Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice
Summary: The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human mono...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-02-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718301141 |
| _version_ | 1828778425377095680 |
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| author | Ankit X. Sharma Ezekiel B. Quittner-Strom Young Lee Joshua A. Johnson Sarah A. Martin Xinxin Yu Jianping Li John Lu Zheqing Cai Shiuhwei Chen May-yun Wang Yiyi Zhang Mackenzie J. Pearson Andie C. Dorn Jeffrey G. McDonald Ruth Gordillo Hai Yan Dung Thai Zhao V. Wang Roger H. Unger William L. Holland |
| author_facet | Ankit X. Sharma Ezekiel B. Quittner-Strom Young Lee Joshua A. Johnson Sarah A. Martin Xinxin Yu Jianping Li John Lu Zheqing Cai Shiuhwei Chen May-yun Wang Yiyi Zhang Mackenzie J. Pearson Andie C. Dorn Jeffrey G. McDonald Ruth Gordillo Hai Yan Dung Thai Zhao V. Wang Roger H. Unger William L. Holland |
| author_sort | Ankit X. Sharma |
| collection | DOAJ |
| description | Summary: The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression. |
| first_indexed | 2024-12-11T16:42:01Z |
| format | Article |
| id | doaj.art-fc9dc67502904242b84786c20471f0be |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T16:42:01Z |
| publishDate | 2018-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fc9dc67502904242b84786c20471f0be2022-12-22T00:58:19ZengElsevierCell Reports2211-12472018-02-012271760177310.1016/j.celrep.2018.01.065Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic MiceAnkit X. Sharma0Ezekiel B. Quittner-Strom1Young Lee2Joshua A. Johnson3Sarah A. Martin4Xinxin Yu5Jianping Li6John Lu7Zheqing Cai8Shiuhwei Chen9May-yun Wang10Yiyi Zhang11Mackenzie J. Pearson12Andie C. Dorn13Jeffrey G. McDonald14Ruth Gordillo15Hai Yan16Dung Thai17Zhao V. Wang18Roger H. Unger19William L. Holland20Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Medical Service, Veteran’s Administration North Texas Health Care System, Dallas, TX 75216, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USADepartment of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Medical Service, Veteran’s Administration North Texas Health Care System, Dallas, TX 75216, USADivision of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USAREMD Biotherapeutics Inc., Camarillo, CA 93012, USACardio-lab, Baltimore, MD 21205, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Medical Service, Veteran’s Administration North Texas Health Care System, Dallas, TX 75216, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USADepartment of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USAREMD Biotherapeutics Inc., Camarillo, CA 93012, USAREMD Biotherapeutics Inc., Camarillo, CA 93012, USADivision of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Medical Service, Veteran’s Administration North Texas Health Care System, Dallas, TX 75216, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Corresponding authorSummary: The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression.http://www.sciencedirect.com/science/article/pii/S2211124718301141ceramidelipotoxicityadiponectinsphingolipid |
| spellingShingle | Ankit X. Sharma Ezekiel B. Quittner-Strom Young Lee Joshua A. Johnson Sarah A. Martin Xinxin Yu Jianping Li John Lu Zheqing Cai Shiuhwei Chen May-yun Wang Yiyi Zhang Mackenzie J. Pearson Andie C. Dorn Jeffrey G. McDonald Ruth Gordillo Hai Yan Dung Thai Zhao V. Wang Roger H. Unger William L. Holland Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice Cell Reports ceramide lipotoxicity adiponectin sphingolipid |
| title | Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice |
| title_full | Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice |
| title_fullStr | Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice |
| title_full_unstemmed | Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice |
| title_short | Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice |
| title_sort | glucagon receptor antagonism improves glucose metabolism and cardiac function by promoting amp mediated protein kinase in diabetic mice |
| topic | ceramide lipotoxicity adiponectin sphingolipid |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718301141 |
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