Role of AMP-activated protein kinase in mechanism of metformin action

Zhou, Gaochao; Myers, Robert P.; Liu, Ying; Chen, Yuli; Shen, Xiangqian; Fenyk-Melody, Judy; Wu, Margaret; Ventre, John; Doebber, Thomas W.; Fujii, Nobutaka; Musi, Nicolas; Hirshman, Michael F.; Goodyear, Laurie J.; Moller, David E.

doi:10.1172/jci200113505

Cited by 1,480 publications

(1,583 citation statements)

References 28 publications

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“…Immunoblots were performed against phospho-ACC (Ser79), phospho-AMPKα (Thr172), AMPKα, and β-actin. (4,7,24). Although direct evidence of colocalization of AMPK and OCTs in a specific cell is not available, we observed that the activation of AMPK by metformin was enhanced in cell lines (or transfected cells) that exhibited OCT activity, suggesting that the tissue-specific action of metformin may be related to expression of influx transporters such as OCTs that can deliver metformin intracellularly.…”

Section: Discussionmentioning

confidence: 70%

“…Quinidine, an OCT inhibitor, decreased the phosphorylation of AMPK and ACC by metformin in wild-type hepatocytes ( Figure 4C). Downstream, metformin-stimulated AMPK phosphorylation results in a decrease in hepatic gluconeogenesis (4,7). Metformin (1 mM) significantly suppressed glucagon-stimulated glucose production in hepatocytes from wild-type mice (30% suppression; P < 0.001) but not in hepatocytes from Oct1 -/-mice ( Figure 4D).…”

Section: Oct Activity Is a Determinant Of Metformin Response In Cell mentioning

confidence: 98%

“…Glucose production in primary mouse hepatocytes was measured by modifying a previously described method (4). Hepatocytes on collagen-coated 6-well plates (1.5 × 10 5 cell/cm 2 ) were incubated in medium containing Matrigel for 16 hours and then were maintained in the regular medium overnight before the glucose production experiments.…”

Section: Figurementioning

confidence: 99%

“…Metformin ameliorates hyperglycemia by reducing gastrointestinal glucose absorption and hepatic glucose production and by improving glucose utilization (1). The molecular mechanisms underlying metformin action appear to be related to its activation (phosphorylation) of the so-called energy sensor AMP-activated protein kinase (AMPK), which suppresses glucagon-stimulated glucose production and causes an increase in glucose uptake in muscle and in hepatic cells (4,5). The activation of AMPK may also be responsible for the improvement of lipid metabolism by metformin (4).…”

Section: Introductionmentioning

confidence: 99%

“…The molecular mechanisms underlying metformin action appear to be related to its activation (phosphorylation) of the so-called energy sensor AMP-activated protein kinase (AMPK), which suppresses glucagon-stimulated glucose production and causes an increase in glucose uptake in muscle and in hepatic cells (4,5). The activation of AMPK may also be responsible for the improvement of lipid metabolism by metformin (4). Recently, serine-threonine kinase 11 (STK11/LKB1), which phosphorylates AMPK, has also been reported to be involved in metformin effects (6,7).…”

Section: Introductionmentioning

confidence: 99%

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Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action

Shu¹,

Sheardown²,

Brown³

et al. 2007

J. Clin. Invest.

839

843

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Metformin is among the most widely prescribed drugs for the treatment of type 2 diabetes. Organic cation transporter 1 (OCT1) plays a role in the hepatic uptake of metformin, but its role in the therapeutic effects of the drug, which involve activation of AMP-activated protein kinase (AMPK), is unknown. Recent studies have shown that human OCT1 is highly polymorphic. We investigated whether OCT1 plays a role in the action of metformin and whether individuals with OCT1 polymorphisms have reduced response to the drug. In mouse hepatocytes, deletion of Oct1 resulted in a reduction in the effects of metformin on AMPK phosphorylation and gluconeogenesis. In Oct1-deficient mice the glucose-lowering effects of metformin were completely abolished. Seven nonsynonymous polymorphisms of OCT1 that exhibited reduced uptake of metformin were identified. Notably, OCT1-420del (allele frequency of about 20% in white Americans), previously shown to have normal activity for model substrates, had reduced activity for metformin. In clinical studies, the effects of metformin in glucose tolerance tests were significantly lower in individuals carrying reduced function polymorphisms of OCT1. Collectively, the data indicate that OCT1 is important for metformin therapeutic action and that genetic variation in OCT1 may contribute to variation in response to the drug.

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Section: Discussionmentioning

confidence: 70%

Section: Oct Activity Is a Determinant Of Metformin Response In Cell mentioning

confidence: 98%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action

Shu¹,

Sheardown²,

Brown³

et al. 2007

J. Clin. Invest.

839

843

View full text Add to dashboard Cite

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Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus

et al. 2015

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IMPORTANCE Caloric restriction mimetic drugs have geroprotective effects that delay or reduce risks for a variety of age-associated systemic diseases, suggesting that such drugs might also have the potential to reduce risks of blinding ophthalmologic conditions for which age is a major risk factor. OBJECTIVE To determine whether the caloric restriction mimetic drug metformin hydrochloride is associated with reduced risk of open-angle glaucoma (OAG) in persons with diabetes mellitus. DESIGN, SETTING, AND PATIENTS Retrospective cohort study of patients aged 40 years or older with diabetes mellitus and no preexisting record of OAG in a large US managed care network from January 1, 2001, through December 31, 2010. EXPOSURES Quantity of metformin and other prescribed diabetes medications as captured from outpatient pharmacy records. MAIN OUTCOMES AND MEASURES Risk of developing OAG. RESULTSOf 150 016 patients with diabetes mellitus, 5893 (3.9%) developed OAG. After adjusting for confounding factors, those prescribed the highest quartile of metformin hydrochloride (>1110 g in 2 years) had a 25% reduced OAG risk relative to those who took no metformin (hazard ratio = 0.75; 95% CI, 0.59-0.95; P = .02). Every 1-g increase in metformin hydrochloride use was associated with a 0.16% reduction in OAG risk (adjusted hazard ratio = 0.99984; 95% CI, 0.99969-0.99999; P = .04), which predicts that taking a standard dose of 2 g of metformin hydrochloride per day for 2 years would result in a 20.8% reduction in risk of OAG. After accounting for potential confounders, including metformin and diabetic medications, the risk of developing OAG was increased by 8% (hazard ratio = 1.08; 95% CI, 1.03-1.13; P = .003) for each unit of increase in glycated hemoglobin level. CONCLUSIONS AND RELEVANCEMetformin use is associated with reduction in risk of developing OAG, and risk is reduced even when accounting for glycemic control in the form of glycated hemoglobin level. Other diabetes medications did not confer a similar OAG risk reduction. This study suggests that metformin may be affecting OAG risk on multiple levels, some involving improved glycemic control and some involving mechanisms outside glycemic control such as neurogenesis, inflammatory systems, or longevity pathways targeted by caloric restriction mimetic drugs. If confirmed by prospective clinical trials, these findings could lead to novel treatments for this sight-threatening disease.

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The tumor suppressor gene lkb1 is essential for glucose homeostasis during zebrafish early development

et al. 2016

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The liver kinase B1 (LKB1) is encoded by tumor suppressor gene STK11, which is mutated in Peutz-Jeghers syndrome patients. Lkb1 plays indispensable roles in energy homeostasis. However, how Lkb1 regulates energy homeostasis in vivo remains to be fully understood. We found that inactivation of zebrafish Lkb1 upregulates pyruvate dehydrogenase kinase 2 expression and inactivates pyruvate dehydrogenase complex by increasing phosphorylation of pyruvate dehydrogenase. As a result, glycolysis is significantly enhanced as indicated by increased lactate production, which resembles the Warburg effect in cancer cells. Inhibition of Pdk2 in lkb1 mutants with dichloroacetate, a promising anticancer drug, rescued the lactate production to wild-type level, suggesting the lkb1 mutant may be used to screen compounds targeting aerobic glycolysis in cancer therapy.

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Role of AMP-activated protein kinase in mechanism of metformin action

Cited by 1,480 publications

References 28 publications

Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action

Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action

Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus

The tumor suppressor gene lkb1 is essential for glucose homeostasis during zebrafish early development

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