(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.