RSC Advances
·
2017
·Vol. 7
·期 17
·10108-10117
·
IF 3.108
Shengsheng Zhang,Hai Zhang,Li Wang,Xiaofei Liu,Yuntang Wu
Insulin receptor (InsR) and GLUTs play a very important role in pathophysiological changes in terms of diabetes and insulin resistance, and metformin can regulate their expression and activity in order to alleviate insulin resistance. By reference to the molecular structure of metformin, chitosan biguanidine hydrochloride (CSGH) was synthesized by reacting chitosan (CS) with dicyandiamide under microwave irradiation and characterized by FT-IR, 13C NMR spectroscopy and XRD. The substitution degree (DS) of CSGH, measured by potentiometric titration method, varied in the range of 41.8% to 68.5%. After cytotoxicity testing of CSGH, nontoxic samples were selected. Then insulin resistance (IR) model using human hepatocarcinoma HepG2 cells was established, and the effect of CSGH on glucose consumption was investigated. Moreover, the expression of InsR and the signal protein glucose transporters-2 (GLUT2) were further investigated to study the mechanism. Results showed that CSGH samples with DS 43.2% and DS 52.7% were nontoxic and could improve the vitality, markedly promoting the glucose consumption of HepG2 cells. Besides, the effect of CSGH (DS 52.7%) on promoting glucose consumption was better than metformin and not dose-dependent. It is also found that CSGH could induce the expression of InsR protein and significantly inhibit the over-expression of GLUT2 transport protein, which was probably the mechanism of the therapeutic effect of CSGH on IR HepG2 cells.
研究领域:
药物化学
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细胞生物学
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糖尿病研究
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产品关联
DOI
高影响因子
Journal of Functional Foods
·
2017
·
IF 3.144
Hai Zhang,Shengsheng Zhang,Li Wang,Xiaofei Liu,Yuntang Wu
Previous results from our laboratory showed that chitosan biguanidine hydrochloride (CSGH) and chitooligosaccharide guanidine (COSG) could control glucose uptake by regulating the expression of glucose transporters (GLUTs) in vitro experiments. In this study, we try to delineate changes observed in activation of diacylglycerol (DAG)/protein kinase C- β (PKC- β ) pathway and GLUT2 in kidney. STZ-induced diabetic rats were administered COSG via daily intra-gastric gavage for 8 weeks. Obviously, COSG significantly attenuated fasting blood glucose and blood glucose level by modulating the over-expression of GLUT2 and the level of DAG as well. Immunohistological examination revealed that factors such as PKC- β and transforming growth factor- β (TGF- β ) diminished to various extents after treatment with COSG, which impinged on the synthesis of extracellular matrix (ECM) components like fibronectin (FN). As a result, high glucose-induced activation of DAG/PKC pathway is inhibited, which is associated with the concentration of glucose controlled by the expression of GLUT2 with the treatment of COSG.
研究领域:
药理学
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糖尿病研究
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肾病学
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DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Peihua Liu,Ling Jiang,Weimin Kong,Qiushi Xie,Ping Li,Xiaonan Liu,Jiayi Zhang,Ming Liu,Zhongjian Wang,Liang Zhu,Hanyu Yang,Ying Zhou,Jianjun Zou,Xiaodong Liu,Li Liu
Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4 α )‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4 α expression, while silencing PXR upregulated HNF4 α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4 α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4 α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR . Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16 α -carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4 α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4 α ‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.
研究领域:
药理学
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分子生物学
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内分泌学
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糖尿病研究
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DOI
PubMed
高影响因子
Foods
·
2022
·Vol. 11
·期 23
·3793
·
IF 5.561
Yang Liu,Jiali Lin,Tiantian Cheng,Yangjie Liu,Fuliang Han
Anthocyanins are substances with multiple physiological activities widely present in red wine, but the influence of structure (methylation, hydroxylation, acylation, glycosylation) on the transport remains ill-defined. In the present study, Caco-2 monolayers were used as an in vitro model of the absorptive intestinal epithelium to transport different types of anthocyanin samples. Results showed that both methylation and acetylation promote the level of transport. Monoglycoside standard exhibited higher transport amount and rate compared to diglycoside standard while the transport level of the monoglycoside mixture was unexpectedly lower than that of the diglycoside mixture. Caco-2 monolayers appeared to be more capable of transporting the single standard than the mixed standard. Meanwhile, the transport of anthocyanins in Caco-2 cell model showed time- and concentration-dependent trends. Anthocyanin treatment had a greater effect on sodium-dependent glucose transporter 1 (SGLT1) mRNA expression than glucose transporter 2 (GLUT2), and significantly down-regulated the protein expression of SGLT1. Although the low bioavailability of anthocyanins requires much more research, further evidence of the role of structure is provided.Keywords:wine;anthocyanins;Caco-2 cell monolayer;absorption;SGLT1;GLUT2
研究领域:
食品科学
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药理学
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营养学
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产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2018
·
IF 4.936
Hong-Xin Cui,Ya-Nan Hu,Jing-Wan Li,Ke Yuan
Both alterations to the intestinal microflora and chronic systemic inflammation predispose towards type 2 diabetes (T2D). Changes in the composition of the intestinal microflora are associated with glucose metabolism changes in rats with T2D. Here, we demonstrate that a berberine fumarate (BF) has a hypoglycemic effect by regulating the intestinal microflora and metabolism of diabetic rats. The T2D rats had disorders of glucose and lipid metabolism, an abnormal intestinal microflora, fewer butyrate-producing and probiotic-type bacteria, larger numbers of potentially pathogenic and sulfate-reducing bacteria, and tissue inflammation. Administration of berberine fumarate significantly ameliorated the metabolic disorder; increased the populations of Bacteroidetes, Clostridia, Lactobacillales, Prevotellaceae, and Alloprevotella; and reduced those of Bacteroidales, Lachnospiraceae, Rikenellaceae, and Desulfovibrio. In addition, it reduced inflammation, inhibiting the overexpression of TLR4 and p-JNK and increasing the expression of PI3K, GLUT2, and other proteins, which are closely related to oxidative stress, thereby promoting the metabolism of glucose.
研究领域:
药理学
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微生物学
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内分泌学
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代谢学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD SCIENCE
·
2025
·Vol. 90
·期 2
·e70046
·
IF 3.4
En-Zhong Chi,Li Wang,Jia-jian Pan,Qiang Zhang,Jiangxiong Zhu,Xin-huai Zhao
This study investigated the structural characteristics and hypoglycemic activity of polysaccharides isolated from Ganpu tea (GPT) in different storage periods. Three polysaccharide fractions (GPTPS1-E2, GPTPS3-E2, and GPTPS5-E2, representing 1, 3, and 5 years of storage, respectively, where GPTPS is Ganpu tea polysaccharides) were extracted and purified from GPT. Chemical composition analysis revealed that all fractions were predominantly acidic polysaccharides with total sugar content exceeding 90%. Monosaccharide composition analysis showed galacturonic acid as the primary component, along with significant amounts of galactose and arabinose. Molecular weight distribution showed that different fractions had distinct distributions, with GPTPS1-E2 and GPTPS3-E2 showing the highest and lowest molecular weights, respectively. Fourier-transform infrared and nuclear magnetic resonance spectroscopy provided insights into the structural characteristics of the polysaccharides. Scanning electron microscopy and X-ray diffraction analyses revealed distinct surface morphologies and crystalline structures. The hypoglycemic activity was evaluated using a Caco-2 cell model, demonstrating potential antidiabetic properties via the IRS1-GLUT2-SGLT1 axis. Comparative analysis revealed that storage time could influence the structural characteristics and hypoglycemic activity of GPTPSs, with a certain storage time generally associated with the transformation of structural characteristics related to hypoglycemic activity and the enhanced hypoglycemic effect. This research contributes to the understanding of GPTPS and their potential applications in functional foods and nutraceuticals.
研究领域:
食品科学
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营养保健品
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生物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
Nutrients
·
2020
·Vol. 12
·期 6
·1889
·
IF 4.546
Nancy Saji,Nidhish Francis,Lachlan J. Schwarz,Christopher L. Blanchard,Abishek B. Santhakumar
Oxidative stress is known to modulate insulin secretion and initiate gene alterations resulting in impairment of β-cell function and type 2 diabetes mellitus (T2DM). Rice bran (RB) phenolic extracts contain bioactive properties that may target metabolic pathways associated with the pathogenesis of T2DM. This study aimed to examine the effect of stabilized RB phenolic extracts on the expression of genes associated with β-cell function such as glucose transporter 2 (Glut2), pancreatic and duodenal homeobox 1 (Pdx1), sirtuin 1 (Sirt1), mitochondrial transcription factor A (Tfam), and insulin 1 (Ins1) in addition to evaluating its impact on glucose-stimulated insulin secretion. It was observed that treatment with different concentrations of RB phenolic extracts (25-250 µg/mL) significantly increased the expression ofGlut2,Pdx1,Sirt1, Tfam,andIns1genes and glucose-stimulated insulin secretion under both normal and high glucose conditions. RB phenolic extracts favourably modulated the expression of genes involved in β-cell dysfunction and insulin secretion via several mechanisms such as synergistic action of polyphenols targeting signalling molecules, decreasing free radical damage by its antioxidant activity, and stimulation of effectors or survival factors of insulin secretion.Keywords:rice bran;phenolic extracts;β-cell function;gene expression;insulin secretion
研究领域:
营养学
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分子生物学
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内分泌学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Wang Mengting,Mao Haiguang,Ke Zhijian,Wang Jinbo
Background: The hypoglycemic effects of Chinese bayberry leaves proanthocyanidins (BLPs) have been demonstrated. It is unclear, nevertheless, whether BLPs reduced postprandial blood glucose levels by regulating glucose uptake and glucose transport.
Method: This study investigated the effect of BLPs (25, 50 and 100 μg/mL) on glucose uptake and glucose transport in human intestinal epithelial cells (Caco-2 cells). The uptake of 2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose (2-NBDG) and disaccharidases activity in Caco-2 cells were measured. The glucose transport ability across the cell membrane was determined using the established Caco-2 monolayer model. The transcript and protein levels of key glucose transporters were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively.
Results: The results showed that BLPs significantly decreased glucose uptake and disaccharidases activity (p<0.05). Otherwise, BLPs treatment obviously inhibited glucose transport across the Caco-2 monolayer in both simulated-fast (5 mM glucose) and simulated-fed (25 mM glucose) conditions. It was attributed to the suppression of glucose transporter2 (GLUT2) and sodium-dependent glucose cotransporter 1 (SGLT1) by BLPs. BLPs were found to significantly downregulated the transcript level and protein expression of glucose transporters (p<0.05). Meanwhile, the mRNA expression of phospholipase C (PLC) and protein kinase C (PKC) involved in the signaling pathway associated with glucose transport were decreased by BLPs.
Conclusion: These results suggested that BLPs inhibited intestinal glucose transport via inhibiting the expression of glucose transporters. It indicated that BLPs could be potentially used as a functional food in the diet to modulate postprandial hyperglycemia.
研究领域:
药理学
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营养学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Baolin Huang,Zimin Lin,Zhenzhen Chen,Jiasheng Chen,Birui Shi,Jingjing Jia,Yuan Li,Yueqing Pan,Yuntao Liang,Zheng Cai
Designing oral drug delivery systems using intestinal glucose transporters (IGTs) may be one of the strategies for improving oral bioavailability of drugs. However, little is known about the biological factors affecting the drug transport capacity of IGTs. Gastrodin is a sedative drug with a structure very similar to glucose. It is a highly water-soluble phenolic glucoside. It can hardly enter the intestine through simple diffusion but exhibits good oral bioavailability of over 80%. We confirmed that gastrodin is absorbed via the intestinal glucose transport pathway. It has the highest oral bioavailability among the reported glycosides’ active ingredients through this pathway. Thus, gastrodin is the most selective drug substrate of IGTs and can be used to evaluate the drug transport capacity of IGTs. Obviously, strain is one of the main biological factors affecting drug absorption. This study firstly compared the drug transport capacity of IGTs between SD rats and Wistar rats and between C57 mice and KM mice by pharmacokinetic experiments and single-pass intestinal perfusion experiments of gastrodin. Then, the sodium-dependent glucose transporter type 1 (SGLT1) and sodium-independent glucose transporters type 2 (GLUT2) in the duodenum, jejunum, ileum and colon of these animals were quantified using RT-qPCR and Western blot. The results showed that the oral bioavailability of gastrodin in Wistar rats was significantly higher than in SD rats and significantly higher in KM mice than in C57 mice. Gastrodin absorption significantly differed among different intestinal segments in SD rats, C57 mice and KM mice, except Wistar rats. RT-qPCR and Western blot demonstrated that the intestinal expression distribution of SGLT1 and GLUT2 in SD rats and C57 mice was duodenum ≈ jejunum > ileum > colon. SGLT1 expression did not differ among different intestinal segments in KM mice, whereas the intestinal expression distribution of GLUT2 was duodenum ≈ jejunum ≈ ileum > colon. However, the expression of SGLT1 and GLUT2 did not differ among different intestinal segments in Wistar rats. It was reported that the intestinal expression distribution of SGLT1 and GLUT2 in humans is duodenum > jejunum > ileum > colon. Hence, the intestinal expression distribution of SGLT1 and GLUT2 of SD rats and C57 mice was more similar to that in humans. In conclusion, the drug transport capacity of IGTs differs in different strains of rats and mice. SD rats and C57 mice are more suitable for evaluating the pharmacokinetics of glycosides’ active ingredients absorbed via the intestinal glucose transport pathway.
研究领域:
药理学
·
药物递送系统
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2023
·
IF 8.1
Qiannan Zhao,Jinyi Yang,Jiahui Li,Lei Zhang,Xiaohai Yan,Tianli Yue,Yahong Yuan
Phenolics of mulberry ( Morus alba L.) leaves (MLs) have potential anti-diabetic effects, but they may be chemically modified during gastrointestinal digestion so affect their biological activity. In this study, an in vitro digestion model coupled with Caco-2 monolayer and Caco-2/insulin-resistant HepG2 coculture model were used to study the transport and hypoglycemic effects of phenolics in raw MLs (U-MLs) and solid-fermented MLs (F-MLs). The results of LC-MS/MS analysis showed that the Papp (apparent permeability coefficient, 10 –6 cm/s) of phenolics in digested MLs ranged from 0.002 ± 0.00 (quercetin 3- O -glucoside) to 60.19 ± 0.67 (ferulic acid), indicating higher phenolic acids absorbability and poor flavonoids absorbability. The Papp values of phenolic extracts of F-MLs in Caco-2 monolayer were significantly higher (p > 0.05) than that of U-MLs. Digested phenolic extracts inhibited the activities of sucrase (60.13 ± 2.03%) and maltase (82.35 ± 0.78%) and decreased 9.28 ± 0.84% of glucose uptake in Caco-2 monolayer. Furthermore, a decrease in the mRNA expression of glucose transporters SGLT1 (0.64 ± 0.18), GLUT2 (0.14 ± 0.02) and the sucrase-isomaltase (0.59 ± 0.00) was observed. In Caco-2/insulin-resistant HepG2 co-culture model, phenolic extracts regulated glucose metabolism by up-regulating the mRNA expressions of IRS1 (9.32-fold), Akt (17.07-fold) and GYS2 (1.5-fold), and down-regulating the GSK-3β (0.22-fold), PEPCK (0.49-fold) and FOXO1 (0.10-fold) mRNA levels. Both U-MLs and F-MLs could improve glucose metabolism, and the partial least squares (PLS) analysis showed that luteoforol and p -coumaric acid were the primary phenolics that strongly correlated with the hypoglycemic ability of MLs. Results suggested that phenolics of MLs can be used as dietary supplements to regulate glucose metabolism.
研究领域:
药理学
·
营养学
·
生物化学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Sa Yang,Shijie Cao,Congyu Li,Jichao Zhang,Chang Liu,Feng Qiu,Ning Kang
Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. Berberine (BBR) is an effective therapeutic agent in alleviating NAFLD. Berberrubine (BRB) is one of the main active metabolites of BBR, which shows significant anti-obesity and antihypoglycemic effects. However, whether BRB is responsible for the in vivo therapeutic effect and the underlying mechanism of BRB on NAFLD have not been elucidated. In this study, the ability of BRB to ameliorate NAFLD, together with its molecular mechanism, was investigated. The results showed that BRB treatments could significantly improve hepatic steatosis and insulin resistance in high-fat diet (HFD)-fed mice and oleic acid (OA)-treated HepG2 cells. Meanwhile, BBR and BRB treatment similarly prevented lipid accumulation by regulating the protein expression of ATGL, GK, PPARα, CPT-1, ACC1, FAS, and CD36. In addition, compared with BBR, BRB could maintain glucose homeostasis via GLUT2, GSK3β, and G6Pase in HFD-fed mice. Furthermore, the components of the gut microbiota in mice were analyzed by 16S rRNA gene sequencing. BBR and BRB treatment could greatly modify the structure and composition of gut microbiota. At the genus level, BBR and BRB treatment decreased Lactobacillus and Romboutsia , while BBR increased beneficial bacteria, such as Akkermansia and Bacteroides , and BRB increased beneficial bacteria, such as Ileibacterium and Mucispirillum . Altogether, both BRB and BBR were active in alleviating NAFLD in vivo and BRB might be used as a functional material to treat NAFLD clinically.
研究领域:
药理学
·
代谢学
·
胃肠病学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2019
·Vol. 9
·期 1
·1-13
·
IF 4.011
Xu Shuwen,Wang Gang,Peng Wei,Xu Yandi,Zhang Yu,Ge Ying,Jing Yue,Gong Zhunan
Type 2 diabetes (T2D) with high morbidity and mortality is characterized by abnormal glucose and lipid metabolism due in part to insulin resistance in liver, which lead to elevated hyperglycemia and hyperlipidemia. This study sough to explore the effects of corosolic acid (CA) in different T2D models and explored the underlying mechanism. Separated from Eriobotrya japonica leaves, CA purity was above 95% measured by a HPLC method. Compared with cAMP and DEX induced T2D HepG2 model, CA significantly stimulated glucose consumption and improved glycogen accumulation by inhibiting PEPCK mRNA expression. And in cAMP and DEX induced T2D zebrafish model, CA reduced glycogen degradation and increased glucose consumption by regulating some key enzymes in carbon metabolism including GLUT1, GLUT2, GLUT3, LDHA, LDHB, GP, G6Pase, GYS1, and PFKFB3. In addition, insulin receptor signals were also involved in CA-regulated hypoglycemic action. Furthermore, in STZ-induced T2D rat model, compared with diabetic control groups, CA remarkably downregulated the levels of serum lipid, blood glucose, ICAM-1, malonaldehyde and insulin resistance index, while upregulated SOD activity and impaired glucose tolerance. In a conclusion, CA can regulate glucose and lipid metabolic adaptation in T2D like HepG2, zebrafish and rat models partly through reducing inflammation and oxidative stress and suppressing PEPCK .
研究领域:
药理学
·
糖尿病研究
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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