Elevated glucagon levels and impaired liver glucose uptake are commonly observed in stressed and diabetic patients. We observed that if dogs are placed on continuous (5 days) nutritional support the liver adapts to become a major consumer of glucose. The majority of the glucose is not stored as glycogen, but is released as lactate (i.e reverse Cori Cycle). We have recently reported (AJP 292: E928, 2007) that if glucagon (2.4 ng/kg/min) is chronically infused during nutritional support, it impairs net glucose uptake by the liver (5.1±0.4 vs. −1.0±0.4 mg/kg/min). This decrease was due to a rise in hepatic glucose production rather than to suppression of glucose uptake. In the present study we assessed mRNA expression in liver tissue (Affymetrix Canine genome 2.0 array). PEPCK and fructose‐1,6‐bisphosphatase‐1 expression were increased 11 fold and 3 fold, while the expression of glucokinase (GK) and acetyl‐CoA carboxylase (ACC) were decreased by 4.8 and 2.4 fold. CREB‐3 mRNA was increased 3 fold (positive regulator of PEPCK) and AtF‐3 decreased 5.4 fold (negative regulator of PEPCK). We are performing both rt‐PCR and westerns to confirm these observations. We also observed that the ratio of AMP/ATP (a negative regulator of ACC) increased 1.8 fold, while the total nucleotide pool did not change. In summary, the long term inhibition of liver glucose uptake by glucagon is mediated by the upregulation of gluconeogenesis. While many of the glucagon‐mediated effects can be explained by activation of the cyclic‐AMP pathway, changes in AMP may also contribute to these effects. (Support DK43748 and ADA)