The Pathway Linking High Glucose to Inflammation That Can Cause Diabetes Complications

Diabetes greatly raises the risk for heart, blood vessel and kidney disease, and scientists have been searching for explanations of why high blood sugar would contribute to these severe complications. Now a team of researchers at the University of Virginia Health System is offering a new explanation for this phenomenon.

The team, led by Jerry Nadler, M.D., has completed the first study that shows high glucose can increase levels of key proteins that result in inflammation. The inflammation process in blood vessels and the kidney can lead to a build-up of cells (atherosclerosis) and damage to tissues that can constrict the passage of blood through vessels. This blockage can lead to heart attacks and affect the kidney, leading to end-stage renal (kidney) disease.

The researchers discovered that high glucose treatment significantly increased levels of several types of pro-inflammatory cytokines like interleukin 12 (IL-12) produced by macrophages, an immune system cell that plays a central role in chronic inflammation in diabetes, atherosclerosis and other immune disorders. Cytokines, substances that are secreted by immune cells, can program certain white blood cells to become T helper cells (Th1). The cytokine IL-12 and Th1 cell infiltration has emerged as an important pathway for the development of autoimmune diabetes as well as chronic inflammation linked with atherosclerosis. Previous studies have found that reducing levels of the cytokine IL-12 is associated with reduced atherosclerosis in mouse models.

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"These findings are significant because increased IL-12 levels are seen in both type 1 diabetes, the more severe type of disease, as well as the more common type 2 diabetes," said Dr. Nadler, chief of the UVa Division of Endocrinology and Metabolism, and his team are very excited about. "In the future, new medications that can fight these blockage actions could provide a new approach to halt the terrible complications caused by elevated glucose seen in diabetes," Nadler said.

Currently, there are no clinically approved medications that can reduce levels of IL-12 or its damaging effects. However, a medication called lisofylline can block IL-12 and has been shown to reduce the inflammation caused by glucose and the metabolic syndrome (a prediabetes syndrome). The results of this study, which was funded by the National Institutes of Health, suggest a new mechanism that could link high glucose levels to heart disease and other possible complications of diabetes.

By UVA Health