Possible Causes of CV Complications in Type 2 Diabetes

Savannah Helm Uncategorized

Two possible causes of the cardiovascular consequences of Type 2 (T2DM) stand out: lower nitric oxide (NO) production and increased advanced glycation end products (AGEs).1

Nitric Oxide and a Healthy Endothelium

As discussed in my last blog, the endothelium of the blood vessels is the main organ involved in the development of cardiovascular disease in T2DM.1 The damage to the endothelium may be the unifying causal factor in hypertension, cardiovascular disease, metabolic syndrome, and more. The endothelium forms the gas nitric oxide (NO), which in turn controls the blood flow throughout the body and brain. It does this by triggering the intrinsic vasodilator cGMP that relaxes blood vessels thus increasing blood flow to all organs.

The typical American Diet, often referred to as the SAD diet (Standard American Diet), is rich in simple carbohydrates that have a damaging effect on the endothelium, resulting in a cumulative effect of impaired blood flow that damages the heart and vasculature. Research has demonstrated that hyperglycemia in men reduces nitric oxide-dependent vasodilation as a result of oxidative stress. Macrovascular endothelial dysfunction involves decreased nitric oxide bioavailability as a central mechanism in healthy and cardiometabolic diseased populations. This dysfunction may be attributed to acute hyperglycemia increasing oxidative stress and its role in disrupting pathways of NO synthesis.2

                  Oxidative stress is an imbalance between pro- and antioxidant species. Oxidative stress plays a pivotal role in the development of age-related diseases such as atherosclerosis and T2DM. Research suggests that antioxidants can help control the production of free radicals thus reducing oxidative stress, improving immune function, and reducing risk of some aging related conditions.3

Prediabetes, which leads to the development of type 2 diabetes in 70-75% of those individuals diagnosed with it, is often symptomless.4 Damage to the endothelium’s ability to synthesize NO is due to chronic hyperglycemia. Once diagnosed, damage has more than likely become chronic and reversal of cardiovascular complications may be more difficult, even in the light of a change to good glycemic control.

Importance of Testing1

Nitric oxide bioavailability is negatively impacted by hyperglycemia and advancing age. Steps to reduce or reverse this decline may help to reduce the risks associated with T2DM and related hypertension and cardiovascular disease. Monitoring blood sugar levels is important in and of itself to provide information on how well hyperglycemia is controlled. Once patients’ blood sugar levels have been normalized, NO testing can be used to determine its availability to support the endothelium. There are several brands of saliva test strips available to measure NO. A low NO reading is significant because of its relationship to T2DM and its complications. A low reading may mean the person’s diet is low in the foods that promote NO production, or advanced age, or excessive levels of by-products of oxidation that interfere with NO production by the body.

AGE-ing the Endothelium

Advanced glycation end products or AGEs are lipids or proteins that become glycated (attached to a sugar molecule such as glucose or fructose) during food preparation methods such as grilling, broiling, or frying. AGEs give foods the crispy texture on darkened parts of fried, grilled, or toasted foods and meats. These harmful by-products are also found in high AGE-potential foods including high fat dairy and meats, and some commercially prepared carbohydrates. AGEs also occur naturally in the body as one ages, especially in people with diabetes. About 6-7% of food-derived AGEs remain in the body for a period increasing susceptibility to endothelial damage.5 AGE-containing foods and AGE-promoting cooking techniques may be especially damaging to those with T2DM.

After being exposed to AGEs, human coronary artery endothelial cells demonstrate decreased levels of endothelium-derived nitric oxide and cellular NO levels through oxidative stress created by free radical production. Reducing AGEs in the diet can improve insulin resistance in persons with T2DM. It has been shown to improve lifespan, and kidney function by 50% in animal models. Those individuals who follow diets higher in protein and fat and lower in carbohydrate have been shown to have higher AGE levels that those following a more plant-based diet.5

Dietary Steps to Reduce AGEs and Increase NO

Nitric oxide can be formed by the endothelium through using L-arginine as a dietary supplement or through eating certain foods in the diet. Dietary nitrate is metabolized by the body to form nitric oxide.2 Many vegetables, especially root vegetables, collect high concentrations of nitrates. Vegetables high in nitrates include lettuce, beets, carrots, green beans, spinach, parsley, cabbage, radishes, celery, and collard greens.

The nitrates that are added to foods as preservatives are quite different from those that occur naturally in produce. Naturally occurring nitrates in food are often found in foods high in vitamin C and other compounds that inhibit conversion into nitrosamines. AGEs can be avoided by using cooking techniques that limit their formation such as stewing, boiling, also by avoiding frying high fat animal products and eating commercially prepared carbohydrates such as biscuits, croissants, frozen waffles, some breakfast cereals, pretzels, cookies, and fast food sandwiches.6

One diet shown to be beneficial in reducing AGEs and increasing NO is the Mediterranean Diet or MedDiet that incorporates concepts of healthy eating.2 The MedDiet is a rich source of foods that provide nitric oxide including some meats that contain L-arginine and greens, beans, and beets that are rich in nitrates. In addition, the diet recommends minimally processed foods, lower fat dairy, and poultry in moderation, limited red meat consumption, twice weekly fatty fish consumption, and olive oil as the primary fat replacing other fats. The MedDiet not only supports cardiovascular health, but it can also help to normalize blood glucose, promote weight loss, reduce the risk of metabolic syndrome, and help prevent premature aging of the endothelium.

Additional complementary approaches that support improved management of T2DM are beginning to appear and can help address the consequences of hyperglycemia.

by Sarah Laidlaw, MS, RDN, CDE



  1. Fried R, Carlton RM. Type 2 Diabetes Cardiovascular and related complications and Evidence-based complementary treatments. Boca Raton: CRC Press; 2019.
  2. Loader J, Montero D, Lorenzen C, et al. Acute Hyperglycemia Impairs Vascular Function in Healthy and Cardiometabolic Diseased Subjects. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015; 35:2060–2072.
  3. Tan BL, Norhaizan ME, Liew W-P-P , Sulaiman Rahman H . Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases. Front. Pharmacol. 2018; 9:1162. doi: 10.3389/fphar.2018.01162.
  4. McCain J. Prediabetes Does Not Mean Preordained. Managed Care. 2016. Available from: https:// www.managedcaremag.com/archives/2016/5/prediabetes-pre-does-not-mean-preordained.
  5. Rhee SY, Kim YS. The Role of Advanced Glycation End Products in Diabetic Vascular Complications. Diabetes Metab J. 2018; 42:188-195.
  6. Uribarri JWoodruff SGoodman S, et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc.2010 Jun;110(6):911-16.e12. doi: 10.1016/j.jada.2010.03.018.

Additional Resources

Mediterranean Diet. Available at: https://oldwayspt.org/traditional-diets/mediterranean-diet

Mediterranean Diet. Available at: https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/nutrition-basics/mediterranean-diet

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