Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction
We previously reported a depletion of murine regenerating islet-derived protein 2 (REG2) in pancreatic islets of glutathione peroxidase-1 (Gpx1) overexpressing (OE) mice. The present study was to explore if and how the REG2 depletion contributed to an augmented glucose stimulated insulin secretion (...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722002294 |
| _version_ | 1828377433434226688 |
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| author | Xi Yan Zeping Zhao Jeremy Weaver Tao Sun Jun-Won Yun Carol A. Roneker Fenghua Hu Nicolai M. Doliba Charles Chipley W. McCormick Marko Z. Vatamaniuk Xin Gen Lei |
| author_facet | Xi Yan Zeping Zhao Jeremy Weaver Tao Sun Jun-Won Yun Carol A. Roneker Fenghua Hu Nicolai M. Doliba Charles Chipley W. McCormick Marko Z. Vatamaniuk Xin Gen Lei |
| author_sort | Xi Yan |
| collection | DOAJ |
| description | We previously reported a depletion of murine regenerating islet-derived protein 2 (REG2) in pancreatic islets of glutathione peroxidase-1 (Gpx1) overexpressing (OE) mice. The present study was to explore if and how the REG2 depletion contributed to an augmented glucose stimulated insulin secretion (GSIS) in OE islets. After we verified a consistent depletion (90%, p < 0.05) of REG2 mRNA, transcript, and protein in OE islets compared with wild-type (WT) controls, we treated cultured and perifused OE islets (70 islets/sample) with REG2 (1 μg/ml or ml · min) and observed 30–40% (p < 0.05) inhibitions of GSIS by REG2. Subsequently, we obtained evidences of co-immunoprecipitation, cell surface ligand binding, and co-immunofluorescence for a ligand-receptor binding between REG2 and transmembrane, L-type voltage-dependent Ca2+ channel (CaV1.2) in beta TC3 cells. Mutating the C-type lectin binding domain of REG2 or deglycosylating CaV1.2 removed the inhibition of REG2 on GSIS and(or) the putative binding between the two proteins. Treating cultured OE and perifused WT islets with REG2 (1 μg/ml or ml · min) decreased (p < 0.05) Ca2+ influx triggered by glucose or KCl. An intraperitoneal (ip) injection of REG2 (2 μg/g) to OE mice (6-month old, n = 10) decreased their plasma insulin concentration (46%, p < 0.05) and elevated their plasma glucose concentration (25%, p < 0.05) over a 60 min period after glucose challenge (ip, 1 g/kg). In conclusion, our study identifies REG2 as a novel regulator of Ca2+ influx and insulin secretion, and reveals a new cascade of GPX1/REG2/CaV1.2 to explain how REG2 depletion in OE islets could decrease its binding to CaV1.2, resulting in uninhibited Ca2+ influx and augmented GSIS. These findings create new links to bridge redox biology, tissue regeneration, and insulin secretion. |
| first_indexed | 2024-04-14T08:12:31Z |
| format | Article |
| id | doaj.art-1ffca74d012b42eda88129d7fa11e263 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-14T08:12:31Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-1ffca74d012b42eda88129d7fa11e2632022-12-22T02:04:30ZengElsevierRedox Biology2213-23172022-10-0156102457Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproductionXi Yan0Zeping Zhao1Jeremy Weaver2Tao Sun3Jun-Won Yun4Carol A. Roneker5Fenghua Hu6Nicolai M. Doliba7Charles Chipley W. McCormick8Marko Z. Vatamaniuk9Xin Gen Lei10Department of Animal Science, Cornell University, Ithaca, NY, 14853, USADepartment of Animal Science, Cornell University, Ithaca, NY, 14853, USADepartment of Animal Science, Cornell University, Ithaca, NY, 14853, USADepartment of Animal Science, Cornell University, Ithaca, NY, 14853, USADepartment of Animal Science, Cornell University, Ithaca, NY, 14853, USA; Laboratory of Veterinary Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of KoreaDepartment of Animal Science, Cornell University, Ithaca, NY, 14853, USADepartment of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14853, USAInstitute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, 19104, USADepartment of Animal Science, Cornell University, Ithaca, NY, 14853, USADepartment of Animal Science, Cornell University, Ithaca, NY, 14853, USA; Corresponding author.Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA; Corresponding author.We previously reported a depletion of murine regenerating islet-derived protein 2 (REG2) in pancreatic islets of glutathione peroxidase-1 (Gpx1) overexpressing (OE) mice. The present study was to explore if and how the REG2 depletion contributed to an augmented glucose stimulated insulin secretion (GSIS) in OE islets. After we verified a consistent depletion (90%, p < 0.05) of REG2 mRNA, transcript, and protein in OE islets compared with wild-type (WT) controls, we treated cultured and perifused OE islets (70 islets/sample) with REG2 (1 μg/ml or ml · min) and observed 30–40% (p < 0.05) inhibitions of GSIS by REG2. Subsequently, we obtained evidences of co-immunoprecipitation, cell surface ligand binding, and co-immunofluorescence for a ligand-receptor binding between REG2 and transmembrane, L-type voltage-dependent Ca2+ channel (CaV1.2) in beta TC3 cells. Mutating the C-type lectin binding domain of REG2 or deglycosylating CaV1.2 removed the inhibition of REG2 on GSIS and(or) the putative binding between the two proteins. Treating cultured OE and perifused WT islets with REG2 (1 μg/ml or ml · min) decreased (p < 0.05) Ca2+ influx triggered by glucose or KCl. An intraperitoneal (ip) injection of REG2 (2 μg/g) to OE mice (6-month old, n = 10) decreased their plasma insulin concentration (46%, p < 0.05) and elevated their plasma glucose concentration (25%, p < 0.05) over a 60 min period after glucose challenge (ip, 1 g/kg). In conclusion, our study identifies REG2 as a novel regulator of Ca2+ influx and insulin secretion, and reveals a new cascade of GPX1/REG2/CaV1.2 to explain how REG2 depletion in OE islets could decrease its binding to CaV1.2, resulting in uninhibited Ca2+ influx and augmented GSIS. These findings create new links to bridge redox biology, tissue regeneration, and insulin secretion.http://www.sciencedirect.com/science/article/pii/S2213231722002294Regenerating islet-derived proteinGlutathione peroxidaseL-type voltage-dependent calcium channelGlucose-stimulated insulin secretionProtein-protein interaction |
| spellingShingle | Xi Yan Zeping Zhao Jeremy Weaver Tao Sun Jun-Won Yun Carol A. Roneker Fenghua Hu Nicolai M. Doliba Charles Chipley W. McCormick Marko Z. Vatamaniuk Xin Gen Lei Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction Redox Biology Regenerating islet-derived protein Glutathione peroxidase L-type voltage-dependent calcium channel Glucose-stimulated insulin secretion Protein-protein interaction |
| title | Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction |
| title_full | Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction |
| title_fullStr | Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction |
| title_full_unstemmed | Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction |
| title_short | Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction |
| title_sort | role and mechanism of reg2 depletion in insulin secretion augmented by glutathione peroxidase 1 overproduction |
| topic | Regenerating islet-derived protein Glutathione peroxidase L-type voltage-dependent calcium channel Glucose-stimulated insulin secretion Protein-protein interaction |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722002294 |
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