatory mechanisms of glucose absorption in the mouse proximal small intestine during fasting and feeding

Fasting is known to alter the function of various organs and the mechanisms of glucose metabolism, which affect health outcomes and slow aging. However, it remains unclear how fasting and feeding affects glucose absorption function in the small intestine. We studied the effects of the fasting and feeding on glucose-induced short-circuit current (Isc) in vitro using an Ussing chamber technique. Glucose-induced Isc by SGLT1 was observed in the ileum, but little or no Isc was observed in the jejunum in ad libitum-fed mice. However, in mice fasted for 24–48 h, in addition to the ileum, robust glucose-induced Isc was observed over time in the jejunum. The expression of SGLT1 in the brush border membranes was significantly decreased in the jejunum under fed conditions compared to 48 h fasting, as analyzed by western blotting. Additionally, when mice were fed a 60% high glucose diet for 3 days, the increase in glucose-induced Isc was observed only in the ileum, and totally suppressed in the jejunum. An increase in Na+ permeability between epithelial cells was concomitantly observed in the jejunum of fasted mice. Transepithelial glucose flux was assessed using a non-metabolizable glucose analog, 14C-methyl α-d-glucopyranoside glucose (MGP). Regardless of whether fed or fasted, no glucose diffusion mechanism was observed. Fasting increased the SGLT1-mediated MGP flux in the jejunum. In conclusion, segment-dependent up- and down-regulation mechanisms during fasting and feeding are important for efficient glucose absorption once the fast is broken. Additionally, these mechanisms may play a crucial role in the small intestine's ability to autoregulate glucose absorption, preventing acute hyperglycemia when large amounts of glucose are ingested.

Mathematical model for BCG-based treatment of type 1 diabetes

This work introduces the first model of immunotherapy treatment, namely the Bacillus Calmette-Guerin (BCG) vaccine, for Type 1 Diabetes (T1D). The model takes into consideration the interaction network between multiple immune cell types and compartments. A set of ordinary differential equations (ODEs) is introduced to capture the connectivity between these variables and the clinical presentation of the disease. Four subsets of the T1D mice and healthy controls that exhibit normal and high-level glucose consumption are evaluated using the proposed model. Numerical results obtained for mice suggest that BCG treatment of the T1D patients that follow healthy eating habits normalizes glucose to levels observed in non-diabetic controls. Furthermore, glucose consumption profoundly influences disease progression. This outcome suggests that immunotherapy may modulate molecular and cellular manifestations of the disease but it does not eliminate T1D. Of note, our data, obtained from numerical simulations, indicate that the BCG immunotherapy treatment may benefit healthy controls on a high-glucose diet and can be used as a tool for further clinical investigation of BCG usage to control T1D.

Harnessing Ashitaba Extract: A Promising Solution for Regulating Blood Glucose in High Glucose Diet Mice

Diabetes mellitus (DM) is a metabolic disorder characterized by elevated blood sugar levels brought on by a deficiency in insulin quality, production, or both. In order to achieve the projected target blood glucose levels and limit the progression of sickness, diet continues to be the first line of ongoing effort. This study aims to determine how ashitaba extract influences blood glucose decrease. The study's subjects were healthy mice over a month old weighing 30–40 grams. The sample consisted of 30 mice in total. The One Way Anova statistical test was utilized for data analysis in this study. The outcomes demonstrated that administering Ashitaba extracts to hyperglycemic mice decreased blood glucose levels, as evidenced by a sig value of 0.004 (sig α &lt; 0.05).

Study on the therapeutic effect and mechanism of Tangningtongluo Tablet on diabetic mice

AimsTo investigate the therapeutic effects of Tangningtongluo Tablet on diabetic mice and its mechanism. This study was established the scientific basis for the clinical application of Tangningtongluo Tablet in the treatment of diabetes mellitus and provided data supporting the transformation of Tangningtongluo Tablet from an in-hospital preparation to a new Chinese medicine. MethodsIn this study, a diabetic mouse model was established by high-glucose and high-fat diet feeding in combination with STZ injection for 4 weeks. Glucose metabolism, lipid metabolism, liver histomorphological changes and liver function related indexes were detected, pancreatic histomorphological changes and insulin resistance related indexes were observed, and the expression of pathway related proteins and inflammatory factors were examined. ResultsGlycemia and glycated hemoglobin were reduced in diabetic mice after the treatment of Tangningtongluo Tablet, and glucose tolerance and lipid results were modified. The insulin resistance status of the mice was diminished and tissue damage to the pancreas and liver was repaired. Expression of ERS/NF-κB related pathway proteins was reduced in liver tissues, and inflammatory factors such as TNF-α, IL-6 and IL-1β were reduced in serum. ConclusionsTangningtongluo Tablet could reduce blood glucose in diabetic mice, regulate the disorder of lipid metabolism, enhance insulin sensitivity, improve insulin resistance, repair pancreatic tissue damage and protect mouse liver in diabetic mice. The mechanism of action might be related to the regulation of ERS/NF-κB signaling pathway and the reduction of TNF-α, IL-6 and IL-1β production.

Vitamin D supplementation alleviates insulin resistance in prediabetic rats by modifying IRS-1 and PPARγ/NF-κB expressions.

Prediabetes is a condition of intermediate hyperglycemia that may progress to type 2 diabetes. Vitamin D deficiency has been frequently linked to insulin resistance and diabetes. The study aimed to investigate the role of D supplementation and its possible mechanism of action on insulin resistance in prediabetic rats. The study was conducted on 24 male Wistar rats that were randomly divided into 6 rats as healthy controls and 18 prediabetic rats. Prediabetic rats were induced with a high-fat and high-glucose diet (HFD-G) combined with a low dose of streptozotocin. Rats with the prediabetic condition were then randomized into three groups of 12-week treatment: one group that received no treatment, one that received vitamin D3 at 100 IU/kg BW, and one group that received vitamin D3 at 1000 IU/kg BW. The high-fat and high-glucose diets were continuously given throughout the twelve weeks of treatment. At the end of the supplementation period, glucose control parameters, inflammatory markers, and the expressions of IRS1, PPARγ, NF-κB, and IRS1 were measured. Vitamin D3 dose-dependently improves glucose control parameters, as shown by the reduction of fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated albumin, insulin levels, and markers of insulin resistance (HOMA-IR). Upon histological analysis, vitamin D supplementation resulted in a reduction of the islet of Langerhans degeneration. Vitamin D also enhanced the ratio of IL-6/IL-10, reduced IRS1 phosphorylation at Ser307, increased expression of PPAR gamma, and reduced phosphorylation of NF-KB p65 at Ser536. Vitamin D supplementation reduces insulin resistance in prediabetic rats. The reduction might be due to the effects of vitamin D on IRS, PPARγ, and NF-κB expression.

Protective Effects of Artemisia selengensis Turcz. Leaf Extract on Caenorhabditis elegans under High Glucose Diet

Artemisia selengensis Turcz. (AST), as a common edible and medicinal herb, exerts multiple biological activities including antioxidant, antihyperuricemia, and inhibition of α-glucosidase activities. However, limited information is available about its beneficial effects on high glucose toxicity in Caenorhabditis elegans (C. elegans). In the current study, Artemisia selengensis Turcz. leaf extract (ASTE), rich in caffeoylquinic acids, was found to alleviate high glucose-induced damages in C. elegans by extending the lifespan, increasing the body bending and pharyngeal pumping rates, and by reducing glucose and lipid accumulation and oxidative stress. Further results demonstrated that ASTE extended the lifespan of C. elegans on high glucose diet by inhibiting the insulin/IGF-1 signaling (IIS), and activating SKN-1 and AAK-2 signaling pathways. In conclusion, our findings reveal the direct evidence for the protective effects of ASTE against high glucose toxicity.

Gut microbiota modulation by high glucose diet invigorates anti-tumor immune response to glioblastoma multiforme

Abstract Most studies about the relationship between high sugar diet and tumor progression state that the pro-tumoral effects of high sugar diet are induced by metabolic diseases such as obesity and diabetes caused by long-term, excessive sugar diet. However, there are still many unknowns about the effect of high sugar diet on tumors when it lasts for a relatively short period that does not cause metabolic diseases. In this background, we find that survival rate of glioblastoma (GBM) is increased through supplement of high glucose diet (HGD) for several weeks. We find that gut microbiota modulation by HGD plays a crucial role in enhancement of anti-tumor immune response. Through single cell RNA sequencing analysis, modulation of gut microbiota by HGD results in an increase in T cell-mediated anti-tumor immune response in GBM. In addition, we find the novel cytotoxic CD4+ T cell population in GBM is increased due to synergistic action with anti PD-1 and the change occurs only through the synergistic action of anti PD-1 treatment and HGD. As a result, we identify that HGD can enhance anti-tumor immune response in GBM through changes in gut microbiota and suggest that the role of glucose diet on GBM needs to be elucidated from a different perspective.

The Synergistic Glucose-lowering Effects of Metformin and Bavachinin on Type II Diabetic Rats

Background: Diabetes is one of the most prevalent endocrine disorders in humans, and its first-line medication is metformin. Peroxisome proliferator-activated receptor gamma (PPAR–γ) agonists are the adjuncts to metformin. Bavachinin is a PPAR pan-agonist with fewer side effects than metformin" into PPAR–γ agonists. In this study, the synergistic effects of metformin and Bavachinin were investigated on type II diabetic rats. Methods: After four weeks of a high fat and glucose diet, type II diabetes was induced in 28 male Wistar rats, using injection of streptozotocin and nicotinamide. The animals were distributed into five groups of seven each: 1) Normal control (N), 2) Diabetic control (D), 3) Diabetic rats receiving metformin (DM), 4) Bavachinin (DB), and 5) Metformin plus Bavachinin (DMB). Oral glucose tolerance test (OGTT), fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of β-cell function (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR), and insulin sensitivity index (ISI) were obtained. Results: The OGTT results in DM, DB, and DMB groups were significantly improved compared to that of D group. The FBG levels were significantly lower in DMB than in DB, DM, and D groups. The FINS levels of DMB were significantly less than those of DB, DM, and D groups. The HOMA-IR and HOMA-β were comparable between DMB and N groups. The ISI improved significantly in DMB compared to those in DM, DB, and D groups. Conclusion: Bavachinin may be used combined with metformin for the treatment of type II diabetes at lower doses of metformin, thus having fewer side effects.

The therapeutic mechanism of Yuye decoctionon type 2 diabetes mellitusbasedon network pharmacology and experimental verification.

Yuye decoction (YYD) has been widely used as a folk Chinese herbal formula in clinical treatment of type 2 diabetes mellitus(T2DM) for many years. However, its mechanism is still unclear. The aim of this study was to explore the potential mechanism of YYD against T2DM initially by UHPLC-MS/MS combining with network pharmacology, molecular docking techniques and experimental validation. The main ingredients in the water extract of YYD were initially identified using UHPLC-MS/MS analysis. Combined with network pharmacology and molecular docking techniques, the YYD key compounds-core targets-key signaling pathways network was constructed and the binding activity of key components to core targets was validated. The T2DM rat model was induced by Streptozotocin combined with high glucose and high fat diets. The apoptosis cell model of mouse islet β-cell of Min6 was induced by high-glucose and palmitic acid. Histopathological and immunofluorescence satining were used to evaluate pancreatic islet β-cell function and apoptosis in rats. Min6 cell viability and apoptosis ratio were evaluated by CCK-8 and TUNEL staining. The predicted targets and pathways were validated by experiments in vitro and in vivo. The 56 compounds from YYD were identified by UHPLC-MS/MS. The potential targets of the above compounds were predicted by online compound target database, among of which 362 targets were associated with T2DM. Protein-protein interaction analysis identified the main targets such as SRC, MAPK1, PIK3R1, AKT1, HRAS and HSP90AA1, which were considered as the therapeutic targets of YYD on against T2DM. Functional enrichment analysis revealed that PI3K/AKT, FoxO and apoptosis signaling pathways were significantly enriched. Molecular docking results showed that compounds of monolinolein, neomangiferin, mangiferin, pelargonidin-3-O-glucoside and acacetin from YYD had high binding activities to PIK3R1, AKT1, Sirt1 and FoxO1. Therefore, PI3K/AKT1, Sirt1/FoxO1 and apoptotic signaling pathways were considered as predicted targets for experimental validation study. Animal experiments showed that YYD reduced blood glucose levels, improved pancreatic dysfunction and pancreatic islet β-cells apoptosis in T2DM rats which contributed to the activation of AKT1 and FoxO1 and their related signaling molecules. These results were confirmed in Min6 cell model induced by high-glucose and palmitic acid. In summary, this study systematically visualized the possible therapeutic effects and mechanisms of YYD on T2DM through the network pharmacology approach and experimental study. The results indicated that YYD could prevent pancreatic islet dysfunction and reverse islet of β-cells apoptosis possibly via PI3K/AKT1, Sirt1/FoxO1 signaling pathways.

Network pharmacology-based screening of the active ingredients and mechanisms of Cymbaria daurica against diabetes mellitus

Cymbaria daurica L. has a long history as a folk medicine and tea for the treatment of diabetes. However, the biological activity and mechanism of its hypoglycemic effect have not been fully elucidated. In this study, the potential mechanism of C. daurica against type 2 diabetes mellitus (T2DM) was postulated via pharmacological network analysis. Based on data mining techniques involving topological parameters, gene ontology, and pathway enrichment, we established a compound-target, protein-protein interaction, and target-pathway network to identify central targets and pathways. Pathway enrichment analysis revealed that the most important pathway associated with C. daurica in treating T2DM is the PI3K-Akt signaling pathway. Molecular docking was performed to validate the predicted results. Then, a HepG2 cell insulin resistance model and a high-fat, high-glucose diet combined with a streptozotocin-induced T2DM rat model was established to assess the fasting glucose changes and lipid profile after C. daurica treatment, respectively. Finally, real-time PCR and western blotting were used to verify changes in key targets. The anti-diabetic mechanism of the active ingredient in C. daurica may involve the regulation of IRS-2, Akt1, GLUT4, and GSK3β.

Akkermansia muciniphila Cell-Free Supernatant Improves Glucose and Lipid Metabolisms in Caenorhabditis elegans.

To explore the mechanism by which Akkermansia muciniphila cell-free supernatant improves glucose and lipid metabolisms in Caenorhabditis elegans, the present study used different dilution concentrations of Akkermansia muciniphila cell-free supernatant as an intervention for with Caenorhabditis elegans under a high-glucose diet. The changes in lifespan, exercise ability, level of free radicals, and characteristic indexes of glucose and lipid metabolisms were studied. Furthermore, the expression of key genes of glucose and lipid metabolisms was detected by qRT-PCR. The results showed that A. muciniphila cell-free supernatant significantly improved the movement ability, prolonged the lifespan, reduced the level of ROS, and alleviated oxidative damage in Caenorhabditis elegans. A. muciniphila cell-free supernatant supported resistance to increases in glucose and triglyceride induced by a high-glucose diet and downregulated the expression of key genes of glucose metabolism, such as gsy-1, pygl-1, pfk-1.1, and pyk-1, while upregulating the expression of key genes of lipid metabolism, such as acs-2, cpt-4, sbp-1, and tph-1, as well as down-regulating the expression of the fat-7 gene to inhibit fatty acid biosynthesis. These findings indicated that A. muciniphila cell-free supernatant, as a postbiotic, has the potential to prevent obesity and improve glucose metabolism disorders and other diseases.

Consumption of a Glucose Diet Enhances the Sensitivity of Pancreatic Islets from Adrenalectomized Genetically Obese (ob/ob) Mice to Glucose-Induced Insulin Secretion

Consumption of a glucose diet for 4 d markedly elevates plasma insulin concentrations in adrenalectomized ob/ob mice. The present study examined regulation of insulin secretion from perifused pancreatic islets of female adrenalectomized genetically obese (ob/ob) and lean mice fed a glucose diet for 4 d. These mice were fed a high carbohydrate commercial diet for 21 d, or the high carbohydrate commercial diet for 17 d and a purified high glucose diet for the last 4 d of the 21-d feeding period. Adrenalectomy equalized plasma insulin concentrations, pancreatic islet size, rates of insulin secretion in response to 20 mmol/L glucose and insulin mRNA relative abundance in ob/ob and lean mice fed the commercial diet, but the threshold for glucose-induced insulin secretion determined by a linear glucose gradient remained lower in islets from adrenalectomized ob/ob mice than in those from lean mice (3.8 ± 0.1 vs. 4.9 ± 0.2 mmol/L glucose), and addition of acetylcholine to the perifusate lowered the threshold to only 2.0 ± 0.1 mmol/L glucose in islets from ob/ob mice vs. 3.3 ± 0.1 mmol/L glucose in lean mice. Switching from the commercial diet to the glucose diet for 4 d increased plasma insulin concentrations ∼10-fold in islets from adrenalectomized ob/ob mice without affecting islet size, 20 mmol/L glucose-induced insulin secretion or insulin mRNA abundance. Consumption of the glucose diet did, however, markedly lower the threshold for glucose-induced insulin secretion in islets from adrenalectomized ob/ob mice to approximate the abnormally low glucose thresholds in intact ob/ob mice. Islets from lean mice were unaffected by the diet switch. The signaling pathway that sensitizes islets to glucose-induced insulin secretion seems to be persistently altered in ob/ob mice.