Low Concentrations of Metformin Suppress Glucose Production in Hepatocytes through AMP-activated Protein Kinase (AMPK)*

Cao, Jia; Meng, Shumei; Chang, En-Chih; Beckwith-Fickas, Katherine; Xiong, Lishou; Cole, Robert N.; Radovick, Sally; Wondisford, Fredric E.; He, Liang

doi:10.1074/jbc.m114.567271

Cited by 140 publications

(157 citation statements)

References 42 publications

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“…Glucose Production Assays-Mouse primary hepatocytes were cultured in William's medium E supplemented with ITS (BD Biosciences) and dexamethasone (10). After 16 h of planting, primary hepatocytes were subjected to 3 h serum starvation.…”

Section: Methodsmentioning

confidence: 99%

“…AMPK␣1S485A was created using site-directed mutagenesis (Stratagene). These genes were transferred into the pAd/CMV/V5-DEST vector (Invitrogen) by recombination to generate expression clones (10). Ad-CMV-Cre and Ad-CMV-GFP adenoviruses were purchased from the Viral Vector Core at the University of Iowa.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, the hyperglucagonemia of diabetes can antagonize metformin efficacy by activating the cAMP-PKA pathway and cause metformin resistance. We and other investigators have found that the cAMP-PKA pathway negatively regulates AMPK activity through phosphorylation of the AMPK␣ subunit at Ser-485, which in turn reduces net phosphorylation at Thr-172 (10,(17)(18)(19). It is conceivable that the blockade of AMPK␣ phosphorylation at Ser-485 will augment AMPK activity and metformin efficacy.…”

mentioning

confidence: 99%

“…Elevated glucagon levels in type 2 diabetic patients are variable, with a ϳ5-fold difference in serum glucagon levels among patients with T2D (16). Low metformin concentrations, typically found in the portal vein after a therapeutic dosage, suppress glucose production in primary hepatocytes through AMPK (10). Therefore, the hyperglucagonemia of diabetes can antagonize metformin efficacy by activating the cAMP-PKA pathway and cause metformin resistance.…”

mentioning

confidence: 99%

“…Recently, we found that treatment with metformin prior to the addition of cAMP led to greater suppression of glucose production and AMPK activation when compared with simultaneous treatment with metformin and cAMP (10), suggesting that the cAMP-PKA pathway exerts a negative effect on AMPK activation. In both diabetic animal models and human subjects, serum glucagon levels and the ratios of glucagon to insulin are often elevated (11)(12)(13)(14) and are responsible for increased hepatic glucose output and hyperglycemia in T2D (15).…”

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confidence: 99%

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Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

Chang

Peng

et al. 2016

Journal of Biological Chemistry

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Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPK␣ subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPK␣1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPK␣ activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/ aspirin prevents the phosphorylation of AMPK␣ at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production.Diabetes is the fastest-growing chronic disease worldwide, and type 2 diabetes (T2D) 2 accounts for more than 90% of diabetes cases. Metformin has been used to treat T2D since the 1950s and works primarily by controlling fasting hyperglycemia (1). Now, over 150 million people worldwide take this medication; guidelines for the treatment of T2D published by the American Diabetes Association and the European Association for the Study of Diabetes in 2012 jointly recommended metformin as the initial drug for T2D treatment (2).Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment (3-6), and many patients become less responsive to metformin over time (4). It remains unknown how metformin resistance/ insensitivity occurs. Several genes have been reported to be associated with glycemic control by metformin. In particular, variants of the organic cation transporter and the metformin transporter, have been linked to a reduction in metformin action (7-9). Because of the high occurrence of metformin resistance in diabetic patients, genetic variants in known genes alone cannot explain this phenomenon; therefore, nongenetic factors may also contribute to the response to metformin.Recently, we found that treatment with metformin prior to the addition of cAMP led to greater suppression of glucose production and AMPK activation when compared with simultaneous treatment with metformin and cAMP (10), suggesting that the cAMP-PKA pathway exerts a negative effect on AMPK activation. In both diabetic animal models and human subjects, serum glucagon levels and the ratios of glucagon to insulin are often elevated (11)(12)(13)(14) and are responsible for increased hepatic glucose output and hyperglycemia in T2D (15). Elevated glucagon l...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

Chang

Peng

et al. 2016

Journal of Biological Chemistry

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SRT1720‐induced activation of SIRT1 alleviates vascular smooth muscle cell senescence through PKA‐dependent phosphorylation of AMPKα at Ser485

et al. 2020

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Aging is a major risk factor for hypertension and atherosclerosis, and vascular smooth muscle cell (VSMC) senescence can promote aging-related vascular diseases. Sirtuin-1 (SIRT1) and AMP-activated protein kinase (AMPK) were previously reported to modulate vascular senescence; however, its effects have not been well characterized. To determine the nature of the interaction between SIRT1 and AMPK in VSMC senescence, we investigated the effects of SRT1720 on its downstream targets of SIRT1 and the phosphorylation of AMPKa at Ser485. During Adriamycin-induced VSMC senescence, SRT1720 increased the activity of SIRT1 and AMPKa phosphorylation at Ser485 via the cAMP-protein kinase A (PKA) pathway. Telomere length and telomerase reverse transcriptase expression were increased by SIRT1 activation with SRT1720. Taken together, these data show that activation of the SIRT1/cAMP-PKA/p-AMPKa (Ser485) pathway may be an effective antisenescence mechanism for VSMCs.

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Anticancer properties of novel pyrazole‐containing biguanide derivatives with activating the adenosine monophosphate‐activated protein kinase signaling pathway

Zhou

Cao

et al. 2019

Archiv der Pharmazie

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Biguanides, including metformin and phenformin, have emerged as promising anticancer agents. However, the high dose needed for their efficient anticancer properties restricts their clinical application. In an attempt to obtain higher active compounds than these parent compounds, pyrazole-containing biguanide derivatives were synthesized and screened for in vitro cytotoxicity against human cancer cell lines. Clonogenic assays and scratch wound healing assays demonstrated that these new derivatives profoundly inhibit cell proliferation and migration. Compounds 10b and 10d exhibited strong potency with low IC 50 values in the range of 6.9-28.3 μM, far superior to phenformin and metformin. Moreover, 20 μM 10b and 10d resulted in 72.3-88.2% (p < 0.001) inhibition of colony formation and 29.3-60.7% (p < 0.05) inhibition of cell migration. Mechanistically, 10b and 10d activated adenosine monophosphate-activated protein kinase, leading to inactivation of the mammalian target of rapamycin (mTOR) signaling pathway with the regulation of 4EBP1 and p70S6K. These results suggest the value of these novel biguanide derivatives as candidates with therapeutic potential for the treatment of bladder and ovarian cancer. K E Y W O R D S AMPK, anticancer, biguanide, pyrazole-containing heterocyclic compounds

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Low Concentrations of Metformin Suppress Glucose Production in Hepatocytes through AMP-activated Protein Kinase (AMPK)*

Cited by 140 publications

References 42 publications

Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

SRT1720‐induced activation of SIRT1 alleviates vascular smooth muscle cell senescence through PKA‐dependent phosphorylation of AMPKα at Ser485

Anticancer properties of novel pyrazole‐containing biguanide derivatives with activating the adenosine monophosphate‐activated protein kinase signaling pathway

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