Oxidative stress and macrophage foam cell formation during diabetes mellitus-induced atherogenesis: role of insulin therapy.
Diabetes mellitus (DM) and hyperglycemia are associated with premature and accelerated atherosclerosis. This is mediated by induction of vascular dysfunction, increased inflammatory burden and increased lipid peroxidation, all leading to enhanced macrophage foam cell formation. In DM, low density lipoprotein (LDL) oxidation by macrophages is increased due to the activation of several pro-oxidant systems, as well as the depletion of antioxidants, such as the paraoxonases (PONs). Paraoxonases protect against atherogenesis, as serum PON1 exerts a protective role against DM development by stimulating insulin secretion from β cells, and its unique antioxidant properties. Oral supplementation of insulin to mice significantly attenuates macrophage foam cell formation, reduces oxidative stress and decreases the atherosclerotic plaque area and. Insulin may directly inhibit lipid peroxidation via inhibition of NADPH oxidase expression. Insulin has additional protective effects against DM-induced macrophage cholesterol accumulation by inhibiting CD36 expression (an oxidized LDL receptor), and by inhibiting HMGCoA reductase expression (the rate limiting enzyme in cholesterol biosynthesis), through inhibition of the formation of active SREBP-1 (the transcription factor that activates HMGCoA reductase). Although insulin is mainly an anti-atherogenic agent, it also has some pro-atherosclerotic effects in insulin resistant individuals including the induction of dyslipidemia, cellular triglycerides accumulation and pro-thrombotic effects. This review's intent is to help clarify the mechanisms underlying the protective anti-atherogenic role of insulin in DM as well as some pro-atherogenic effects. A better understanding of insulin's involvement in the pathogenesis of atherosclerosis in DM could have major therapeutic implications for DM treatment and its consequent cardiovascular complications.
The Laboratory of Clinical Biochemistry, Technion Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel.
Marielle
M
Kaplan
Michael
M
Aviram
Tony
T
Hayek
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy / Q000209:etiology*; D005487:Foam Cells / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D018384:Oxidative Stress; D014280:Triglycerides / Q000378:metabolism
D000975:Antioxidants; D017127:Glycation End Products, Advanced; D007328:Insulin; D008077:Lipoproteins, LDL; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D002784:Cholesterol