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Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency

Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insuli...

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Autores principales: Gao, Mei Hua, Giamouridis, Dimosthenis, Lai, N. Chin, Guo, Tracy, Xia, Bing, Kim, Young Chul, Huu, Viet Anh Nguyen, Skowronska-Krawczyk, Dorota, Lantier, Louise, Bhargava, Raag, Hammond, H. Kirk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965520/
https://www.ncbi.nlm.nih.gov/pubmed/31970200
http://dx.doi.org/10.1016/j.omtm.2019.12.002
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author Gao, Mei Hua
Giamouridis, Dimosthenis
Lai, N. Chin
Guo, Tracy
Xia, Bing
Kim, Young Chul
Huu, Viet Anh Nguyen
Skowronska-Krawczyk, Dorota
Lantier, Louise
Bhargava, Raag
Hammond, H. Kirk
author_facet Gao, Mei Hua
Giamouridis, Dimosthenis
Lai, N. Chin
Guo, Tracy
Xia, Bing
Kim, Young Chul
Huu, Viet Anh Nguyen
Skowronska-Krawczyk, Dorota
Lantier, Louise
Bhargava, Raag
Hammond, H. Kirk
author_sort Gao, Mei Hua
collection PubMed
description Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp. The combined increases in both insulin availability and sensitivity resulted in improved glycemic indices—events that were not anticipated in these insulin-deficient models. In addition, urocortin 2 gene transfer reduced ocular manifestations of long-standing insulin deficiency such as vascular leak and improved retinal function. Finally, mortality was reduced by urocortin 2 gene transfer. The mechanisms for these beneficial effects included increased activities of AMP-activated protein kinase and Akt (protein kinase B) in skeletal muscle, increased skeletal muscle glucose uptake, and increased insulin release. These data suggest that urocortin 2 gene transfer may be a viable therapy for new onset type 1 diabetes and might reduce insulin needs in later stage disease.
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spelling pubmed-69655202020-01-22 Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency Gao, Mei Hua Giamouridis, Dimosthenis Lai, N. Chin Guo, Tracy Xia, Bing Kim, Young Chul Huu, Viet Anh Nguyen Skowronska-Krawczyk, Dorota Lantier, Louise Bhargava, Raag Hammond, H. Kirk Mol Ther Methods Clin Dev Article Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp. The combined increases in both insulin availability and sensitivity resulted in improved glycemic indices—events that were not anticipated in these insulin-deficient models. In addition, urocortin 2 gene transfer reduced ocular manifestations of long-standing insulin deficiency such as vascular leak and improved retinal function. Finally, mortality was reduced by urocortin 2 gene transfer. The mechanisms for these beneficial effects included increased activities of AMP-activated protein kinase and Akt (protein kinase B) in skeletal muscle, increased skeletal muscle glucose uptake, and increased insulin release. These data suggest that urocortin 2 gene transfer may be a viable therapy for new onset type 1 diabetes and might reduce insulin needs in later stage disease. American Society of Gene & Cell Therapy 2019-12-14 /pmc/articles/PMC6965520/ /pubmed/31970200 http://dx.doi.org/10.1016/j.omtm.2019.12.002 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Gao, Mei Hua
Giamouridis, Dimosthenis
Lai, N. Chin
Guo, Tracy
Xia, Bing
Kim, Young Chul
Huu, Viet Anh Nguyen
Skowronska-Krawczyk, Dorota
Lantier, Louise
Bhargava, Raag
Hammond, H. Kirk
Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency
title Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency
title_full Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency
title_fullStr Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency
title_full_unstemmed Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency
title_short Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency
title_sort urocortin 2 gene transfer improves glycemic control and reduces retinopathy and mortality in murine insulin deficiency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965520/
https://www.ncbi.nlm.nih.gov/pubmed/31970200
http://dx.doi.org/10.1016/j.omtm.2019.12.002
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