Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.

To investigate the therapeutic efficacy and mechanism of β-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabe...

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Autores principales:	Mi-Hyun Kim, Seung-Hyun Hong, Moon-Kyu Lee
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b6c0fc4eaa5e4480a1038eaec66780a6
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spelling	oai:doaj.org-article:b6c0fc4eaa5e4480a1038eaec66780a62021-11-18T07:38:13ZInsulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.1932-620310.1371/journal.pone.0067802https://doaj.org/article/b6c0fc4eaa5e4480a1038eaec66780a62013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874448/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203To investigate the therapeutic efficacy and mechanism of β-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabetic rats. Compared with INS-1 cells, INS-IR cells showed improved β-cell function, including the increase in glucose utilization, calcium mobilization, and insulin secretion, and exhibited a higher rate of cell proliferation, and maintained lower levels of blood glucose in diabetic rats. These results were attributed to the increase of β-catenin/PPARγ complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of β-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by β-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. In addition, the promotion of cell proliferation and insulin secretion by Wnt signaling activation was shown by 100 nM insulin treatment, and to a similar degree, was shown in INS-IR cells. In this regard, this study suggests that transferring INS-IR cells into diabetic animals is an effective and feasible DM treatment. Accordingly, the method might be a promising alternative strategy for treatment of DM given the adverse effects of insulin among patients, including the increased risk of modest weight gain and hypoglycemia. Additionally, this study demonstrates that the novel mechanism of cross-talk between insulin and Wnt signaling plays a primary role in the higher therapeutic efficacy of IR-overexpressing β-cells.Mi-Hyun KimSeung-Hyun HongMoon-Kyu LeePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e67802 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mi-Hyun Kim Seung-Hyun Hong Moon-Kyu Lee Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.
description	To investigate the therapeutic efficacy and mechanism of β-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabetic rats. Compared with INS-1 cells, INS-IR cells showed improved β-cell function, including the increase in glucose utilization, calcium mobilization, and insulin secretion, and exhibited a higher rate of cell proliferation, and maintained lower levels of blood glucose in diabetic rats. These results were attributed to the increase of β-catenin/PPARγ complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of β-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by β-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. In addition, the promotion of cell proliferation and insulin secretion by Wnt signaling activation was shown by 100 nM insulin treatment, and to a similar degree, was shown in INS-IR cells. In this regard, this study suggests that transferring INS-IR cells into diabetic animals is an effective and feasible DM treatment. Accordingly, the method might be a promising alternative strategy for treatment of DM given the adverse effects of insulin among patients, including the increased risk of modest weight gain and hypoglycemia. Additionally, this study demonstrates that the novel mechanism of cross-talk between insulin and Wnt signaling plays a primary role in the higher therapeutic efficacy of IR-overexpressing β-cells.
format	article
author	Mi-Hyun Kim Seung-Hyun Hong Moon-Kyu Lee
author_facet	Mi-Hyun Kim Seung-Hyun Hong Moon-Kyu Lee
author_sort	Mi-Hyun Kim
title	Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.
title_short	Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.
title_full	Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.
title_fullStr	Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.
title_full_unstemmed	Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.
title_sort	insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through wnt signaling activation.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/b6c0fc4eaa5e4480a1038eaec66780a6
work_keys_str_mv	AT mihyunkim insulinreceptoroverexpressingbcellsamelioratehyperglycemiaindiabeticratsthroughwntsignalingactivation AT seunghyunhong insulinreceptoroverexpressingbcellsamelioratehyperglycemiaindiabeticratsthroughwntsignalingactivation AT moonkyulee insulinreceptoroverexpressingbcellsamelioratehyperglycemiaindiabeticratsthroughwntsignalingactivation
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Insulin receptor-overexpressing β-cells ameliorate hyperglycemia in diabetic rats through Wnt signaling activation.

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