Cardiovascular disease is caused by a combination of all three factors, but lipid control is thought to be the most influential. Often, cardiovascular problems can arise from the development of atherosclerosis which is an increased risk in diabetics. Poor glucose control or resistance to insulin causes a lack of nitric oxide production which is important in maintaining vascular flow. The lack of sufficient nitric oxide leads to an increase in plaque formation within the blood vessels. Lastly, neuropathy is caused by a metabolic cascade resulting from a lack of glycemic control, a long duration of diabetes, and potentially vascular abnormalities as well. Hyperglycemia causes the polyol pathway to produce more sorbitol from glucose, but at the same time this process consumes NADPH which results in less cofactor available for glutathione reductase. This inhibits the cells’ ability to respond to oxidative stress. Oxidative stress is defined as an imbalance between antioxidants and free radicals in one’s body. Too many free radicals cause chemical chain reactions due to their high reactivity. Conversely, anti-oxidants have been proposed to prevent generation of free radicals (or reduce the impact of free radicals). Oxidative stress can alter nerve blood supply, nerve structure, and endoneural metabolism. High glucose levels also are found to be directly correlated with the production of advanced glycation end-products (AGE). AGE’s are produced by a chemical transformation of sugars binding amino acids or fats. High blood glucose levels and increased fat/lipid levels can lead to the production of AGE’s. When AGE interacts with receptors (RAGE) it can lead to oxidative stress. In rats RAGE is expressed in endothelial and Schwann cells. Incubation of these neuronal and Schwann cells with AGE’s leads to cell death. Vascular complications can also lead to neuropathy. A lack of glycemic control can cause microvascular blood vessels to narrow or harden due to plaque build-up known as atherosclerosis resulting in a restricted blood flow to the nerves. This lack of blood flow causes damage to the peripheral nervous system thus leading to complications such as neuropathy and foot ulcers.
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