Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes.
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 kappa B kinase/nuclear factor kappa B 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.
Ruderman
N B
NB
Diabetes Unit, Section of Endocrinology and Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA. nruderman@medicine.bu.edu
Cacicedo
J M
JM
Itani
S
S
Yagihashi
N
N
Saha
A K
AK
Ye
J M
JM
Chen
K
K
Zou
M
M
Carling
D
D
Boden
G
G
Cohen
R A
RA
Keaney
J
J
Kraegen
E W
EW
Ido
Y
Y
D055372:AMP-Activated Protein Kinases; D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D015444:Exercise; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008316:Malonyl Coenzyme A / Q000378:metabolism / Q000502:physiology*; D008687:Metformin / Q000494:pharmacology; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*
D005227:Fatty Acids; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D008316:Malonyl Coenzyme A; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases