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Abstract

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 reduced glycolytic and respiratory capacity was not reflected in the ATP production and reactive metabolite production. Interestingly, the non-glycolytic acidification was increased in Schwann cells indicating an alternative energy source for the mitochondria to produce ATP and/or reactive metabolites.

Another important energy source for mitochondria is the oxidation of fatty acids. This study showed a metabolic switch from glycolysis towards increased fatty acid oxidation in Schwann cells in response to high glucose. In addition, increased dependency on the medium chain fatty acid octanoate in high glucose cultured Schwann cells was observed, confirming the importance of fatty acid metabolism in Schwann cells. Moreover, an increase in nitric oxide synthesis, nitric oxide production, and protein S-nitrosylation was observed in the Schwann cells cultured under chronic high glucose conditions. Upon stimulation with the nitric oxide inducer DetaNONOate the mitochondrial maximal respiration and spare respiratory capacity of Schwann cells was reduced as observed upon hyperglycemia. Previous studies have shown that nitric oxide and S-nitrosylation can induce a shift from fatty acids towards lipid oxidation, leading to an accumulation of fatty Beta-oxidation in intermediates, such as acetyl carintines. Once released it leads to neuron degeneration and neuron demyelination and subsequently to neuropathy. Future experiments are required to confirm this hyperglycemia induced nitric oxide synthesis and lipid oxidation alterations and interaction in Schwann cells.

This study indirectly confirms the importance of lipid metabolism in Schwann cell in response to hyperglycemia and that nitric oxide synthesis and protein S-nitrosylation may play an important role in the mitochondrial metabolic switch from glycolysis toward fatty acid oxidation. Future study should concentrate on 1) which proteins are S-nitrosylated in response to hyperglycemia in Schwann cells and how this is associated with altered mitochondrial Schwann cell metabolism, including decreased glycolysis and increased lipid oxidation, 2) the effect of increased lipid oxidation in Schwann cells on neuronal function and 3) how these metabolic changes in Schwann cell upon diabetes affect the nearby neurons. Increasing our knowledge about cell specific alterations in mitochondrial metabolism in diabetes will lead to a better understanding of the pathophysiology of diabetic neuropathy and the development of new therapeutic targets.