Role of the xenobiotic-activated pregnane X receptor in type 1 and type 2 diabetes in male mice.

Pregnane X receptor (PXR) primarily regulates enzymes that detoxify xenobiotics and therapeutic drugs, but its surprising role in diabetes has recently emerged. In this study we treated male wild-type (WT) and Pxr-null (PXR-KO) mice for 14 weeks with control or obesity- and type 2 diabetes-promoting high-fat diet (HFD), followed by a single dose of vehicle or 100 mg/kg of the pancreatic beta cell-specific toxin streptozotocin (STZ) and two more weeks of their respective diets. Mice were evaluated for hyperglycemia and serum and tissue markers of metabolic syndrome to characterize potential PXR modulation of type 1 (T1DM, STZ + control diet) and type 2 diabetes mellitus (T2DM, STZ + HFD). In the WT but not PXR-KO mouse T1DM and T2DM models, we observed hyperglycemia, reduced insulin levels, weight loss, pancreatic beta-cell destruction, elevated phosphoenolpyruvate carboxykinase 1, reduced glucokinase and liver fatty acid binding protein 1, and lower fibroblast growth factor 21 mRNA. In WT but not PXR-KO T2DM model mice, farnesoid X receptor mRNA was decreased, while glucose 6-phosphatase mRNA, cholesterol-7a-hydroxylase (CYP7A1) and cytochrome P450 2E1 proteins, serum liver injury markers, hepatic triglycerides and non-esterified fatty acids were increased. HFD-fed WT mice developed obesity, dyslipidemia, hyperinsulinemia, hepatotoxicity, and lipogenesis but not PXR-KO mice. In contrast, T2DM PXR-KO mice showed elevated glucose transporters (GLUT1, 2, and 4) and phosphorylated-adenosine monophosphate-activated protein kinase α (p-AMPKα) proteins associated with reduced hyperglycemia and lipogenesis. These data revealed that PXR contribute to STZ-induced pathologies, identifying this receptor as a potential therapeutic target for the prevention and treatment of diabetes.