Fasting
hyperglycemia in patients with
type 2 diabetes mellitus (T2DM) is attributed to increased hepatic gluconeogenesis, which has been ascribed to increased transcriptional expression of
phosphoenolpyruvate carboxykinase (PEPCK) and
glucose-6-phosphatase, catalytic (G6Pc). To test this hypothesis, we examined hepatic expression of these 2 key gluconeogenic
enzymes in 2 rodent models of fasting
hyperglycemia and in patients with T2DM. In rats, high-fat feeding (HFF) induces
insulin resistance but a robust beta-cell response prevents
hyperglycemia. Fasting
hyperglycemia was induced in the first rat model by using
nicotinamide and
streptozotocin to prevent beta-cell compensation, in combination with HFF (STZ/HFF). In a second model, control and HFF rats were infused with
somatostatin, followed by portal vein infusion of
insulin and
glucagon. Finally, the expression of these
enzymes was measured in liver biopsy samples obtained from
insulin sensitive,
insulin resistant, and untreated T2DM patients undergoing
bariatric surgery. Rats treated with STZ/HFF developed modest fasting
hyperglycemia (119 +/- 4 vs. 153 +/- 6 mg/dL, P < 0.001) and increased rates of endogenous
glucose production (EGP) (4.6 +/- 0.6 vs. 6.9 +/- 0.6 mg/kg/min, P = 0.02). Surprisingly, the expression of PEPCK or G6Pc was not increased. Matching plasma
insulin and
glucagon with portal infusions led to higher plasma glucoses in the HFF rats (147 +/- 4 vs. 161 +/- 4 mg/dL, P = 0.05) with higher rates of EGP and gluconeogenesis. However, PEPCK and G6Pc expression remained unchanged. Finally, in patients with T2DM, hepatic expression of PEPCK or G6Pc was not increased. Thus, in contrast to current dogma, these data demonstrate that increased transcriptional expression of PEPCK1 and G6Pc does not account for increased gluconeogenesis and fasting
hyperglycemia in patients with T2DM.