From the Journals

Atherosclerosis severity in diabetes can be predicted by select biomarkers

Publish date: February 8, 2017
By
Doug Brunk

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Findings underscore importance of early diabetes control

For a long time the question about how glucose control relates to macrovascular disease has not been easy to answer. There are reports suggesting that glucose control correlates with macrovascular disease later in life, and others that do not make the association so convincing. This paper provides an important link between glucose control and the subsequent development of macrovascular disease. The link is by way of advanced glycation end products as well as oxidative byproducts and how they set the stage for macrovascular disease later on in life. It’s something that clinicians have postulated as being important, but to my knowledge this is one of the only studies to actually show the association.

Dr. Paul S. Jellinger

Dr. Paul S. Jellinger

The investigators used important endpoints like coronary artery calcification and carotid intima-media thickness. I was surprised at how well the relationship between glycosylated end products and oxidative products correlated, but there’s biologic plausibility; it makes sense. Glucose not only glycosates hemoglobin, but glycosates proteins throughout. This provides a logical, stepwise pathway for how the initial glycosylated protein will result years later in macrovascular disease as evidenced by the parameters that were used.

It was interesting to learn from this study that glycosylated end products and oxidative products interact with each other. That’s important, because as blood sugars rise acutely, both oxidative products and glycosylated products are produced. As a result of the oxidative stress that’s created by the sharp rise in blood sugar, endothelial function is affected and more glycosylated proteins are being formed.

Clinically, this study shows the importance of early, aggressive control of diabetes to not allow accumulation of both glycosylated end products and oxidative end products. It demonstrates that accumulation of these byproducts years later seems to relate strongly to macrovascular disease.

The study should be reproduced in younger, less sick patients. That may or may not further clarify the findings, but these findings need to be demonstrated in patients at a much earlier stage as well. We’ve been saying for a long time that early control of diabetes is so important because years later it makes a difference. This is a link to that rationale.

Paul S. Jellinger, MD, MACE, is professor of clinical medicine at the University of Miami Miller School of Medicine, Ft. Lauderdale. He is past president of the American Association of Clinical Endocrinologists (AACE) and past president of the American College of Endocrinology. Dr. Jellinger provided these comments in an interview.


 

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.

dbrunk@frontlinemedcom.com

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