Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor
Abstract Aim Heparin, a widely used antithrombotic drug has many other anticoagulant‐independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an approach for developing heparin‐targeted therapies for diabetes. Methods For serum heparin levels...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-07-01
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| Series: | Endocrinology, Diabetes & Metabolism |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/edm2.253 |
| _version_ | 1819097048199200768 |
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| author | Canjun Zhu Zhiyue Xu Yexian Yuan Tao Wang Chang Xu Cong Yin Peipei Xie Pingwen Xu Hui Ye Nirali Patel Sarah Schaul Lina Wang Xiaotong Zhu Songbo Wang Ping Gao Qianyun Xi Yongliang Zhang Gang Shu Qingyan Jiang |
| author_facet | Canjun Zhu Zhiyue Xu Yexian Yuan Tao Wang Chang Xu Cong Yin Peipei Xie Pingwen Xu Hui Ye Nirali Patel Sarah Schaul Lina Wang Xiaotong Zhu Songbo Wang Ping Gao Qianyun Xi Yongliang Zhang Gang Shu Qingyan Jiang |
| author_sort | Canjun Zhu |
| collection | DOAJ |
| description | Abstract Aim Heparin, a widely used antithrombotic drug has many other anticoagulant‐independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an approach for developing heparin‐targeted therapies for diabetes. Methods For serum heparin levels and correlation analysis, 122 volunteer’s plasma, DIO (4 weeks HFD) and db/db mice serums were collected and used for spectrophotometric determination. OGTT, ITT, 2‐NBDG uptake and muscle GLUT4 immunofluorescence were detected in chronic intraperitoneal injection of heparin or heparinase (16 days) and muscle‐specific loss‐of‐function mice. In 293T cells, the binding of insulin to its receptor was detected by fluorescence resonance energy transfer (FRET), Myc‐GLUT4‐mCherry plasmid was used in GLUT4 translocation. In vitro, C2C12 cells as mouse myoblast cells were further verified the effects of heparin on glucose homeostasis through 2‐NBDG uptake, Western blot and co‐immunoprecipitation. Results Serum concentrations of heparin are positively associated with blood glucose levels in humans and are significantly increased in diet‐induced and db/db obesity mouse models. Consistently, a chronic intraperitoneal injection of heparin results in hyperglycaemia, glucose intolerance and insulin resistance. These effects are independent of heparin’s anticoagulant function and associated with decreases in glucose uptake and translocation of glucose transporter type 4 (GLUT4) in skeletal muscle. By using a muscle‐specific loss‐of‐function mouse model, we further demonstrated that muscle GLUT4 is required for the detrimental effects of heparin on glucose homeostasis. Conclusions Heparin reduced insulin binding to its receptor by interacting with insulin and inhibited insulin‐mediated activation of the PI3K/Akt signalling pathway in skeletal muscle, which leads to impaired glucose uptake and hyperglycaemia. |
| first_indexed | 2024-12-22T00:08:53Z |
| format | Article |
| id | doaj.art-5039ae79ffc24639ab83b4436836f6be |
| institution | Directory Open Access Journal |
| issn | 2398-9238 |
| language | English |
| last_indexed | 2024-12-22T00:08:53Z |
| publishDate | 2021-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Endocrinology, Diabetes & Metabolism |
| spelling | doaj.art-5039ae79ffc24639ab83b4436836f6be2022-12-21T18:45:29ZengWileyEndocrinology, Diabetes & Metabolism2398-92382021-07-0143n/an/a10.1002/edm2.253Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptorCanjun Zhu0Zhiyue Xu1Yexian Yuan2Tao Wang3Chang Xu4Cong Yin5Peipei Xie6Pingwen Xu7Hui Ye8Nirali Patel9Sarah Schaul10Lina Wang11Xiaotong Zhu12Songbo Wang13Ping Gao14Qianyun Xi15Yongliang Zhang16Gang Shu17Qingyan Jiang18Guangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaHuadong Sanatorium Wuxi ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaDivision of Endocrinology, Diabetes and Metabolism Department of Medicine The University of Illinois at Chicago Chicago IL USADivision of Endocrinology, Diabetes and Metabolism Department of Medicine The University of Illinois at Chicago Chicago IL USADivision of Endocrinology, Diabetes and Metabolism Department of Medicine The University of Illinois at Chicago Chicago IL USADivision of Endocrinology, Diabetes and Metabolism Department of Medicine The University of Illinois at Chicago Chicago IL USAGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaGuangdong Laboratory of Lingnan Modern Agriculture Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry College of Animal Science South China Agricultural University Guangzhou ChinaAbstract Aim Heparin, a widely used antithrombotic drug has many other anticoagulant‐independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an approach for developing heparin‐targeted therapies for diabetes. Methods For serum heparin levels and correlation analysis, 122 volunteer’s plasma, DIO (4 weeks HFD) and db/db mice serums were collected and used for spectrophotometric determination. OGTT, ITT, 2‐NBDG uptake and muscle GLUT4 immunofluorescence were detected in chronic intraperitoneal injection of heparin or heparinase (16 days) and muscle‐specific loss‐of‐function mice. In 293T cells, the binding of insulin to its receptor was detected by fluorescence resonance energy transfer (FRET), Myc‐GLUT4‐mCherry plasmid was used in GLUT4 translocation. In vitro, C2C12 cells as mouse myoblast cells were further verified the effects of heparin on glucose homeostasis through 2‐NBDG uptake, Western blot and co‐immunoprecipitation. Results Serum concentrations of heparin are positively associated with blood glucose levels in humans and are significantly increased in diet‐induced and db/db obesity mouse models. Consistently, a chronic intraperitoneal injection of heparin results in hyperglycaemia, glucose intolerance and insulin resistance. These effects are independent of heparin’s anticoagulant function and associated with decreases in glucose uptake and translocation of glucose transporter type 4 (GLUT4) in skeletal muscle. By using a muscle‐specific loss‐of‐function mouse model, we further demonstrated that muscle GLUT4 is required for the detrimental effects of heparin on glucose homeostasis. Conclusions Heparin reduced insulin binding to its receptor by interacting with insulin and inhibited insulin‐mediated activation of the PI3K/Akt signalling pathway in skeletal muscle, which leads to impaired glucose uptake and hyperglycaemia.https://doi.org/10.1002/edm2.253GLUT4 activityheparinhyperglycaemiainsulin resistancemuscle glucose uptake |
| spellingShingle | Canjun Zhu Zhiyue Xu Yexian Yuan Tao Wang Chang Xu Cong Yin Peipei Xie Pingwen Xu Hui Ye Nirali Patel Sarah Schaul Lina Wang Xiaotong Zhu Songbo Wang Ping Gao Qianyun Xi Yongliang Zhang Gang Shu Qingyan Jiang Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor Endocrinology, Diabetes & Metabolism GLUT4 activity heparin hyperglycaemia insulin resistance muscle glucose uptake |
| title | Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor |
| title_full | Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor |
| title_fullStr | Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor |
| title_full_unstemmed | Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor |
| title_short | Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor |
| title_sort | heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor |
| topic | GLUT4 activity heparin hyperglycaemia insulin resistance muscle glucose uptake |
| url | https://doi.org/10.1002/edm2.253 |
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