Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo
The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in...
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2025-02-01
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| author | Nabin Ghimire Morgan Welch Cassandra Secunda Alexis Fink Ahmed Lawan |
| author_facet | Nabin Ghimire Morgan Welch Cassandra Secunda Alexis Fink Ahmed Lawan |
| author_sort | Nabin Ghimire |
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| description | The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in the regulation of cell proliferation and the development of metabolic disorders. However, whether there is a causal relationship between MKP-2 and diabetes onset is unclear. The aim of this study was to determine the role of MKP-2 in the regulation of whole-body glucose homeostasis and the impact on pancreatic islet function using streptozotocin-induced pancreatic injury. Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in mouse models treated with multiple low doses of streptozotocin (STZ). In comparison, both male MKP-2 wild-type and knockout mice were hyperglycemic. Consistent with the hyperglycemia, female MKP-2-deficient mice exhibited reduced islet size. Under T2D conditions, MKP-2-deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with the downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA. Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas. MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice. These studies demonstrate the critical role of MKP-2 in the development of T2D diabetes in vivo. This suggests that MKP-2 may have a gender-specific role in diabetes development. This discovery raises the possibility that postmenopausal prevention of T2D may benefit from the activation of MKP-2 activity in islet cells. |
| format | Article |
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| publishDate | 2025-02-01 |
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| spelling | doaj-art-bdeafee7419a4a2d92c5ca4a4b010bfc2025-08-20T02:44:38ZengMDPI AGCells2073-44092025-02-0114426110.3390/cells14040261Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In VivoNabin Ghimire0Morgan Welch1Cassandra Secunda2Alexis Fink3Ahmed Lawan4Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USADepartment of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USADepartment of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USADepartment of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USADepartment of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USAThe development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in the regulation of cell proliferation and the development of metabolic disorders. However, whether there is a causal relationship between MKP-2 and diabetes onset is unclear. The aim of this study was to determine the role of MKP-2 in the regulation of whole-body glucose homeostasis and the impact on pancreatic islet function using streptozotocin-induced pancreatic injury. Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in mouse models treated with multiple low doses of streptozotocin (STZ). In comparison, both male MKP-2 wild-type and knockout mice were hyperglycemic. Consistent with the hyperglycemia, female MKP-2-deficient mice exhibited reduced islet size. Under T2D conditions, MKP-2-deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with the downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA. Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas. MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice. These studies demonstrate the critical role of MKP-2 in the development of T2D diabetes in vivo. This suggests that MKP-2 may have a gender-specific role in diabetes development. This discovery raises the possibility that postmenopausal prevention of T2D may benefit from the activation of MKP-2 activity in islet cells.https://www.mdpi.com/2073-4409/14/4/261hyperglycemiadiabetesMKP-2MAPKislet |
| spellingShingle | Nabin Ghimire Morgan Welch Cassandra Secunda Alexis Fink Ahmed Lawan Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo Cells hyperglycemia diabetes MKP-2 MAPK islet |
| title | Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo |
| title_full | Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo |
| title_fullStr | Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo |
| title_full_unstemmed | Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo |
| title_short | Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo |
| title_sort | mitogen activated protein kinase phosphatase 2 deletion promotes hyperglycemia and susceptibility to streptozotocin induced diabetes in female mice in vivo |
| topic | hyperglycemia diabetes MKP-2 MAPK islet |
| url | https://www.mdpi.com/2073-4409/14/4/261 |
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