Diabetes: How Diabetes Steers Atherosclerosis

Atherosclerosis diabetes

Atherosclerosis is the cause of a majority of cardiovascular events, and atherosclerosis is accelerated by diabetes and the metabolic syndrome. Many risk factors are associated with the metabolic syndrome and help explain the increased cardiovascular disease (CVD) in that condition. Because the metabolic syndrome occurs in most people with type 2 diabetes, its presence likely accounts for most of the increased incidence of CVD in type 2 diabetes. However, the presence of diabetes increases the risk of CVD beyond that seen with the metabolic syndrome alone. Moreover, CVD risk is increased in type 1 diabetes, in which the presence of the metabolic syndrome and these other risk factors is less common. So what is unique about diabetes that distinguishes it from the metabolic syndrome and might underlie the increased risk of atherosclerotic CVD in types 1 and 2 diabetes? The most logical explanation is hyperglycemia, which defines the diabetic state and which is common to type 1 and type 2 diabetes.

In this post, we critically examine the evidence that glucose plays a role in atherogenesis and also discuss the relative importance of glucose versus lipids. We examine the epidemiological evidence that suggests that hyperglycemia and glycemic control are CVD risk factors. We then evaluate in vitro evidence, animal studies, and clinical trials to help understand the relationship between hyperglycemia and atherosclerosis risk, and discuss the advantages and shortcomings of each approach.

Diabetes: Atherosclerosis Risk

Glycemic control and CVD

Strong epidemiological evidence supports an association between glycemic control and CVD risk. The United Kingdom Prospective Diabetes Study (UKPDS) provided additional insights into the relationship between glycemic control and CVD in patients with type 2 diabetes, indicating a linear relationship between HbA1c and CVD endpoints, particularly myocardial infarction. However, the slope of the relationship between HbA1c and microvascular complications is much steeper that than for myocardial infarction, raising the question of whether glucose plays a greater role in the pathogenesis of microvascular than cardiovascular complications of diabetes. Similar but less-robust relationships have been observed in patients with type 1 diabetes. However, epidemiological studies only indicate associations, and provide no evidence of causality. Therefore, other approaches are necessary to understand the potential role of hyperglycemia in the pathogenesis of cardiovascular disease.

Experts once believed that atherosclerosis, or hardening of the arteries, developed when too much cholesterol clogged arteries with fatty deposits called plaques. When blood vessels became completely blocked, heart attacks and strokes occurred. Today most agree that the reaction of the body’s immune system to fatty build-up, more than the build-up itself, creates heart attack risk. Immune cells traveling with the blood mistake fatty deposits for intruders, akin to bacteria, home in on them, and attack. This causes inflammation that makes plaques more likely to swell, rupture and cut off blood flow.

Making matters worse, nearly 21 million Americans have diabetes, a disease where patients’ cells cannot efficiently take in dietary sugar, causing it to build up in the blood. In part because diabetes increases atherosclerosis-related inflammation, diabetic patients are twice as likely to have a heart attack or stroke.

Past work has shown that high blood sugar has two effects on cells lining blood vessels as part of atheroslerosis. First, it increases the production of free radicals, highly reactive molecules that tear about sensitive cell components like DNA, causing premature cell death (apoptosis). This process also reduces the availability of nitric oxide (NO), which would otherwise enable blood vessels to relax and blood flow to increase.

In contrast to diabetes, exercise and good diet bring about faster blood flow through blood vessels. The force created by fast, steady blood flow as it drags along blood vessel walls has been shown by recent studies to protect arteries from atherosclerosis. Physical force has emerged recently as a key player in bodily function, capable of kicking off biochemical processes (e.g. weightlifting thickens bone).

“Inflammation in blood vessels is one of the main drivers of atherosclerosis, and diabetes makes it much worse,” said Jun-ichi Abe, M.D., Ph.D., associate professor with the Aab Cardiovascular Research Center at the University of Rochester Medical Center, and a study author. “Our study argues that a pathway surrounding a key signaling enzyme both protects the heart in normal cases, and is sabotaged by the chemicals produced in diabetes. We believe we have found a new therapeutic target for the treatment of diabetes-related damage to blood vessels.”

How diabetes does it

In people without diabetes, fast blood flow triggers an enzyme called extracellular signal-regulated kinase 5 (ERK-5). ERK5 in turn signals endothelial nitric oxide synthase (eNOS) to produce more nitric oxide and dilate blood vessels. It also activates Kruppel-like factor 2 (KLF2) and peroxisome proliferator-activated receptor-g (PPARg), both of which block the ability of pro-inflammatory immune cells to home in on and adhere to diseased portions of blood vessels.

Past studies had shown diabetes to worsen atherosclerosis, but its exact link to related inflammation had remained unclear. The current results provides the first mechanistic description of how diabetes takes away the ability of fast blood flow force to protect blood vessels, arguing that it does so by interfering with ERK5 and its signaling partners.

Abe’s team showed that molecules called advanced glycation end products (AGEs), produced in greater levels by patients with diabetes, interfere with ERK5 cardioprotection. Glycation reactions cause the release of oxidizing side products like hydrogen peroxide (H202) that drive free radical production, inflammation and cell damage in many diseases.

Researchers found that AGEs and H202 sabotage ERK5 by encouraging the attachment to it of a small ubiquitin-related modifier (SUMO), a protein tag used by cells to fine-tune their control over proteins. In normal function, a cell may extend a protein’s lifespan, or send it from one part of the cell to another, by attaching a SUMO tag. In the current study, researchers found that AGEs and H202 induced ERK5-SUMOylation as part of disease. In addition, the team found that ERK5-SUMOylation was increased in the aortas of diabetic mice.

Along with Abe, Chang-Hoon Woo, Tetsuro Shishido and Carolyn McClain contributed to the work within the Aab Cardiovascular Research Center. Jae Hyang Lim and Jian-Dong Li within the Department of Microbiology & Immunology at the Medical Center contributed expertise, along with Jay Yang, professor of Anesthesiology at Columbia University. This work is supported by grants from the America Heart Association and the National Institutes of Health.

“Our experiments found that taking away the “SUMO tag” from ERK protects blood vessels against diabetes,” Abe said. “We believe that the SUMOylation of ERK turns off ‘good’ genes that are important in countering atherosclerosis. In the next phase, we will be looking for drug candidates that can turn on ERK5 as diabetes attempts to shut it down.”

Reproduced from materials provided by University of Rochester Medical Center and NCBI government archive.

Diabetes-Related Atherosclerosis

2 Responses to Diabetes: How Diabetes Steers Atherosclerosis

  1. AppleSouffle says:

    This is fascinating! Well, the subject is fascinating. The video part was very well done, but the speaker’s voice monotone.

    I read Doctor Malcolm Kendrick’s book – The Great Cholesterol Con. He showed the cholesterol has nothing to do with atherosclerosis.

    Unfortunately, the only cause he suggested was stress. Certainly there must be other causes.

    From what I’ve read so far, it seems that sugar and insulin resistance are behind atherosclerosis.

  2. Sim2500 says:

    there are numerous causes of atherosclerosis. e.g. smokig and certain pathogenes. sometimes muiltiple factors and certain people are predisposed to it.

    in a large number of studies over 30 years have shown that cholesterol does cause and play a role in atherosclerosis

    the disease is a immune/imflammatory response.

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