The Hepatic Response to the Pathogenesis of Type 2 Diabetes in a Rat Model

The liver plays a pivotal role in the maintenance of whole body energy homeostasis given its responsibilities in glucose, lipid and ketone body regulation. T2DM is a complex disease and the underlying mechanisms resulting in loss of hepatic energy regulation are yet to be fully elucidated. This thesis employs large scale ‘omics’ techniques, including proteomics, metabolomics and lipidomics, to examine alterations in the liver that contribute to the pathogenesis of T2DM in addition to analysis of blood plasma in an attempt to identify novel biomarkers that may be used to aid in the earlier diagnosis of T2DM. To achieve this, we developed a rodent model of T2DM that was generated using a combination of high fat diet (HFD) and streptozotocin (STZ) injection. Metabolomics and lipidomics analysis of the liver demonstrated increased gluconeogenesis and de novo lipogenesis at the expense of TCA flux. This is supported by proteomics analysis, which suggested inhibition of the ETC and reduced β-oxidation. Investigation into the role of phosphorylation in T2DM indicated dysregulation of Akt, PKC and AMPK, which are key regulators in insulin signalling and cellular energetic homeostasis. Additionally, anaplerotic enzymes responsible for the replenishment of the TCA cycle show altered phosphorylation suggesting their inability to supply TCA intermediates. Significant changes in plasma levels of LPC and long chain TGs suggest alteration to lipoprotein metabolism, which may potentially be used as a biomarker for the early stages of T2DM. Increased levels of plasma ketone bodies also reflected the dysregulation of the hepatic TCA cycle. Overall, this thesis provides a global and unbiased molecular overview of the liver in a rodent model of T2DM, and detects pathways that likely contribute to T2DM pathogenesis, as well as identifies omics signatures that may aid in the early diagnosis of T2DM