**5. Conclusion**

Subtle changes in GK activity or in GKRP function have consequences in glucose and lipid metabolism. However, further studies must be done to completely understand the mechanism underlying GK/GKRP biology. Our results on increasing GK protein in the liver of both healthy and insulin-deficient mice (lacking endogenous GK) resulted in dyslipidemia. On the other hand, our analysis of the metabolic consequences of GK-GKRP deregulation by overexpressing a GK activating mutant (GKA456V) in the liver of both healthy and type 1 diabetic mice demonstrates an impact on glycaemia in the absence of dyslipidemia or hepatic lipid deposition. These data provide novel insights into the capacity of the complex GK-GKRP to influence the fate of metabolized glucose in the liver, providing a framework for further research on GK activating drugs in the liver.

We conclude that GKRP regulation impairment and GK-A456V altered kinetics greatly influence liver metabolism, in line with results in humans carrying a mutant GKRP (Køster, 2005; Sparsø, 2007; Vaxillaire, 2008 & Orho-Melander, 2008). Besides, it suggests that activating GK exclusively in the liver could be a feasible strategy to funnel excess glucose from the diet out of circulation, widening the scope for GK synthetic activators research.
