Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Protein kinase D regulates hepatic glucose metabolism in vitro and in vivo (#15)

Amanda J Genders 1 , Tim Connor 1 , Shona Morrison 1 , Sean L McGee 1
  1. Deakin University, Geelong, VIC, Australia

The liver plays a key role in whole body glucose and lipid metabolism. In a state of insulin resistance such as that seen in type 2 diabetes dysregulation of hepatic metabolism occurs leading to elevations in fasting and postprandial glucose and lipid levels. Previous work from our laboratory has suggested that protein kinase D (PKD) activity is altered in insulin resistant states while other laboratories have shown that PKD can inhibit components of the canonical insulin signalling pathway. Thus the aim of this study was to determine whether PKD is involved in the underlying biology that leads to insulin resistance in the liver.

In FAO hepatocytes in vitro, short term treatment with metabolic insults such as chronic insulin, glucose oxidase and palmitate increased PKD phosphorylation and PKD substrate phosphorylation. PKD inactivation by overexpression of dominant negative (DN) PKD enhanced insulin’s ability to decrease PEPCK and G6Pase gene expression and also showed a trend to decrease basal glucose production, whilst insulin suppression of glucose production was normal.  Conversely, constitutively active PKD overexpression made cells resistant to insulin suppression of glucose production, while basal glucose production was normal.  

We next investigated the effect of liver specific DN PKD expression in mice.  C57/bl6 mice were injected via the tail vein with 5 x 1010 genomes DN PKD or GFP AAV8 viral vector.  DN PKD had no effect on body weight or food intake.  DN PKD significantly increased both the respiratory quotient and glucose oxidation in chow fed mice (this effect was absent in high fat fed mice).  PKD inactivation by DN PKD expression also resulted in sustained Akt activation following fasting and refeeding

These data suggests that PKD alters liver glucose metabolism both in vitro and in vivo, indicating that it may have a role in regulation of liver metabolism.