Relationship between diabetes and cardiovascular disease Understanding the relationship between diabetes and cardiovascular disease all

boils down to understanding the underlying pathology in most cardiovascular disease. In most cases, the underlying pathology of heart disease is atherosclerosis. What is atherosclerosis? It is generally considered to be a response to injury the primary event is damage to the endothelial layer of blood vessels, and so immune cells (monocytes) target this injury. However, the injury on its own is not enough to cause atherosclerosis, you also need to have high levels of LDL-cholesterol in the blood. This LDL-cholesterol is oxidised very easily when it is in the plasma compartment, and is transported across the endothelium to the underlying intima. Monocytes leave the circulation at the site of injury and enter the intimal layer, where they differentiate into macrophages and pick up this oxidised LDL, through a scavenger receptor-mediated mechanism. The oxidised LDL in the cytoplasm gives the cell a foamy appearance hence the name foam cells. These foam cells secrete a number of cytokines that attract more monocytes to join the fun. These cytokines also make smooth muscle cells from the underlying media migrate into the plaque. These also accumulate oxidised LDL, but they also secrete collagen, which forms a cap over the plaque, which stabilises it. This plaque will narrow the lumen of the blood vessel, restricting flow, which may cause stable angina. It also makes blood vessels less compliant, so will contribute to hypertension, and the increased workload necessary to pump blood into stiff vessels may contribute to heart failure. If the plaque ruptures, the collagen cap (which would normally be lying underneath the endothelial layer) is exposed to the blood, triggering clot formation. Clots that completely obscure blood vessels in the heart will cause a heart attack (MI). Clots that block blood vessels in the brain will be one cause of stroke. Partial/temporary occlusions of blood vessels in the heart will cause unstable angina; in the brain they will cause transient ischaemic attacks. OK, so what does this mean with respect to diabetes? In short, for plaque to form you need two things: (i) injury (ii) increased lipid levels in the blood. (i) In diabetes, there will be reduced control of blood glucose. Even with the best possible control, there will be occasions when blood glucose levels become much higher than normal. High blood glucose levels lead to glycation of proteins on endothelial cells, which damages them. Most of the complications of diabetes (including nephropathy and retinopathy) involve endothelial damage. (ii) You will get high levels of lipids in the blood if lots of fat is taken in in the diet, and it isnt burnt by exercise or stored as fat. Storing fat in adipose tissue protects the circulation from high lipid (this is why weight loss is so important in treating heart disease most people will put on weight until they reach a plateau after this time, any excess fat remains in the blood. If you lose weight, you make more room for fat to be stored from the blood). What role does diabetes play in this? Remember back to your lectures on insulin signalling: we said that insulin is necessary for fat storage to occur. I

find the easiest way to remember this is to think about the Atkins diet you are not allowed to eat carbohydrate with fat. This is because if you dont eat carbohydrate, you dont produce insulin, and you cant store fat in adipocytes. In diabetes (type 2) you have insulin resistance, so failed insulin signalling in adipocytes prevents fat storage. So, in short, diabetes causes endothelial injury and high blood lipid levels - the perfect recipe for atherosclerosis. (For icing on the cake type marks, you could also say that elevated blood pressure may cause endothelial damage when you increase blood pressure, you increase the shear forces acting on endothelial cells. Remember that normal insulin signalling leads to production of endothelial nitric oxide synthase, which will tend to reduce blood pressure. In failed insulin signalling associated with type 2 diabetes, you get a reduction in eNOS activity, and this is likely to contribute to hypertension and therefore endothelial damage).