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Secretagogin Regulates Insulin Signaling by Direct Insulin Binding

Secretagogin (SCGN) is a β-cell enriched, secretory/cytosolic Ca(2+)-binding protein with unknown secretory regulation and functions. Recent findings suggest that SCGN deficiency correlates with compromised insulin response and diabetes. However, the (patho)physiological SCGN-insulin nexus remains u...

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Autores principales: Sharma, Anand Kumar, Khandelwal, Radhika, Kumar, M. Jerald Mahesh, Ram, N. Sai, Chidananda, Amrutha H., Raj, T. Avinash, Sharma, Yogendra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864339/
https://www.ncbi.nlm.nih.gov/pubmed/31734536
http://dx.doi.org/10.1016/j.isci.2019.10.066
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author Sharma, Anand Kumar
Khandelwal, Radhika
Kumar, M. Jerald Mahesh
Ram, N. Sai
Chidananda, Amrutha H.
Raj, T. Avinash
Sharma, Yogendra
author_facet Sharma, Anand Kumar
Khandelwal, Radhika
Kumar, M. Jerald Mahesh
Ram, N. Sai
Chidananda, Amrutha H.
Raj, T. Avinash
Sharma, Yogendra
author_sort Sharma, Anand Kumar
collection PubMed
description Secretagogin (SCGN) is a β-cell enriched, secretory/cytosolic Ca(2+)-binding protein with unknown secretory regulation and functions. Recent findings suggest that SCGN deficiency correlates with compromised insulin response and diabetes. However, the (patho)physiological SCGN-insulin nexus remains unexplored. We here report that SCGN is an insulin-interacting protein. The protein-protein interaction between SCGN and insulin regulates insulin stability and increases insulin potency in vitro and in vivo. Mutagenesis studies suggest an indispensable role for N-terminal domain of SCGN in modulating insulin stability and function. SCGN supplementation in diabetogenic-diet-fed mice preserves physiological insulin responsiveness while relieving obesity and cardiovascular risk. SCGN-insulin interaction mediated alleviation of hyperinsulinemia by increased insulin internalization, which translates to reduced body fat and hepatic lipid accumulation, emerges as a plausible mechanism for the preservation of insulin responsiveness. These findings establish SCGN as a functional insulin-binding protein (InsBP) with therapeutic potential against diabetes.
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spelling pubmed-68643392019-11-22 Secretagogin Regulates Insulin Signaling by Direct Insulin Binding Sharma, Anand Kumar Khandelwal, Radhika Kumar, M. Jerald Mahesh Ram, N. Sai Chidananda, Amrutha H. Raj, T. Avinash Sharma, Yogendra iScience Article Secretagogin (SCGN) is a β-cell enriched, secretory/cytosolic Ca(2+)-binding protein with unknown secretory regulation and functions. Recent findings suggest that SCGN deficiency correlates with compromised insulin response and diabetes. However, the (patho)physiological SCGN-insulin nexus remains unexplored. We here report that SCGN is an insulin-interacting protein. The protein-protein interaction between SCGN and insulin regulates insulin stability and increases insulin potency in vitro and in vivo. Mutagenesis studies suggest an indispensable role for N-terminal domain of SCGN in modulating insulin stability and function. SCGN supplementation in diabetogenic-diet-fed mice preserves physiological insulin responsiveness while relieving obesity and cardiovascular risk. SCGN-insulin interaction mediated alleviation of hyperinsulinemia by increased insulin internalization, which translates to reduced body fat and hepatic lipid accumulation, emerges as a plausible mechanism for the preservation of insulin responsiveness. These findings establish SCGN as a functional insulin-binding protein (InsBP) with therapeutic potential against diabetes. Elsevier 2019-11-02 /pmc/articles/PMC6864339/ /pubmed/31734536 http://dx.doi.org/10.1016/j.isci.2019.10.066 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
Sharma, Anand Kumar
Khandelwal, Radhika
Kumar, M. Jerald Mahesh
Ram, N. Sai
Chidananda, Amrutha H.
Raj, T. Avinash
Sharma, Yogendra
Secretagogin Regulates Insulin Signaling by Direct Insulin Binding
title Secretagogin Regulates Insulin Signaling by Direct Insulin Binding
title_full Secretagogin Regulates Insulin Signaling by Direct Insulin Binding
title_fullStr Secretagogin Regulates Insulin Signaling by Direct Insulin Binding
title_full_unstemmed Secretagogin Regulates Insulin Signaling by Direct Insulin Binding
title_short Secretagogin Regulates Insulin Signaling by Direct Insulin Binding
title_sort secretagogin regulates insulin signaling by direct insulin binding
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864339/
https://www.ncbi.nlm.nih.gov/pubmed/31734536
http://dx.doi.org/10.1016/j.isci.2019.10.066
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