The role of the hexosamine biosynthesis pathway in type 2 diabetes

Type 2 diabetes is associated with increased hepatic lipogenesis and glucose production. Enzymes of lipogenesis are co-ordinately induced by insulin and glucose. However, the enzyme glucose 6-phosphatase (G6Pc), which catalyses the final reaction in hepatic glucose production is repressed by insulin but induced by glucose and is markedly elevated in type 2 diabetes. Another gene that is repressed by insulin and induced by glucose in muscle is thioredoxin interacting protein (TXNIP), which is abnormally elevated in muscle in type 2 diabetes. TXNIP gene regulation in liver has not been reported. The induction of hepatic lipogenic enzymes by glucose is attributed to the transcription factor ChREBP-Mlx, whereas the glucose-induction of G6Pc is attributed to covalent modification of FOXO transcription factors by O-GlcNAc formed by the hexosamine biosynthesis pathway (HBP). The aim of this thesis was to investigate the role of the HBP in regulation by glucose of G6Pc and TXNIP gene expression in hepatocytes.