Diabetics have an increased risk of developing coronary artery disease and plaque build-up in their arteries, even if they receive cholesterol-lowering therapies. New research published in the May 7th issue of the Cell Press journal Cell Metabolism reveals that high blood sugar levels also boost the production of inflammatory cells, which contribute to plaque build-up in blood vessels. The researchers identify the cause of this increased production in inflammatory cells and find that blocking this new pathway could help safeguard the heart health of diabetic patients.
"We have found that the bone marrow production of immune cells is affected by high blood sugar and have identified a possible molecule mediating this effect. Both this molecule and its receptor in the bone marrow could be targeted to prevent the inflammation that occurs with type 1 diabetes," says co-senior author Dr. Ira Goldberg of Columbia University College of Physician & Surgeons in New York City.
Dr. Goldberg and his team made their discovery by studying two mouse models of diabetes. In both diabetic models, high blood sugar levels caused a significant increase in the blood counts of certain immune cells called monocytes and neutrophils. The investigators also discovered that neutrophils secrete a molecule called S100A8/S100A9 that interacts with a receptor named RAGE (the Receptor for Advanced Glycation Endproducts) on bone marrow cells. Binding of S100A8/S100A9 to RAGE stimulated bone marrow cells to produce monocytes. This monocyte production created a vicious cycle whereby high blood sugar levels boosted neutrophil numbers, leading to excess secretion of S100A8/S100A9, which in turn stimulated bone marrow cells to produce more monocytes. These monocytes then migrated to blood vessel walls and prevented the healing of plaques.
The researchers found that treating the mice with a drug that lowers blood sugar levels not only reduced the numbers of circulating monocytes and neutrophils but also allowed plaques to normally heal after blood cholesterol was reduced. In addition, blood levels of S100A8/S100A9 in humans with type 1 diabetes correlated with immune cell counts and coronary artery disease.
"These findings illustrate a new marker for risk of vascular disease in patients with type 1 diabetes, and they suggest several new molecular targets for preventing diabetes complications," says Dr. Goldberg.
Cell Metabolism, Nagareddy et al.: "Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis."