Based on available evidence, we would propose the following. (i) Excesses of glucose and free fatty acids cause insulin resistance in skeletal muscle and damage to the endothelial cell by a similar mechanism. (ii) Key pathogenetic events in this mechanism very likely include increased fatty acid esterification, protein kinase C activation, an increase in oxidative stress (demonstrated to date in endothelium) and alterations in the inhibitor κB kinase/nuclear factor κB system. (iii) Activation of AMP-activated protein kinase (AMPK) inhibits all of these events and enhances insulin signalling in the endothelial cell. It also enhances insulin action in muscle; however, the mechanism by which it does so has not been well studied. (iv) The reported beneficial effects of exercise and metformin on cardiovascular disease and insulin resistance in humans could be related to the fact that they activate AMPK. (v) The comparative roles of AMPK in regulating metabolism, signalling and gene expression in muscle and endothelial cells warrant further study.
- acetyl-CoA carboxylase
- fatty acid oxidation
- fuel sensing
- oxidative stress
- protein kinase C
- tumour necrosis factor α
AMPK 2002: 2nd International Meeting on AMP-activated Protein Kinase, a Biochemical Society-sponsored meeting held at University of Dundee, Scotland, 12–14 September 2002
Abbreviations used: ACC, acetyl-CoA carboxylase; AICAR, 5-amino-4-imidazolecarboxamide riboside; AMPK, AMP-activated protein kinase; HUVEC, human umbilical vein endothelial cells; IKK, inhibitor κB kinase; NFκB, nuclear factor κB; PKC, protein kinase C; ROS, reactive oxygen species; TNFα, tumour necrosis factor α; FFA, free (non-esterified) fatty acid.
- Copyright 2003 Biochemical Society