AMP-activated protein kinase as a drug target

被引:343
作者
Hardie, D. Grahame [1 ]
机构
[1] Univ Dundee, Div Mol Physiol, Dundee DD1 5EH, Scotland
基金
英国惠康基金;
关键词
metformin; biguanides; thiazolidinediones; obesity; diabetes;
D O I
10.1146/annurev.pharmtox.47.120505.105304
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The AMP-activated protein kinase (AMPK) system is a regulator of energy balance at both the cellular and whole-body levels that, once activated by low energy status, effects a switch from ATP-consuming anabolic pathways to ATP-producing catabolic pathways. It now appears to be the major target for two existing classes of drug used to treat type 2 diabetes, i.e., the biguanides and thiazolidinediones. However, in both cases these activate AMPK indirectly, and an interesting question concerns whether a drug that directly activated AMPK would retain the therapeutic benefits of the existing drugs while eliminating unwanted side effects. AMPK activators also now have potential as anticancer drugs.
引用
收藏
页码:185 / 210
页数:26
相关论文
共 164 条
  • [11] MODULATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE-ACTIVITY WITH CAMP AND WITH PROTEIN FRACTIONS OF RAT-LIVER CYTOSOL
    BEG, ZH
    ALLMANN, DW
    GIBSON, DM
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1973, 54 (04) : 1362 - 1369
  • [12] Effect of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats
    Bergeron, R
    Previs, SF
    Cline, GW
    Perret, P
    Russell, RR
    Young, LH
    Shulman, GI
    [J]. DIABETES, 2001, 50 (05) : 1076 - 1082
  • [13] The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes
    Blázquez, C
    Geelen, MJH
    Velasco, G
    Guzmán, M
    [J]. FEBS LETTERS, 2001, 489 (2-3) : 149 - 153
  • [14] AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling.
    Bolster, DR
    Crozier, SJ
    Kimball, SR
    Jefferson, LS
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (27) : 23977 - 23980
  • [15] Analysis of the LKB1-STRAD-MO25 complex
    Boudeau, J
    Scott, JW
    Resta, N
    Deak, M
    Kieloch, A
    Komander, D
    Hardie, DG
    Prescott, AR
    van Aalten, DMF
    Alessi, DR
    [J]. JOURNAL OF CELL SCIENCE, 2004, 117 (26) : 6365 - 6375
  • [16] LKB1, a protein kinase regulating cell proliferation and polarity
    Boudeau, J
    Sapkota, G
    Alessi, DR
    [J]. FEBS LETTERS, 2003, 546 (01) : 159 - 165
  • [17] Increased cancer-related mortality for patients with type 2 diabetes who use sulforrylureas or insulin
    Bowker, SL
    Majumdar, SR
    Veugelers, P
    Johnson, JA
    [J]. DIABETES CARE, 2006, 29 (02) : 254 - 258
  • [18] Thiazolidinediones, like metformin, inhibit respiratory complex I -: A common mechanism contributing to their antidiabetic actions?
    Brunmair, B
    Staniek, K
    Gras, F
    Scharf, N
    Althaym, A
    Clara, R
    Roden, M
    Gnaiger, E
    Nohl, H
    Waldhäusl, W
    Fürnsinn, C
    [J]. DIABETES, 2004, 53 (04) : 1052 - 1059
  • [19] Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome
    Buhl, ES
    Jessen, N
    Pold, R
    Ledet, T
    Flyvbjerg, A
    Pedersen, SB
    Pedersen, O
    Schmitz, O
    Lund, S
    [J]. DIABETES, 2002, 51 (07) : 2199 - 2206
  • [20] Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the γ2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency
    Burwinkel, B
    Scott, JW
    Bührer, C
    van Landeghem, FKH
    Cox, GF
    Wilson, CJ
    Hardie, DG
    Kilimann, MW
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2005, 76 (06) : 1034 - 1049