The infusion of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (
AICAR) causes a rise in tissue concentrations of the
AMP analog 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranotide (
ZMP), which mimics an elevation of cellular
AMP levels. The purpose of this work was to determine the effect of raising hepatic
ZMP levels on hepatic
insulin action in vivo. Dogs had sampling and infusion
catheters as well as flow probes implanted 16 days before an experiment. After an 18-h fast,
blood glucose was 82 +/- 1 mg/dl and basal net hepatic
glucose output 1.5 +/- 0.2 mg . kg(-1) . min(-1). Dogs received portal venous
glucose (3.2 mg . kg(-1) . min(-1)), peripheral venous
somatostatin, and basal portal venous
glucagon infusions from -90 to 60 min. Physiological
hyperinsulinemia was established with a portal
insulin infusion (1.2 mU . kg(-1) . min(-1)). Peripheral venous
glucose infusion was used to clamp arterial
blood glucose at 150 mg/dl. Starting at t = 0 min, dogs received portal venous
AICAR infusions of 0, 1, or 2 mg . kg(-1) . min(-1). Net hepatic
glucose uptake was 2.4 +/- 0.5 mg . kg(-1) . min(-1) (mean of all groups) before t = 0 min. In the absence of
AICAR, net hepatic
glucose uptake was 1.9 +/- 0.4 mg . kg(-1) . min(-1) at t = 60 min. The lower-dose
AICAR infusion caused a complete suppression of net hepatic
glucose uptake (-1.0 +/- 1.7 mg . kg(-1) . min(-1) at t = 60 min). The higher
AICAR dose resulted in a profound shift in hepatic
glucose balance from net uptake to a marked net output (-6.1 +/- 1.9 mg . kg(-1) . min(-1) at t = 60 min), even in the face of
hyperglycemia and
hyperinsulinemia. These data show that elevations in hepatic
ZMP concentrations, induced by portal venous
AICAR infusion, cause acute hepatic
insulin resistance. These findings have important implications for the targeting of
AMP kinase for the treatment of
insulin resistance, using
AMP analogs.