AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Wong, Aaron; Howie, J. W.; Petrie, John R.; Lang, Chim C.

doi:10.1042/cs20080066

Cited by 144 publications

(133 citation statements)

References 138 publications

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“…Despite being in clinical use for over 50 years (He et al 2009, Wong et al 2009), its exact mechanism of action is yet to be fully characterised. Here, we report that metformin increases hepatic GCN5 and SIRT1, and that the ability to induce these key regulators of gluconeogenic gene expression potentially represents an important mechanism of the action of metformin.…”

Section: Discussionmentioning

confidence: 99%

Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Caton¹,

Nayuni²,

Kieswich³

et al. 2010

Journal of Endocrinology

176

135

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Abnormal elevation of hepatic gluconeogenesis is central to the onset of hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). Metformin corrects hyperglycaemia through inhibition of gluconeogenesis, but its mechanism of action is yet to be fully described. SIRT1 and GCN5 (listed as KAT2A in the MGI Database) have recently been identified as regulators of gluconeogenic gene expression through modulation of levels and activity of the coactivators cAMP-response element binding protein-regulated transcription coactivator 2 (TORC2 or CRTC2 as listed in the MGI Database) and peroxisome proliferator-activated receptor-g coactivator-1a (PGC1a or PPARGC1A as listed in the MGI Database). We report that in db/db mice, metformin (250 mg/kg per day; 7 days) increases hepatic levels of GCN5 protein and mRNA compared with the untreated db/db mice, as well as increases levels of SIRT1 protein and activity relative to controls and untreated db/db mice. These changes were associated with reduced TORC2 protein level and decreased gene expression and activation of the PGC1a gene target phosphoenolpyruvate carboxykinase, and lower plasma glucose and insulin. Inhibition of SIRT1 partially blocked the effects of metformin on gluconeogenesis. SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD C . Moreover, levels of GCN5 were dramatically reduced in db/db mice compared with the controls. This indicates that loss of GCN5-mediated inhibition of gluconeogenesis appears to constitute a major mechanism for the onset of abnormally elevated hepatic glucose production in db/db mice. In conclusion, induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin. In addition, these data identify induction of hepatic GCN5 as a potential therapeutic strategy for treatment of T2DM.

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Section: Discussionmentioning

confidence: 99%

Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Caton¹,

Nayuni²,

Kieswich³

et al. 2010

Journal of Endocrinology

176

135

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“…Treatments such as metformin, which decrease insulin resistance, are thought to reduce the risk of tumour development [9][10][11][12][13][14]. On the other hand, treatments that increase circulating insulin levels, such as sulfonylureas and exogenous insulin, are thought to increase the risk of cancer [15,16].…”

Section: Introductionmentioning

confidence: 99%

Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure

et al. 2010

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Aims/hypothesis We explored the relationship between glucose-lowering agents and cancer mortality rates in type 2 diabetes patients, hypothesising a decreased risk of cancer mortality with metformin use and a dose-risk gradient for insulin therapy. Methods This was a population-based cohort study using administrative data from Saskatchewan Health, Canada. We identified new users of metformin or sulfonylureas from 1 January 1991 to 31 December 1996, with follow-up until death, departure from the province or 31 December 1999. Cox regression analyses were used to estimate the HR of death from cancer, accounting for time-varying exposure to metformin, sulfonylurea, and exogenous insulin therapy. Results We identified 10,309 new users of metformin or sulfonylurea. The average follow-up was 5.4 (1.9) years, during which 407 (4.0%) cancer deaths occurred. Adjusting for age, sex and chronic disease score, the adjusted HR for metformin use was 0.80 (95% CI 0.65-0.98) compared with sulfonylurea monotherapy users. Adjusted HRs for subsequent insulin use were 2.22 (0.99-5.00), 3.33 (2.26-4.89) and 6.40 (4.69-8.73) for <3, 3 to 11 and ≥12 insulin dispensations/year, respectively, compared with patients not on insulin. We observed a similar risk gradient among the sub-cohort of new insulin users. Conclusions/interpretation Our results support previous reports of a decreased risk of cancer outcomes associated with metformin use relative to sulfonylurea monotherapy.We also provide new evidence of a gradient of cumulative insulin dispensations and cancer mortality rates.

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“…AMPK also has an important role in the mechanism of action of some drugs treating MS, such as metformin, statins and thiazolinediones. 52,53 The parallel effect of PA and drugs used for MS treatment on AMPK could represent the physiological basis for considering PA itself as a 'drug' for MS in children.…”

Section: Physiopathological Basis Of the Msmentioning

confidence: 99%

“…49 The adenosine 5 0 -monophospate-activated protein kinase (AMPK) is now considered a key player in regulating energy metabolism. 52,53 AMPK is activated in response to a variety of stimuli including exercise, and is considered an important end point of PA effect on insulin sensitivity. AMPK also has an important role in the mechanism of action of some drugs treating MS, such as metformin, statins and thiazolinediones.…”

Section: Physiopathological Basis Of the Msmentioning

confidence: 99%

Physical activity as the main therapeutic tool for metabolic syndrome in childhood

Brambilla¹,

Pozzobon

Pietrobelli

2010

Int J Obes

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Physical activity (PA) and diet directly influence obesity and metabolic syndrome (MS) as important determinants of body composition. Understanding how PA relates to MS in youth is of great importance, and could offer a common strategy for clinical and public health approaches to control this condition. The underlying disorder of MS is a condition of insulin resistance, and a strong relationship between PA level and insulin sensitivity is clearly ascertained. The type, duration, frequency and intensity of PA affect fuel metabolism, in particular carbohydrate and lipid oxidation. The possible modulation of metabolism because of increased fat oxidation by PA is the basis for both prevention and restoration of insulin resistance and MS in obese children. In daily clinical practice, diet followed by pharmacologic treatment are usually the approaches taken, whereas PA is often considered just a suggestion. Although diet and PA have different effects on body composition, with both contributing to fat loss, only PA increases muscle mass and thus has a direct effect on metabolic function, expressed by changes in cardiovascular risk factors. Therefore, it is important to remember their complementary but different targets in daily clinical practice, such as body weight control for diet and metabolic health for PA. In this review, we have summarized the literature on the relationship between PA and MS in pediatrics. Then, we have analyzed the possibility of using PA for MS treatment, as an alternative to drugs, by discussing the results of intervention studies, reasons for low compliance to PA, related benefits, adherence difficulties and costs. Finally, we have tried to suggest recommendations for a multiple-step PA strategy in children and adolescents at risk for MS, by considering PA as the 'key' player in treatment.

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AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Cited by 144 publications

References 138 publications

Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure

Physical activity as the main therapeutic tool for metabolic syndrome in childhood

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