| Type 2 diabetes (T2D) is rapidly approaching epidemic proportions and the complications associated with T2D have become a financial burden worldwide. T2D is characterized by insulin resistance that leads to defects in insulin secretion and increased hepatic gluconeogenesis, which results in a state of fasting and postporandial hyperglycemia. Since CREB, SirT1, and Torc2 are key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic the expression of these transcription factors would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a specific antisense oligonucleotide (ASO) to knock down the expression of these genes in liver. In addition to investigating the effect of knocking down each of these transcriptional factors to induce their physiological relevance, we investigated the molecular mechanism of metformin. Metformin is one of the first efficacious diabetes drugs discovered but the complete mechanism of action has yet to be elucidated. Meformin reduces hepatic glucose production through the inhibition of hepatic gluconeogenesis however it is unclear if the inhibition occurs through reduction of gluconeogenic gene expression. Additionally, metformin activates AMPK through an indirect mechanism. However, the link between AMPK activation and inhibition of glucose production remains unclear. Here, by using an analog of metformin called galegine, we find that biguanides are able to work acutely and independent of gluconeogenic gene expression. This thesis entails details of the transcriptional regulation of gluconeogenesis. |
