{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T11:04:57Z","timestamp":1761563097864,"version":"build-2065373602"},"reference-count":70,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011479","name":"University of Alabama in Huntsville (UAH)","doi-asserted-by":"publisher","award":["251359"],"award-info":[{"award-number":["251359"]}],"id":[{"id":"10.13039\/100011479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells14040261","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T06:06:06Z","timestamp":1739340366000},"page":"261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2100-8085","authenticated-orcid":false,"given":"Nabin","family":"Ghimire","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan","family":"Welch","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cassandra","family":"Secunda","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2109-5317","authenticated-orcid":false,"given":"Alexis","family":"Fink","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9166-9548","authenticated-orcid":false,"given":"Ahmed","family":"Lawan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11886-019-1107-y","article-title":"Epidemiology of Diabetes Mellitus and Cardiovascular Disease","volume":"21","author":"Glovaci","year":"2019","journal-title":"Curr. 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