Portal venous 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion overcomes hyperinsulinemic suppression of endogenous glucose output.

AMP-activated protein kinase (AMPK) plays a key role in regulating metabolism, serving as a metabolic master switch. The aim of this study was to assess whether increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-1-beta-D-ribosyl-5-monophosphate, in the liver would create a metabolic response consistent with an increase in whole-body metabolic need. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted >16 days before a study. Protocols consisted of equilibration (-130 to -30 min), basal (-30 to 0 min), and hyperinsulinemic-euglycemic or -hypoglycemic clamp periods (0-150 min). At t = 0 min, somatostatin was infused and glucagon was replaced in the portal vein at basal rates. An intraportal hyperinsulinemic (2 mU . kg(-1) . min(-1)) infusion was also initiated at this time. Glucose was clamped at hypoglycemic or euglycemic levels in the presence (H-AIC, n = 6; E-AIC, n = 6) or absence (H-SAL, n = 6; E-SAL, n = 6) of a portal venous 5-aminoimidazole-4-carboxamide-ribofuranoside (AICAR) infusion (1 mg . kg(-1) . min(-1)) initiated at t = 60 min. In the presence of intraportal saline, glucose was infused into the vena cava to match glucose levels seen with intraportal AICAR. Glucagon remained fixed at basal levels, whereas insulin rose similarly in all groups. Glucose fell to 50 +/- 2 mg/dl by t = 60 min in hypoglycemic groups and remained at 105 +/- 3 mg/dl in euglycemic groups. Endogenous glucose production (R(a)) was similarly suppressed among groups in the presence of euglycemia or hypoglycemia before t = 60 min and remained suppressed in the H-SAL and E-SAL groups. However, intraportal AICAR infusion stimulated R(a) to increase by 2.5 +/- 1.0 and 3.4 +/- 0.4 mg . kg(-1) . min(-1) in the E-AIC and H-AIC groups, respectively. Arteriovenous measurement of net hepatic glucose output showed similar results. AICAR stimulated hepatic glycogen to decrease by 5 +/- 3 and 19 +/- 5 mg/g tissue (P < 0.05) in the presence of euglycemia and hypoglycemia, respectively. AICAR significantly increased net hepatic lactate output in the presence of hypoglycemia. Thus, intraportal AICAR infusion caused marked stimulation of both hepatic glucose output and net hepatic glycogenolysis, even in the presence of high levels of physiological insulin. This stimulation of glucose output by AICAR was equally marked in the presence of both euglycemia and hypoglycemia. However, hypoglycemia amplified the net hepatic glycogenolytic response to AICAR by approximately fourfold.