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Review
. 2013 Jul;123(7):2764-72.
doi: 10.1172/JCI67227. Epub 2013 Jul 1.

AMPK, insulin resistance, and the metabolic syndrome

Neil B Ruderman  1 , David Carling, Marc Prentki, José M Cacicedo
Affiliations
Review

AMPK, insulin resistance, and the metabolic syndrome

Neil B Ruderman et al. J Clin Invest. 2013 Jul.

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.

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Figures

Figure 1
Figure 1. AMPK actions and putative linkage between decreased AMPK activity and metabolic syndrome–associated diseases.
(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.
Figure 2
Figure 2. Subunit structure and regulation of AMPK.
(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.
Figure 3
Figure 3. Proposed interrelations of AMPK and sirtuins 1 and 3 (SIRTs) with oxidative and ER stress and inflammation.
AMPK and SIRT1 both activate each other and diminish oxidative and ER stress and low-grade inflammation in various settings. Conversely, oxidative and ER stress and inflammation, which activate each other, appear to diminish AMPK and SIRT1. In principle, any of these factors could be _targeted to combat IR and the development of metabolic syndrome–associated disorders; however, to date, the most success has been observed with therapies that _target AMPK.
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