The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus
Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDA...
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MDPI AG
2020-02-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/2/481 |
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| author | Srinivas Pittala Idan Levy Soumasree De Swaroop Kumar Pandey Nataly Melnikov Tehila Hyman Varda Shoshan-Barmatz |
| author_facet | Srinivas Pittala Idan Levy Soumasree De Swaroop Kumar Pandey Nataly Melnikov Tehila Hyman Varda Shoshan-Barmatz |
| author_sort | Srinivas Pittala |
| collection | DOAJ |
| description | Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ/HFD-32 fed mice caused an increase in the expression of β-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the β-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to β-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes. |
| first_indexed | 2024-03-12T05:56:55Z |
| format | Article |
| id | doaj.art-de089741292c4e9eaf3855b668bcedc1 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T05:56:55Z |
| publishDate | 2020-02-01 |
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| spelling | doaj.art-de089741292c4e9eaf3855b668bcedc12023-09-03T04:33:56ZengMDPI AGCells2073-44092020-02-019248110.3390/cells9020481cells9020481The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes MellitusSrinivas Pittala0Idan Levy1Soumasree De2Swaroop Kumar Pandey3Nataly Melnikov4Tehila Hyman5Varda Shoshan-Barmatz6Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDepartment of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelDiabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ/HFD-32 fed mice caused an increase in the expression of β-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the β-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to β-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes.https://www.mdpi.com/2073-4409/9/2/481β-cellshigh-fat dietmitochondriatype 2 diabetesvdac1-based r-tf-d-lp4 peptide |
| spellingShingle | Srinivas Pittala Idan Levy Soumasree De Swaroop Kumar Pandey Nataly Melnikov Tehila Hyman Varda Shoshan-Barmatz The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus Cells β-cells high-fat diet mitochondria type 2 diabetes vdac1-based r-tf-d-lp4 peptide |
| title | The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus |
| title_full | The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus |
| title_fullStr | The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus |
| title_full_unstemmed | The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus |
| title_short | The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus |
| title_sort | vdac1 based r tf d lp4 peptide as a potential treatment for diabetes mellitus |
| topic | β-cells high-fat diet mitochondria type 2 diabetes vdac1-based r-tf-d-lp4 peptide |
| url | https://www.mdpi.com/2073-4409/9/2/481 |
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