Metabolic switch from glycolysis towards fatty acid oxidation in Schwann cells in response to high glucose

Diabetic neuropathy (DN) is a prevalent, complex and debilitating chronic complication of diabetes mellitus. The main clinical treatment is the tight control of blood glucose levels. However, there is accumulating evidence that this does not reduce the incidence and the progression of DN, suggesting that other pathways are involved. Aberrant Schwann cells metabolism, characterized by a shift from fatty acid synthesis towards fatty acid oxidation, may play an important role in neuronal dysfunction and subsequently neuropathy. In this study the effect of high glucose condition on the downstream mitochondrial metabolism in different cell types was investigated. This study revealed a cell type specific increase in glucose uptake, mitochondrial properties and reactive metabolites in response to high glucose. Collectively, this data supports the emerging idea of tissue-specific alterations in energy metabolism in diabetic complications-prone tissues, such as the peripheral nerves. Hence, this data shows the importance to investigate the tissue- and cell-specific effect and interactions in response to hyperglycemia in diabetes. Focusing on the effect of hyperglycemia in diabetic neuropathy, the research was continued in Schwann cells and fibroblasts. Markers of the unifying theory including sorbitol, PCK activity and methylglyoxal were mainly unaffected in both fibroblast and Schwann cells in response to high glucose, as compared to low glucose cultured cells. Moreover according to unifying theory, hyperglycemia induces an increased glucose flux through glycolysis leading to increased mitochondrial bioenergetics and subsequently to increased ROS formation causing cellular damage and the development of diabetic complications. However, under long term hyperglycemia the glycolytic capacity and the mitochondrial spare respiratory capacity was reduced in both cell lines, indicating that the capacity of the cells to respond to an energetic demand was diminished when cultured for 6 days under high glucose condition. The ...