Date of Award
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biotechnology Science and Engineering
Committee Chair
Ahmed Lawan
Committee Member
Luis Cruz-Vera
Committee Member
Bradley R. Kraemer
Committee Member
Louis Lantier
Committee Member
Jerome Baudry
Research Advisor
Ahmed Lawan
Subject(s)
Phosphatases, Pancreatic beta cells, Type 2 diabetes
Abstract
Diabetes mellitus is a chronic metabolic disease characterized by persistent hyperglycemia. Type 1 diabetes results from autoimmune destruction of β-cells, whereas Type 2 diabetes is associated with obesity and insulin resistance. Type 2 diabetes (T2D) and metabolic-associated fatty liver disease (MAFLD) are closely linked, as individuals with T2D are twice as likely to develop MAFLD. Previous work from our lab demonstrated that overexpression of MKP-2 in obesity promotes hepatic steatosis, diet-induced obesity, reduced insulin sensitivity, and increased body weight. However, the role of MKP-2 in the onset and progression of diabetes remains unclear. The objectives of this study were to investigate the role of MKP-2 in pancreatic β-cell function and diabetes development using streptozotocin (STZ)-induced diabetes model. We found that global deletion of MKP-2 in mice shows sex differences in T2D. STZ-treated female MKP-2-deficient mice exhibit chronic hyperglycemia and have reduced islet size compared with wild-type controls. These mice exhibit enhanced JNK and ERK phosphorylation in the pancreas, associated with downregulation of transcription factors, including Pdx-1 and Mafa, required for pancreatic islet development and function. Additionally, MKP-2 deficiency in female mice increases adiposity and reduces Akt activation, indicating peripheral insulin resistance. Consistent with the T2D phenotype, female MKP-2 knockout mice display mild hepatic steatosis, elevated inflammatory markers, and dysregulation of genes important for the regulation of hepatic glucose and lipid metabolism. However, there was no significant difference in blood glucose level between STZ-treated male MKP-2-deficient mice and MKP-2 wild-type mice, although both were hyperglycemic on STZ-treatment. These findings suggest that MKP-2 has a gender-specific role in the development of diabetes and plays a regulatory role in pancreatic β-cell function and metabolic homeostasis in T2D. Further research is required to explore the tissue-specific role of MKP-2 in the development of diabetes and metabolic regulation in insulin-responsive tissues.
Recommended Citation
Ghimire, Nabin, "Role of MKP-2 in pancreatic beta cell function & development of diabetes" (2026). Dissertations. 492.
https://louis.uah.edu/uah-dissertations/492