Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

The prevalence of type 2 diabetes is increasing at an alarming rate among Canadians. Chronic hyperglycemia is the leading cause of diabetes-related complications. The major metabolic defect that contributes to hyperglycemia is uncontrolled glucose production (gluconeogenesis) from the insulin-resistant liver. Hydrogen sulphide (H2S) is produced in liver cells via cystathionine gamma-lyase (CSE). Abnormal metabolism of H2S and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha are major pathogenic factors for diabetes development. Indeed, our CSE knockout (CSE-KO) mice exhibited a delayed onset of diabetic status and a reduced rate of gluconeogenesis. We also discovered a significant reduction in the expression level of PGC-1alpha in the CSE-KO mice, which was up-regulated by NaHS treatments. It is intriguing how H2S up-regulates PGC-1alpha and what are the functional consequences of this interaction on hepatic glucose production. We hypothesize that the CSE/H2S system stimulates hepatic gluconeogenesis through the induction of PGC-1alpha by up-regulating the cAMP signaling pathway. As such, our objectives are to determine the signaling mechanism of H2S-induced PGC-1alpha up-regulation; to examine PGC-1alpha dependency of H2S-induced glucose production; and to investigate therapeutic approaches to correct H2S-induced over-stimulated hepatic glucose production. To achieve our goals, we will perform a series of in vitro and in vivo gluconeogenic experiments and induce type 2 diabetes in the CSE-KO and wild-type mice. Thereafter, the rate of gluconeogenesis and the development of diabetes will be determined and compared. We will also examine whether PPG, a CSE inhibitor, can reverse H2S-related diabetes development. Our study will unmask a novel approach to treat diabetes by highlighting the importance of targeting the overproduction of H2S to prevent its induction of PGC-1alpha in order to normalize an otherwise enhanced gluconeogenic system.