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Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

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Science  04 Aug 2017:
Vol. 357, Issue 6350, pp. 507-511
DOI: 10.1126/science.aah5582
  • Fig. 1 In vitro properties of MK-8722.

    (A) Structure of MK-8722. (B) Dose-dependent activation of purified, recombinant pAMPK complexes 1 (α1β1γ1) and 11 (α2β2γ2) by MK-8722 and AMP (activity at 10 μM AMP defined as 100%). (C) Synergistic activation of purified, recombinant pAMPK complex 12 (α2β2γ3) by saturating AMP (25 μM), saturating MK-8722 (195 nM), and saturating levels of both activators. (D) Effect on pAMPK and pACC after MK-8722 and AICAR treatment in HepG2 cells. (E) Effect of AMPK activators ionomycin (1 μM), MK-8722 (0.5 μM), and AICAR (500 μM), with and without 1 hour of pretreatment with the AMPK inhibitor Compound C (40 μM), on pACC formation [electrochemiluminescence (ECL) units from the MSD assay] in HeLa cells. Vehicle (Veh) for all studies was dimethyl sulfoxide (DMSO). Data are means ± SEM. ***P < 0.001, one-way analysis of variance (ANOVA).

  • Fig. 2 Acute glucose-lowering efficacy of MK-8722 in rodents.

    (A to E) Effect of acute MK-8722 administration (1 to 30 mpk, p.o.) in an ipGTT in lean C57BL/6 mice (8- to 10-week-old male, n = 8 per group; data are representative of three independent experiments, unblinded). (A) Blood glucose versus time. (B) Fasting blood glucose 1 hour after dose, prior to the glucose challenge. (C) Net AUC of the data in (A). (D) Skeletal muscle pACC levels 2.5 hours after dose. (E) Plasma insulin versus time after glucose challenge in mice pretreated with vehicle or MK-8722 (30 mpk). (F) Effect on blood glucose versus time after MK-8722 administration (1 to 30 mpk, p.o.) in an oGTT in diabetic GK rats (14-week-old male, n = 7 or 8 per group; data are representative of three independent experiments, unblinded). Data are means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, one-way ANOVA.

  • Fig. 3 MK-8722 increases glucose uptake into skeletal muscle in vitro and in vivo.

    (A) Effect on [14C]2DG uptake and intracellular pACC after treatment with MK-8722 and insulin (100 nM) in human skeletal myocytes. (B) Effect of MK-8722 and insulin treatment on 2DG6P formation in perfused, lean rat hindlimb skeletal muscles. (C) Effect on [14C]2DG uptake after treatment with MK-8722 (3 and 10 μM) and insulin (100 nM) in primary human myocytes, with and without pretreatment with Compound C (30 μM). #P < 0.05, ###P < 0.001 versus corresponding no–Compound C treatment group. (D) Effect on [3H]2DG6P production in gastrocnemius muscle 90 min after MK-8722 administration (30 mpk, p.o.) to lean C57BL/6 mice (10-week-old male, n = 8 per group; single experiment, unblinded). (E) Effect on [1-13C]d-glucose metabolite production in gastrocnemius muscle 2 hours after MK-8722 administration (10 mpk, p.o.) to GK rats (14-week-old male, n = 8 per group; data are representative of three independent experiments, unblinded). Data are means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, one-way ANOVA.

  • Fig. 4 Effects of MK-8722 in the db/db T2DM mouse model and on glucose homeostasis in diabetic and lean rhesus macaque monkeys.

    (A) Effect on trough ambient blood glucose during 12 days of administration of MK-8722 (3 to 30 mpk/day, p.o.) or rosiglitazone (3 mpk/day, p.o.) in db/db mice (8-week-old male, n = 8 to 10 per group; data are representative of three independent experiments, unblinded). (B to F) Effect of MK-8722 in diabetic rhesus monkeys (mixed ages and sexes, single unblinded experiment). [(B) and (C)] Effect of MK-8722 treatment (5 and 10 mpk p.o.) on blood glucose during an MMTT performed acutely and after chronic treatment with MK-8722 (5 mpk/day p.o.) (n = 10 and 4 for 5- and 10-mpk groups, respectively). [(D) to (F)] Effect of chronic treatment with MK-8722 (5 mpk/day p.o.) on integrated blood glucose measurements. (D) Effect on HbA1c after 7 weeks of MK-8722 administration. (E) Effect on 1,5-anhydroglucitol throughout the study. (F) Effect on fructosamine throughout the study. Shaded portions of graphs in (E) and (F) represent the MK-8722 administration period. (G) Effects on [18F]FDG PET maximum intensity projection at baseline and after acute MK-8722 administration (5 mpk, iv), 90 min after injection of [18F]FDG in the same lean rhesus monkey (6-year-old male, n = 1; data are representative of three independent experiments, unblinded). Data are means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, one-way ANOVA.

  • Fig. 5 Effect of chronic MK-8722 administration on cardiac parameters in rodents and rhesus monkeys.

    (A) Effect on heart weight/brain weight ratio after 1 month of MK-8722 administration (3 to 30 mpk/day, p.o.), followed by 2 months of drug withdrawal (washout) in Wistar Han rats (5-week-old male and female, n = 10 each; single unblinded study). (B) Effect on heart weight/brain weight ratio and cardiac glycogen after 2 weeks of MK-8722 administration (10 to 50 mpk/day, p.o.) in Wistar Han rats (6-week-old male, n = 5, single unblinded study). (C) Effect on heart weight/brain weight ratio of 1 month of MK-8722 administration (5 to 50 mpk/day, p.o.) in rhesus monkeys (sexes combined, n = 6 total; single unblinded study). (D) Effect on heart weight of 14-day MK-8722 administration (4 to 20 mpk/day in feed) in db/db mice (8-week-old male, n = 8; single unblinded study). Data are means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, trend analysis (C), one-way ANOVA (other panels).

Supplementary Materials

  • Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

    Robert W. Myers, Hong-Ping Guan, Juliann Ehrhart, Aleksandr Petrov, Srinivasa Prahalada, Effie Tozzo, Xiaodong Yang, Marc M. Kurtz, Maria Trujillo, Dinko Gonzalez Trotter, Danqing Feng, Shiyao Xu, George Eiermann, Marie A. Holahan, Daniel Rubins, Stacey Conarello, Xiaoda Niu, Sandra C. Souza, Corin Miller, Jinqi Liu, Ku Lu, Wen Feng, Ying Li, Ronald E. Painter, James A. Milligan, Huaibing He, Franklin Liu, Aimie Ogawa, Douglas Wisniewski, Rory J. Rohm, Liyang Wang, Michelle Bunzel, Ying Qian, Wei Zhu, Hongwu Wang, Bindu Bennet, Lisa LaFranco Scheuch, Guillermo E. Fernandez, Cai Li, Michael Klimas, Gaochao Zhou, Margaret van Heek, Tesfaye Biftu, Ann Weber, David E. Kelley, Nancy Thornberry, Mark D. Erion, Daniel M. Kemp, Iyassu K. Sebhat

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Figs. S1 to S27
    • Tables S1 to S5

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