Date on Master's Thesis/Doctoral Dissertation
Biochemistry and Molecular Biology
Biochemistry and Molecular Biology, PhD
Committee Co-Chair (if applicable)
glutathione s-transferase p; glucose intolerance; diabetes; JNK; gluconeogenesis; insulin secretion
High calorie diets have fostered the current pandemic of obesity and comorbid conditions of non-alcoholic fatty liver disease (NAFLD), systemic insulin resistance (IR) and type 2 diabetes (T2D). Hepatic glutathione S-transferases (GSTs) are dysregulated in obesity, NAFLD and diabetes. The multifunctional GST pi isoform (GSTP) catalyzes acrolein metabolism and inhibits JNK (c-Jun NH2-terminal kinase). The purpose of this study was to test specifically whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high fat diet (HFD) in wild type (WT) mice concomitant with glucose intolerance, increased hepatic JNK activation and protein-acrolein adducts. To address whether GSTP contributes specifically to HFD-induced sequelae, metabolic phenotype of GSTP-null mice was assessed. Body composition, fasted levels of blood glucose and insulin were similar in WT and GSTP-null mice. However, the study revealed that GSTP-null mice were glucose intolerant. GSTP-null mice were glucose intolerant. Furthermore, this defect in glucose homeostasis was due not to peripheral IR but to an impaired capacity to increase plasma insulin level in response to hyperglycemia. In exploring the effect of insufficient insulin release, the pyruvate tolerance test (PTT) revealed greater PTT AUC in GSTP-null mice, indicating enhanced hepatic glucose output. Glucose intolerance was positively correlated with the level of pyruvate intolerance. However, no differences were found in fasting mRNA levels of the gluconeogenic enzymes: phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6pc) between WT and GSTP-null livers. Treatment of GSTP-null mice with the JNK inhibitor, SP600125, attenuated hepatic gluconeogenesis compared with vehicle-treated littermate controls. Collectively, these data illustrate a novel role of GSTP in glucose handling via JNK regulation and hepatic gluconeogenesis – a heretofore unrecognized function. Thus, future studies are warranted for studying how GSTP dysregulation influences the metabolic complications of human obesity, NAFLD and diabetes.
Ghosh Dastidar, Shubha, "Glutathione s-transferase p in glucose homeostasis in mice." (2016). Electronic Theses and Dissertations. Paper 2561.