Diabetes mellitus-associated atherosclerosis: mechanisms involved and potential for pharmacological invention.
While diabetes mellitus is most often associated with hypertension, dyslipidemia, and obesity, these factors do not fully account for the increased burden of cardiovascular disease in patients with the disease. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease and, more specifically, diabetes-associated atherosclerosis. In addition to the recognized metabolic abnormalities associated with diabetes mellitus, upregulation of putative pathological pathways such as advanced glycation end products, the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines have been shown to play a causal role in atherosclerotic plaque formation and may explain the increased risk of macrovascular complications. This review discusses the methods used to assess the development of atherosclerosis in the clinic as well as addressing novel biomarkers of atherosclerosis, such as low-density lipoprotein receptor-1. Experimental models of diabetes-associated atherosclerosis are discussed, such as the streptozocin-induced diabetic apolipoprotein E knockout mouse. Results of major clinical trials with inhibitors of putative atherosclerotic pathways are presented. Other topics covered include the role of HMG-CoA reductase inhibitors and fibric acid derivatives with respect to their lipid-altering ability, as well as their emerging pleiotropic anti-atherogenic actions; the effect of inhibiting the renin-angiotensin system by either ACE inhibition or angiotensin II receptor antagonism; the effect of glycemic control and, in particular, the promising role of thiazolidinediones with respect to their direct anti-atherogenic actions; and newly emerging mediators of diabetes-associated atherosclerosis, such as advanced glycation end products, vascular endothelial growth factor and platelet-derived growth factor. Overall, this review aims to highlight the observation that various pathways, both independently and in concert, appear to contribute toward the pathology of diabetes-associated atherosclerosis. Furthermore, it reflects the need for combination therapy to combat this disease.
JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Baker Heart Research Institute, Melbourne, Victoria, Australia. anna.calkin@baker.edu.au
Anna C
AC
Calkin
Terri J
TJ
Allen
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D050197:Atherosclerosis / Q000178:diet therapy / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy*; D015415:Biomarkers / Q000097:blood; D002986:Clinical Trials as Topic; D002995:Clofibric Acid / Q000627:therapeutic use; D048909:Diabetes Complications / Q000178:diet therapy / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy*; D006133:Growth Substances / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007328:Insulin / Q000819:agonists
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D006133:Growth Substances; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D002995:Clofibric Acid