5-Aminoimidazole-4-Carboxamide-1-β-<scp>d</scp>-Ribofuranoside Causes Acute Hepatic Insulin Resistance In Vivo

Pencek, Richard; Shearer, Jane; Camacho, Raul C.; James, Freyja D.; Lacy, D. Brooks; Fueger, Patrick T.; Donahue, E. Patrick; Snead, Wanda L.; Wasserman, David H.

doi:10.2337/diabetes.54.2.355

Cited by 34 publications

(53 citation statements)

References 40 publications

(40 reference statements)

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“…1A). These results are consistent with several studies that have reported that phosphorylation of ACC is a sensitive marker of AMPK activity, often more sensitive even than increased levels of phosphoThr172-AMPK [29][30][31][32][33], and verify that phenformin treatment activated AMPK in differentiated hippocampal neurons.…”

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphorsupporting

confidence: 93%

“…Treatment with 10 mM phenformin caused a rapid, time-dependent increase in the phosphorylation of Ser79-ACC (Fig. 1A), a well-characterized substrate of AMPK [28] that is widely used as a detector of AMPK activation [29][30][31][32][33]. The phenformin-induced increase in phospho-Ser79-ACC was evident within 10 min of treatment and was maintained for 120 min.…”

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphormentioning

confidence: 96%

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AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

King

Lee

Jope

2006

Biochemical Pharmacology

121

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AMP-activated protein kinase (AMPK) is a key cellular sensor of reduced energy supply that is activated by increases in the cellular ratio of AMP/ATP. Phenformin and 5-aminoimida-zole-4-carboxamide riboside (AICAR) are two drugs widely used to activate AMPK experimentally. In both differentiated hippocampal neurons and neuroblastoma SH-SY5Y cells we found that these two agents not only activated AMPK, but conversely greatly reduced the activating Ser/Thr phosphorylation of Akt. This blockade of Akt activity consequently lowered the inhibitory serinephosphorylation of its substrates, glycogen synthase kinase-3a/b (GSK3a/b). An inhibitor of AMPK (Compound C) did not block dephosphorylation of Akt and GSK3. Thus, both drugs widely used to activate AMPK also caused dephosphorylation of Akt and of GSK3. The mechanism for Akt dephosphorylation caused by phenformin, but not AICAR, was due to inhibition of growth factorinduced signaling that leads to Akt phosphorylation. Stimulation of muscarinic receptors with carbachol in SH-SY5Y cells also activated AMPK and transiently caused dephosphorylation of Akt. These findings show that Akt dephosphorylation often occurs concomitantly with AMPK activation when cells are treated with phenformin or AICAR, indicating that these drugs do not only affect AMPK but also cause a coordinated inverse regulation of AMPK and Akt.

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Section: Phenformin Treatment Activates Ampk and Reduces The Phosphorsupporting

confidence: 93%

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphormentioning

confidence: 96%

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

King

Lee

Jope

2006

Biochemical Pharmacology

121

View full text Add to dashboard Cite

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“…However, our results indicate that this can be questionned, at least in liver and for the concentrations used, since both compounds induced ATP depletion. This confirms previous observations showing that concentrations of AICAR Ͼ0.5 mmol/l decreased intracellular ATP in hepatocytes (32,33) and liver (21). The exact mechanism of this fall is not fully understood, but our preliminary results (34) suggest that AICAR, like metformin (31), could inhibit liver mitochondrial oxidative phosphorylation by an AMPK-independent mechanism.…”

Section: Discussionsupporting

confidence: 80%

“…Incubation of hepatocytes from starved rat with AICAR inhibited glucose phosphorylation, decreased fructose 2,6-bisphosphate (Fru-2,6-P 2 ) concentration, and inhibited glycolytic flux (20). This was recently confirmed by the demonstration that in vivo infusion of AICAR in dogs also induced a nearly complete inhibition of net hepatic glucose uptake (21). ZMP, which accumulates in hepatocytes, was found to directly inhibit glucokinase catalytic activity at high concentrations, but this was not sufficient to explain the inhibition of glucose phosphorylation by AICAR (20).…”

supporting

confidence: 56%

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

et al. 2006

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AMP-activated protein kinase (AMPK) controls glucose uptake and glycolysis in muscle. Little is known about its role in liver glucose uptake, which is controlled by glucokinase. We report here that 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), metformin, and oligomycin activated AMPK and inhibited glucose phosphorylation and glycolysis in rat hepatocytes. In vitro experiments demonstrated that this inhibition was not due to direct phosphorylation of glucokinase or its regulatory protein by AMPK. By contrast, AMPK phosphorylated liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase without affecting activity. Inhibitors of the endothelial nitric oxide synthase, stress kinases, and phosphatidylinositol 3-kinase pathways did not counteract the effects of AICAR, metformin, or oligomycin, suggesting that these signaling pathways were not involved. Interestingly, the inhibitory effect on glucose phosphorylation of these well-known AMPK activators persisted in primary cultured hepatocytes from newly engineered mice lacking both liver ␣ 1 and ␣ 2 AMPK catalytic subunits, demonstrating that this effect was clearly not mediated by AMPK. Finally, AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions. Diabetes 55: [865][866][867][868][869][870][871][872][873][874] 2006

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“…The AICAR stimulated fall in ATP is even larger in the absence of hepatic AMPK, which manifests into a greater drop in EC and increase in AMP/ATP. In vivo (37,52) and in vitro (8,16) delivery of AICAR can disrupt the hepatic adenylate energy pool and induce a drop in ATP. AMPK clearly plays a protective role, maintaining energy state in the presence of the metabolic challenge induced by nucleotide phosphate disequilibrium.…”

Section: Discussionmentioning

confidence: 99%

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

Hasenour

Ridley

Hughey

et al. 2014

Journal of Biological Chemistry

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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.

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5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Causes Acute Hepatic Insulin Resistance In Vivo

Cited by 34 publications

References 40 publications

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

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

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