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
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糖尿病研究
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生物化学
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产品关联
DOI
PubMed
高影响因子
TRANSPLANTATION
·
2005
·Vol. 80
·期 8
·1003
·
IF 3.568
Sweet Ian R.,Gilbert Merle,Jensen Rich,Sabek Omaima,Fraga Daniel W.,Gaber Ahmed O.,Reems JoAnna
Background. An in vitro method to assess human islets could prevent transplantation of nonviable islets and facilitate the optimization of islet preparation. We hypothesize that glucose-stimulated cytochrome c reduction and oxygen consumption by human islets can be used as predictors of transplant success. Methods. Isolated human islets were obtained from research-grade pancreata. Using a previously developed islet flow culture system, the response of cytochrome c reduction and oxygen consumption to glucose was compared to the ability of islets transplanted into nondiabetic NOD-SCID mice to secrete C-peptide in response to a glucose tolerance test conducted 7 days following transplant (n=10). Results. In vitro responses by human islets were qualitatively similar to those seen in rat islets: glucose increased both oxygen consumption and cytochrome c reduction. However, the responses were smaller in magnitude and quite variable. Scatter plots of C-peptide and quantiles for ln(C-peptide) indicated that 12 ng/ml could be used as threshold of transplant success with which to evaluate the diagnostic potential of cytochrome c and oxygen consumption. Data was analyzed by generating receiver operating curves and the area under the curve was 0.889 (95% CI: 0.645–1.000) and 0.738 (95% CI: 0.413–1.000) for cytochrome c reuction and oxygen consumption respectively (1 indicates absolute predictive capability and 0.5 indicates no predictive capability). Conclusions. The detection of glucose-stimulated cytochrome c reduction and oxygen consumption may have utility as criteria for the assessment of human islet quality.
研究领域:
生物医学工程
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内分泌学
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DOI
PubMed
高影响因子
Advanced Therapeutics
·
2019
·Vol. 2
·期 5
·1800136
·
IF 0
Yalu Zou,Yuanyuan Wang,Shengsheng Zhang,Yuntang Wu,Xiaofei Liu
Islet β cell failure is a critical metabolic disorder in the development of type 2 diabetes (T2DM), and the decreased viability and dysfunction of β cells accelerate diabetic pathogenesis in association with higher mortality. In this study, the therapeutic effects of chitooligosaccharide biguanide (COSG), which is similar in structure to metformin and has negligible side effects, on islet β-cell dysfunction and the possible mechanism are explored. Streptozocin-induced diabetic rats are administered COSG via daily intragastric gavage for 8 weeks. COSG significantly controlled body weight loss, attenuated glucose levels in blood and urine, and increased serum insulin. Histological examination of the pancreas reveals that COSG also alleviated pancreatic atrophy in T2DM rats. Furthermore, COSG stimulated insulin receptor substrate-2 (IRS-2) signaling in rat islet β cells, thereby mediating the activation of the phosphatidylinositol 3 kinase/protein kinase (PI3K/Akt) signaling pathway. In addition, COSG promoted downstream forkhead transcription factor O1 (FoxO1) nuclear output to potentially activate pancreas duodenum homeobox-1 (PDX-1)/glucose transporter type-2 (GLUT-2)/glucose kinase (GCK) pathway-regulated insulin secretion. COSG also inhibited the glycogen synthase kinase-3β (GSK-3β)/caspase-3 pathway to prevent cell apoptosis. The intrinsic protective effects of COSG on the impaired insulin signaling system to delay β-cell apoptosis, increase β-cell growth and proliferation, improve β-cell function and promote insulin secretion highlight the possibilities of COSG as a novel strategy for the prevention of T2DM.
研究领域:
医学
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内分泌学
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产品关联
DOI
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
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DOI
高影响因子
CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
·
2013
·Vol. 29
·期 4
·730-734
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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
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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
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糖尿病研究
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分子生物学
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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
XENOTRANSPLANTATION
·
2022
·Vol. 30
·期 1
·e12787
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IF 3.788
Zhen Geng,Qi Zhang,Ting Li,Ting Huang,Hailian Wang,Qiao Zhou,Shaoping Deng,Yanshuang Zhao,Yanjiao Li,Chunming Cheng,Carmen Gonelle-Gispert,Leo H. Buhler,Yi Wang
Objective Islet allotransplantation has demonstrated improved clinical outcomes using the hepatic portal vein as the standard infusion method. However, the current implantation site is not ideal due to the short-term thrombotic and long-term immune destruction. Meanwhile, the shortage of human organ donors further limits its application. To find a new strategy, we tested a new polymer combination for islet encapsulation and transplantation. Meanwhile, we explored a new site for xenogeneic islet transplantation in mice. Method We synthesized a hydrogel combining alginate plus poly-ethylene-imine (Alg/PEI) for the encapsulation of rat, neonatal porcine, and human islets. Transplantation was performed into the retroperitoneal retro-colic space of diabetic mice. Control mice received free islets under the kidney capsule or encapsulated islets into the peritoneum. The biochemical indexes were measured, and the transplanted islets were harvested for immunohistochemical staining of insulin and glucagon. Results Mice receiving encapsulated rat, porcine and human islets transplanted into the retroperitoneal space maintained normoglycemia for a median of 275, 145.5, and 146 days, respectively. In contrast, encapsulated xenogeneic islets transplanted into the peritoneum, maintained function for a median of 61, 95.5, and 82 days, respectively. Meanwhile, xenogeneic islets transplanted free into the kidney capsule lost their function within 3 days after transplantation. Immunohistochemical staining of encapsulated rat, porcine and human islets, retrieved from the retroperitoneal space, allowed to distinguish morphological normal insulin expressing β- and glucagon expressing α-cells at 70, 60, and 100 days post-transplant, respectively. Conclusion Transplantation of Alg/PEI encapsulated xenogeneic islets into the retroperitoneal space provides a valuable new implantation strategy for the treatment of type 1 diabetes.
研究领域:
移植学
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糖尿病
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生物材料
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免疫学
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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
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代谢学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2019
·
IF 4.471
Fei Tong,Xiangyuan Tang,Daojun Liu
Background Hepatic ischemia/reperfusion-induced pancreatic islet injury (HI/RIPII) was an important pathophysiological phenomenon in clinics. In the present study, we observed the effects of phycocyanin on HI/RIPII. However, the half-life of phycocyanin was extremely short and limited its use in vivo.Materials and methods In order to overcome this shortcoming, poly(ethylene glycol)-b-(poly(l-glutamic acid)-g-polyethylenimine) (PEG-b-(PG-g-PEI)) was synthesized and estimated as a nanocarrier for lengthening delivery of phycocyanin through the abdominal subcutaneous injection in rats. Phycocyanin (isoelectric point=4.3) was encapsulated with PEG-b-(PG-g-PEI) via electrostatic interactions at pH 7.4.Results In vitro phycocyanin was fast and efficiently encapsulated and showing efficient loading and sustained release. In vivo the anti-HI/RIPII function of phycocyanin/PEG-b-(PG-g-PEI) complex was surveyed in rats using free phycocyanin as the controls, and the results showed that phycocyanin/PEG-b-(PG-g-PEI) complex reduced HI/RIPII property and enlarged islet functionality.Conclusion These results suggested that PEG-b-(PG-g-PEI) might be treated as a potential phycocyanin nanocarrier.
研究领域:
药理学
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纳米技术
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医学
✓ 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
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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
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）