FROM DIABETES CARE
Plasma levels of specific advanced glycation end products and oxidation products are associated with future severity of subclinical measures of atherosclerosis in patient with type 2 diabetes, results from a long-term analysis of VA patients suggest.
Advanced glycation end products (AGEs) and oxidation products (OxPs) “can damage vascular cells by different mechanisms,” wrote researchers led by corresponding authors Aramesh Saremi, MD, and Peter D. Reaven, MD, and colleagues. The report appeared online Feb. 1 in Diabetes Care.
“One frequently reported pathway is AGE binding to their purported (and relatively promiscuous) receptors on cells, such as macrophages, vascular endothelial cells, and vascular smooth muscle cells, although this has not been consistent for all AGEs. Other mechanisms include, among others, binding to and altering the function of intracellular proteins, the activation of vascular NADPH [nicotinamide adenine dinucleotide phosphate] oxidase, and the uncoupling of endothelial nitric oxide synthase.”
Noting that data in the current medical literature are lacking with respect to long-term longitudinal associations between plasma levels of AGEs and OxPs on the extent of subclinical atherosclerosis in T2D patients, the researchers set out to determine whether baseline plasma levels of AGEs and OxPs are associated with the extent of carotid intima-media thickness (CIMT), coronary artery calcification (CAC), and abdominal aortic artery calcification (AAC) over an average of 10 years of follow-up in the VA Diabetes Trial (VADT). They also examined whether this relationship was altered by intervening improved glucose control ( Diabetes Care 2017 Feb. 1. doi: 10.2337/dc16-1875 ]).
At baseline of the VADT, 411 study participants underwent plasma measurements of methylglyoxal hydroimidazolone, N epsilon–carboxymethyl lysine (CML), N epsilon–carboxyethyl lysine (CEL), 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone (G-H1), 2-aminoadipic acid (2-AAA), and methionine sulfoxide. The mean age of the study subjects was 58 years, 64% were non-Hispanic white, 96% were male, 69% had a history of hypertension, and they had diabetes for a mean of 11 years.
After a mean follow-up of 10 years, the 411 patients underwent ultrasound assessment of CIMT, and computed tomography scanning of CAC and AAC.
In risk factor–adjusted multivariable regression models, G-H1was associated with the extent of CIMT as well as with the extent of CAC (P = .01 for both associations). In addition, 2-AAA was strongly associated with the extent of CAC (P = .03 for continuous variables and P less than .01 for dichotomous variables), and CEL was strongly associated with the extent of AAC (P less than .01).
“These findings suggest that the effect of hyperglycemia and subsequent increased levels of AGEs and OxPs in patients with long-standing T2D may have long-lasting adverse effects on the development of macrovascular complications,” the researchers concluded. They acknowledged certain limitations of the analysis, including the fact that it was conducted in an older, primarily male population. Therefore, “extrapolation of the study findings to other populations must be done with caution,” they wrote. “This study also does not allow us to make a definite claim of causation between AGEs and OxPs with the extent of atherosclerosis.”
The Veterans Affairs Cooperative Studies Program of the U.S. Department of Veterans Affairs Office of Research and Development funded the study. Additional support was received from National Institutes of Health, the American Diabetes Association, and the National Institute of Diabetes and Digestive and Kidney Diseases. Two study authors, Scott Howell, MS, and Paul J. Beisswenger, MD, disclosed that they are affiliated with PreventAGE Healthcare. The other researchers reported having no financial disclosures.
