5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo

Abstract

Background: AMPK is implicated as the mediator of AICAR action on liver metabolism. Results: AICAR suppresses glucose production independent of AMPK. Regulation of mitochondrial function is AMPK-dependent. Conclusion: Nucleotide monophosphates rely on AMPK to regulate energy metabolism but not to suppress glucose production. Significance: Targeted AMPK activation will not lower glucose production in metabolic diseases but could improve hepatic energetics.

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

“…The activation of AMPK in skeletal muscle improves insulin sensitivity (O'Neill et al, 2014;Kjøbsted et al, 2015), stimulates glucose uptake (Jørgensen et al, 2004) and enhances fat oxidation (O'Neill et al, 2014), while AMPK activation in the liver leads to reductions in gluconeogenesis (Foretz et al, 2005). The effects of AICAR in the liver are likely not solely attributable to AMPK as the AICAR-mediated inhibition of glucose production was intact in liver-specific AMPK knockout mice (Hasenour et al, 2014).…”

“…AICAR is an adenosine analogue that is phosphorylated and converted into 5-aminoimidazole-4-carboxamide ribonucleoside 5'-monophosphate (ZMP) (Hasenour et al, 2014). Increases in ZMP, similar to AMP, activate the This article has not been copyedited and formatted.…”

Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

“…Metformin and AICAR both activate AMPK. Previous work, including experiments in which AMPK activity was genetically ablated, indicate that AMPK is not essential for regulation of HGP, although both drugs activate AMPK 13, 14, 15, 17, 18. In the current study, we used AMPK activation purely as a marker of drug entry into the cell.…”

“…Studies using cAMP analogues have shown previously that the T2D drug metformin and 5‐Aminoimidazole‐4‐carboxamide ribonucleoside (AICAR) repress cAMP‐stimulated hepatocyte glucose production (HGP) 13, 14, 15. Inside cells, AICAR is phosphorylated by adenosine kinase to form ZMP, which then mimics AMP to activate AMPK 16.…”

“…Inside cells, AICAR is phosphorylated by adenosine kinase to form ZMP, which then mimics AMP to activate AMPK 16. Metformin and AICAR are both activators of AMPK; however, earlier studies, including some carried out in mice where the catalytic subunits of AMPK are genetically ablated, demonstrated that suppression of HGP occurs independently of AMPK activation 13, 14, 15, 17, 18. Metformin is transported across hepatocyte cell membranes, at least in part, by an organic cation transporter (OCT) family of transporters 18, 19, 20.…”