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AMPK, insulin resistance, and the metabolic syndrome
Neil B. Ruderman, … , Marc Prentki, José M. Cacicedo
Neil B. Ruderman, … , Marc Prentki, José M. Cacicedo
Published July 1, 2013
Citation Information: J Clin Invest. 2013;123(7):2764-2772. https://doi.org/10.1172/JCI67227.
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Science in Medicine

AMPK, insulin resistance, and the metabolic syndrome

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Abstract

Insulin resistance (IR) and hyperinsulinemia are hallmarks of the metabolic syndrome, as are central adiposity, dyslipidemia, and a predisposition to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension, and certain cancers. Regular exercise and calorie restriction have long been known to increase insulin sensitivity and decrease the prevalence of these disorders. The subsequent identification of AMP-activated protein kinase (AMPK) and its activation by exercise and fuel deprivation have led to studies of the effects of AMPK on both IR and metabolic syndrome–related diseases. In this review, we evaluate this body of literature, with special emphasis on the hypothesis that dysregulation of AMPK is both a pathogenic factor for these disorders in humans and a target for their prevention and therapy.

Authors

Neil B. Ruderman, David Carling, Marc Prentki, José M. Cacicedo

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Figure 1

AMPK actions and putative linkage between decreased AMPK activity and metabolic syndrome–associated diseases.

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AMPK actions and putative linkage between decreased AMPK activity and me...
(A) Effects of AMPK activation. In addition to activating processes that produce ATP and diminish its consumption, AMPK inhibits inflammation, ER and oxidative stress, and activates autophagy, all of which appear to be involved in the pathogenesis of IR. Where studied, SIRT1 can produce many of the same effects as AMPK (see also text and Figure 3). The above-listed actions of AMPK and others have been extensively reviewed (5, 6, 67). GNG, gluconeogenesis; ULK1, UNC-51–like kinase 1; JNK, JUN-activated kinase. (B) Proposed link between AMPK and IR in the setting of the metabolic syndrome. It has long been held that the combination of overnutrition (obesity), inactivity, and indeterminate genetic factors predispose humans to the metabolic syndrome and associated disorders. Based on studies of the offspring of patients with metabolic syndrome–associated disorders, hyperinsulinemia and IR may antedate such diseases as hypertension, type 2 diabetes, and ASCVD by many years (reviewed in ref. 28). Likewise, studies in both experimental animals and humans have implicated oxidative and ER stress and low-grade inflammation and decreased adiponectin in the pathogenesis of these disorders. An emerging body of evidence, predominantly but not exclusively from animal models, suggests that dysregulation of AMPK, and probably sirtuins, could both contribute to these abnormalities and be a target for their prevention and therapy (13). One possibility is that such dysregulation of AMPK and sirtuins causes epigenetic changes (methylation, acetylation, etc.) that could contribute to the diseases (151). NAFLD, nonalcoholic fatty liver disease; T2D, type 2 diabetes.

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