AMPK activation as a strategy for reversing the endothelial lipotoxicity underlying the increased vascular risk associated with insulin resistance syndrome.
The endotheliopathy associated with insulin resistance syndrome appears to result largely from excessive free fatty acid (FFA) exposure that boosts endothelial production of diacylglycerol, thereby activating protein kinase C. This endothelial "lipotoxicity" can be alleviated by very-low-fat diets and by appropriate weight loss. In addition, pharmacological activation of endothelial AMP-activated kinase (AMPK), as with the drug metformin, has the potential to decrease the FFA content of endothelial cells by stimulating fat oxidation; AMPK may also suppress endothelial de novo synthesis of diacylglycerol by inhibiting glycerol-3-phosphate acyltransferase. These considerations may rationalize the superior impact of metformin therapy on the macrovascular health of diabetics. More generally, metformin - or, preferably, better tolerated activators of AMPK - may have considerable potential for promoting vascular health in the large proportion of the adult population afflicted with insulin resistance syndrome.
McCarty
Mark F
MF
NutriGuard Research, 1051 Hermes Avenue, Encinitas, CA 92024, USA. mccarty@pantox.com
D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D052242:Adiponectin; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000517:prevention & control; D002951:Citrates / Q000494:pharmacology; D048909:Diabetes Complications / Q000453:epidemiology / Q000517:prevention & control; D004041:Dietary Fats / Q000009:adverse effects / Q000493:pharmacokinetics; D004075:Diglycerides / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects*; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D009765:Obesity / Q000150:complications; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012306:Risk; D002787:Sterol Esterase / Q000037:antagonists & inhibitors
D052242:Adiponectin; D002951:Citrates; D004041:Dietary Fats; D004075:Diglycerides; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; C007999:hydroxycitric acid; D008687:Metformin; D005992:Glycerol-3-Phosphate O-Acyltransferase; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; D002787:Sterol Esterase