Scientific Reports
·
2025
·Vol. 15
·期 1
·1-13
·
IF 3.9
Yu Min,Zhang Chuanzhi,Xu Hongjiang,Dong Yuanzhen,Zhu Hongxiang,Xia Chunguang,Feng Jun
Insulin is a potent medication for managing diabetes, yet its short half-life requires daily administration. Currently, Novo Nordisk’s icodec is the sole insulin available on the market that requires administration only once a week. Insulin icodec, developed by Novo Nordisk through amino acid mutations and fatty acid side chain modifications, has demonstrated the capability to control blood glucose levels on a once-weekly basis. To improve its efficacy, we modified the acylation side chain of icodec to generate insulin analogs appropriate for weekly dosing. A promising insulin analog, TBE001-A-S033, was synthesized and conjugated, and its efficacy was assessed in ICR and db/db mice. TBE001-A-S033 prolonged blood glucose control in ICR mice and exhibited a comparable blood glucose trend to insulin icodec in db/db mice. These findings suggest that TBE001-A-S033 possesses a favorable hypoglycemic effect and a differential half-life across species compared to insulin icodec, indicating its potential for once-weekly use in humans. This preclinical investigation indicates that TBE001-A-S033 may serve as an effective therapeutic for type 2 diabetes mellitus (T2DM).
研究领域:
药理学
·
糖尿病研究
·
生物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2021
·Vol. 22
·期 15
·7797
·
IF 5.924
Joseph A. M. J. L. Janssen
For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.
研究领域:
内分泌学
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营养学
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老年医学
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肿瘤学
✓ 已验证
DOI
高影响因子
CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
·
2013
·Vol. 29
·期 4
·730-734
·
IF 0.735
Zhang Lei,Zhang Shi-tao,Zhang Xiao-ping,Sun Jing,Wang Yong-sen,Liu Yue-long,Xue Miao-miao,Wang Zhi,Xing Shu,Ma Jun-feng,Li Wan-nan,Fu Xue-qi
The protein tyrosine phosphatases(PTPs) comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-1 has been regarded as one of the best validated intracellular tyrosine phosphatases. Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway. In this study, we found the role of Candesartan cilexetil targeting at SHP-1. The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1(IC 50 =85.6 μmol/L and K
i =24 μmol/L). We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs. Through the consequence of Western blotting, it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor(IR), insulin receptor substrate(IRS) and ERK]_in insulin signaling pathway in HepG 2 cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1. These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great application potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.
研究领域:
药理学
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分子生物学
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糖尿病研究
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产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Hui Zhang,Junfeng Hui,Jing Yang,Jianjun Deng,Daidi Fan
Eurocristatine (ECT) is an alkaloid isolated from Eurotium cristatum , and it has been used in multiple applications. However, its use as a treatment for type 2 diabetes mellitus (T2DM) has not yet been reported. In this study, we investigated the anti-T2DM effect of ECT and explored its potential molecular mechanism. In vivo , after treatment with ECT (20, 40 mg/kg) for 6 weeks, fasting blood glucose (FBG) was remarkably reduced in db/db mice. Moreover, glucose tolerance, insulin sensitivity and hyperinsulinemia were ameliorated treatment with ECT. The values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) also showed that ECT could alleviate liver toxicity caused by diabetes in db/db mice. In vitro , ECT (15 and 30 μM) alleviated insulin resistance by increasing glucose consumption, glucose uptake and glycogen content in high glucose-induced HepG2 cells. The Western blotting (WB) results showed that ECT could upregulate the expression of phosphatidylinositol 3-kinase (PI3K), increase the phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT) in vivo and in vitro . Besides, ECT improved the glycogen content by inhibiting the expression of glycogen synthase kinase3β (GSK3β) and promoting that of glycogen synthase (GS). Furthermore, administration of the PI3K/AKT signaling pathway inhibitor LY294002 abolished the beneficial effects of ECT. These findings are the first to verify that ECT has the potential to improve glucose metabolism and alleviate insulin resistance by activating the PI3K/AKT signaling pathway in db/db mice.
研究领域:
药理学
·
糖尿病研究
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Li Hu,Haiping Liu,Haixiang Ma,Xingyue Zeng,Yongkai Cao,Bing Liu,Huijun Li,Xiaohan Zhang
AKT, also known as protein kinase B (PKB), serves as a crucial regulator of numerous biological functions, including cell growth, metabolism, and tumorigenesis. Increasing evidence suggests that the kinase activity of AKT is regulated via ubiquitination by various E3 ligase enzymes in response to different stimuli. However, the molecular mechanisms underlying insulin-induced AKT ubiquitination are not yet fully understood. Here, we show that activation of the insulin receptor (IR) leads to enhanced ubiquitination of AKT1 at K8 and K14 residues, facilitated by the cytosolic E3 ubiquitin ligase enzyme, TRAF6. Further investigation using AKT1 mutants with modified nucleocytoplasmic shuttling properties reveals that TRAF6-mediated AKT1 ubiquitination occurs within the nucleus in a β-Arr2-dependent manner. The nuclear entry of TRAF6 depends on importin β1, while β-Arr2 regulates this process by facilitating the interaction between TRAF6 and importin β1. Additionally, the ubiquitination of AKT1 is essential for its translocation to the activated IR on the plasma membrane, where it plays a functional role in recruiting Glut4 and facilitating glucose uptake. This study uncovers the cellular components and processes involved in insulin-induced ubiquitination and activation of AKT1, providing insights and detailed strategies for manipulating AKT1.
研究领域:
细胞生物学
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分子生物学
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内分泌学
·
信号转导
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产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2024
·Vol. 81
·期 1
·1-15
·
IF 6.2
Sun Wen-Xing,Zhang Kai-Hui,Zhou Qian,Hu Song-Hua,Lin Yan,Xu Wei,Zhao Shi-Min,Yuan Yi-Yuan
Increased circulating amino acid levels have been linked to insulin resistance and development of type 2 diabetes (T2D), but the underlying mechanism remains largely unknown. Herein, we show that tryptophan modifies insulin receptor (IR) to attenuate insulin signaling and impair glucose uptake. Mice fed with tryptophan-rich chow developed insulin resistance. Excessive tryptophan promoted tryptophanyl-tRNA synthetase (WARS) to tryptophanylate lysine 1209 of IR (W-K1209), which induced insulin resistance by inhibiting the insulin-stimulated phosphorylation of IR, AKT, and AS160. SIRT1, but not other sirtuins, detryptophanylated IR W−K1209 to increase the insulin sensitivity. Collectively, we unveiled the mechanisms of how tryptophan impaired insulin signaling, and our data suggested that WARS might be a target to attenuate insulin resistance in T2D patients.
研究领域:
内分泌学
·
代谢学
·
糖尿病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TALANTA
·
2019
·
IF 4.916
Fang Tan,Zhifang Wang,Yan Yang,Xiaoxue Xie,Xinyi Hua,Xiumei Yang,Haowen Huang
To obtain sensitive analytical detection methods, many unique materials have been developed and made them promising candidates for biosensing. In this study, a type of core-shell gold nanorods , [email protected] 2 S/AuAgS/CuS, possessing peroxidase-like activity was prepared in a simple, facile manner. A colorimetric strategy for detection of blood glucose, insulin and differentiating type 1 and type 2 diabetes was developed based on the unique [email protected] 2 S/AuAgS/CuS. The sensitive colorimetric approach for detection of glucose in the dynamic range of 2.5–200 μM was first established based on the catalytic performance of [email protected] 2 S/AuAgS/CuS. Meanwhile, the catalytic activity of the peroxidase-like [email protected] 2 S/AuAgS/CuS can be regulated by introducing the high affinity and specific reaction between DNA aptamer and insulin on the surface of [email protected] 2 S/AuAgS/CuS, which allows the colorimetric assay to be extended to the detection of insulin, and a quantitative analysis of insulin based on the specific recognition can be implemented at the range from 0.014 to 1.08 μU/mL. Furthermore, colorimetric approach coupling peroxidase-like performance and specific recognition on the surface of [email protected] 2 S/AuAgS/CuS nanoparticles was developed to measure glucose/insulin ratio and directly differentiate type 1 and type 2 diabetes mellitus. Practical human serum samples were tested and only the glucose/insulin ratio greater than 2.2 (μU/mL) may lead to the appearance of color change. The coupling of this different bioassay on the same nanoparticles reflects the versatility and integration characteristics of the colorimetric assay and is highly promising for improving diabetes management.
研究领域:
生物传感
·
医学诊断
·
纳米材料科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2021
·
IF 10.588
Chen Wang,Yeyong Li,Lingjun Zeng,Chongli Shi,Yi Peng,Hui Li,Haibo Chen,Jun Yu,Jin Zhang,Biao Cheng,Ruolin Pan,Xiaoli Wang,Minghui Xiang,Yuan Huang,Yongdi Liu
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) has received concerns due to its frequent detection in environmental media and biological samples. Our previous study has indicated TDCPP reduced the lifespan of Caenorhabditis elegans ( C. elegans ) by triggering an unconventional insulin/insulin-like growth factor signaling (IIS) pathway. This study continued to investigate the possible deleterious effects of TDCPP relating to longevity regulation signal pathways and biological processes. Specifically, this study uniquely performed small RNA transcriptome sequencing (RNA-seq), focusing on the underlying mechanisms of TDCPP-reduced the longevity of C. elegans in-depth in microRNAs (miRNAs) . Based on Small RNA-seq results and transcript levels of mRNA involved in the unconventional IIS pathway, a small interaction network of miRNAs-mRNAs following TDCPP exposure in C. elegans was preliminarily established. Among them, up-regulated miR-48 and miR-84 ( let-7 family members) silence the mRNA of daf-16 (the crucial member of the FoxO family and pivotal regulator in longevity) via post-transcription and translation dampening abilities, further inhibit its downstream target metallothionein-1 ( mtl-1 ), and ultimately contributed to the reduction of nematode longevity and locomotion behaviors. Meanwhile, the high binding affinities of TDCPP with miRNAs cel-miR-48–5p and cel-miR-84–5p strongly support their participation in the regulation of nematode mobility and longevity. These findings provide a comprehensive analysis of TDCPP-reduced longevity from the perspective of miRNAs.
研究领域:
毒理学
·
分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 18
·13682
·
IF 5.6
Shiyao Wang,Dongfa Lin,Jiaofei Cao,Liping Wang
Animal studies have proven that 1-acetyl-5-phenyl-1H-pyrrol-3-yl acetate (APPA) is a powerful antioxidant as a novel aldose reductase inhibitor independently synthesized by our laboratory; however, there is no current information on APPA’s anti-aging mechanism. Therefore, this study examined the impact and mechanism of APPA’s anti-aging and anti-oxidation capacity using theCaenorhabditis elegansmodel. The results demonstrated that APPA increasesC. elegans’ longevity without affecting the typical metabolism ofEscherichia coliOP50 (OP50). APPA also had a non-toxic effect onC. elegans, increased locomotor ability, decreased the levels of reactive oxygen species, lipofuscin, and fat, and increased anti-stress capacity. QRT-PCR analysis further revealed that APPA upregulated the expression of antioxidant genes, includingsod-3,gst-4, andhsp-16.2, and the critical downstream transcription factors,daf-16,skn-1, andhsf-1of the insulin/insulin-like growth factor (IGF) receptor,daf-2. In addition,fat-6andnhr-80were upregulated. However, the APPA’s life-prolonging effects were absent on thedaf-2,daf-16,skn-1, andhsf-1mutants implying that the APPA’s life-prolonging mechanism depends on the insulin/IGF-1 signaling system. The transcriptome sequencing also revealed that the mitochondrial route was also strongly associated with the APPA life extension, consistent withmev-1andisp-1mutant life assays. These findings aid in the investigation of APPA’s longevity extension mechanism.Keywords:APPA;lifespan;stress resistant;insulin/IGF-1;Caenorhabditis elegans
研究领域:
衰老研究
·
分子生物学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2023
·
IF 7.4
Caihua Wang,Xiaofang Li,Wei Zhang,Wenxuan Liu,Ziwei Lv,Runlin Gui,Man Li,Yujia Li,Xiaomin Sun,Ping Liu,Xiaobin Fan,Shiyao Yang,Yuyan Xiong,Lu Qian
Excessive free fatty acids (FFAs) accumulation is a leading risk factor for the pathogenesis of insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine-phosphate phospho-lyase (ETNPPL), a newly identified metabolic enzyme , catalyzes phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde and is highly expressed in hepatic tissue. Whether it plays a role in regulating FFA-induced IR in hepatocytes has yet to be understood. In this study, we established an in vitro palmitic acid (PA)-induced IR model in human HepG2 cells and mouse AML12 cells with chronic treatment of PA. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without PA stimulation. We show that ETNPPL expression is significantly elevated in PA-induced IR and that silencing ETNPPL ameliorates this IR in hepatocytes. Inversely, overexpressing ETNPPL under normal conditions without PA promotes IR, reactive oxygen species generation, and ARG2 activation in both HepG2 and AML12 cells. Moreover, ETNPPL depletion markedly down-regulates ARG2 expression in hepatocytes. Besides, silencing ARG2 prevents ETNPPL-induced ROS accumulation and inhibition of autophagic flux and IR in hepatocytes. Finally, we found that phytopharmaceutical disruption of ETNPPL by quercetin ameliorates PA-induced IR in hepatocytes. Our study discloses that ETNPPL inhibiting autophagic flux mediates insulin resistance triggered by PA in hepatocytes via ARG2/ROS signaling cascade. Our findings provide novel insights into elucidating the pathogenesis of obesity-associated hepatic IR, suggesting that targeting ETNPPL might represent a potential approach for T2DM therapy.
研究领域:
代谢
·
分子生物学
·
细胞生物学
·
内分泌学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2022
·
IF 6.978
Xiaowen Xu,Yu Ran,Chengyuan Huang,Zongning Yin
Although “closed-loop” smart insulin delivery systems have been extensively investigated, the majority of them suffer from low insulin loading efficiency and slow glucose response. Here, we constructed a novel nanocomplex (NC), which was prepared by electrostatic interaction between negatively charged insulin prodrug nanoparticles (NPs) and positively charged polycaprolactone–polyethylenimine (PCL–PEI) micelles. The insulin prodrug was linked to acetalated dextran (AD) via borate ester bonds to form IAD NPs, and glucose oxidase (GOx) was encapsulated in PCL–PEI micelles. The NC was negatively charged with a high insulin grafting rate (0.473 mg/mg), and in vitro experiments revealed that IAD was sensitive to hyperglycemia and H2O2, whereas GOx significantly improved the response to glucose by altering the microenvironment to promote sustained insulin release. Furthermore, compared with free insulin and IAD NPs, subcutaneously injected NCs in diabetic rats had long-term hypoglycemic effects, showing excellent biocompatibility in vitro and in vivo, which had good potential in insulin self-regulation delivery.
研究领域:
药学
·
纳米技术
·
生物医学工程
·
糖尿病研究
✓ 已验证
DOI
PubMed
高影响因子
Nanoscale
·
2019
·Vol. 11
·期 13
·6471-6479
·
IF 6.97
Yujie Zhang,Mingxin Wu,Wubin Dai,Yinping Li,Xin Wang,Di Tan,Zhilu Yang,Sheng Liu,Longjian Xue,Yifeng Lei
Diabetes has become the third threat to public health worldwide. Traditional treatments of diabetes require frequent blood glucose testing and insulin injections, which not only bring great pain to patients but also exhibit difficulty in controlling the blood glucose accurately. In order to solve these problems, we developed a smart glucose-responsive insulin delivery system responding to the environmental glucose concentration based on gold nanoclusters (GNCs). First, we prepared GNCs as high drug-loading nanocarriers, and we decorated GNCs with phenylboronic acid molecules (4-carboxyphenylboronic acid (PBA) and 4-carboxy-3-fluorophenylboronic acid (FPBA)) as responsive ligands; then, we grafted insulin on the surface to form glucose-responsive insulin-release nanocomplexes GNC-PBA-Ins and GNC-FPBA-Ins, respectively. In the in vitro test, these complexes exhibited high sensitivity to glucose concentrations and rapidly released insulin in a hyperglycemic state. In type 1 diabetic mice in vivo, these complexes could maintain the blood glucose levels of mice in a normoglycemic range for up to 48 h without peaks of hyperglycemia or hypoglycemia, where the GNC-FPBA-Ins complex showed a better regulation of glucose than the GNC-PBA-Ins complex. These gold nanocluster systems mimic the function of the natural pancreas for blood glucose control, which has great potentials for the diagnosis and treatment of diabetes in the future.
研究领域:
纳米技术
·
生物医学工程
·
药学
·
内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）