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

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 2

Subunit structure and regulation of AMPK.

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Subunit structure and regulation of AMPK. (A) Structure of AMPK. Schemat...
(A) Structure of AMPK. Schematic representation of AMPK highlighting important regions within each of its 3 subunits, as described in the main text (adapted from ref. 64). AID, autoinhibitory domain; CBM, carbohydrate-binding module; CBS, cystathionine-β synthase. (B) Regulation of AMPK. LKB1 and CaMKKβ activate AMPK by phosphorylation of threonine 172 (T172) within the kinase domain of the α subunit. AMPK is returned to an inactive form by dephosphorylation catalyzed by the action of protein phosphatases (PPase). Binding of ADP and AMP to the γ subunit of AMPK protects against dephosphorylation, maintaining the kinase in an active conformation, although recent studies suggest that ADP is likely to be the important physiological regulator of this process. ADP and AMP have also been reported to promote LKB1-mediated phosphorylation of AMPK, whereas calcium directly activates CaMKKβ. In addition, AMP causes a modest allosteric activation of AMPK. Finally, glycogen (and branched-chain carbohydrates) bind to the glycogen-binding domain within the β subunit, allosterically inhibiting AMPK. P, phosphorylation of T172.