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Abstract

Diabetes is a metabolic disease with increasing incidence worldwide and with important economic effects. The disease is characterized by hyperglycaemia, which may be caused by an alteration of insulin production secondary to degeneration of pancreatic beta cells (type-1 diabetes), or by an insulin resistance and insufficient secretion from the pancreas (type-2 diabetes). Diabetic neuropathy is the most frequent complication of diabetes mellitus and is characterised by demyelination of neurons accompanied by sensory loss. In addition, hyperglycaemia and local hypoxia can cause glucose oxidation, formation and accumulation of glycation end-products, which lead to oxidative stress. In this work, we investigated the sequence of event occurring in alteration of metabolic pathways in relation to nerve damage and sensory loss in C57BL6/j mice in the model of type 1 diabetes. We employed a mass spectrometry-based screen to study alterations in levels of metabolites in peripheral sciatic nerve and amino acids in serum over several months. Our results indicated that the impaired metabolites in peripheral nerve are the primary cause of shunting metabolic substrate to compensatory pathways, which leads to sensory nerve fibre loss in skin and contribute to onset and progression of peripheral neuropathy. Furthermore, hyperglycaemia-induced mitochondrial dysfunction and the generation of reactive oxygen species (ROS) have gained attention as possible mechanisms of organ damage in diabetes. We analysed the regulation of transcription factor HIF1α in response to prolonged hyperglycaemia in mutant mice, lacking HIF1α in peripheral sensory neurons. Our results indicated that HIF1α is an upstream modulator of ROS in peripheral sensory neurons and possess a protective function in suppressing hyperglycaemia-induced nerved damage by limiting ROS levels, therefore, HIF1α stabilization may be thus a new strategy target for limiting sensory loss, a debilitating late complication of diabetes. In peripheral nervous system, Schwann cells wrap and myelinate spirally around axons, which is indispensable for the efficient propagation of nerve impulses along axons by saltatory conduction. Periaxin protein is expressed in the membrane of myelinating Schwann cells and it is a scaffold protein for coupling peripheral proteins to elements of the Schwann cell cytoskeleton. Post-translational modification via sumoylation has emerged as a central regulatory mechanism of protein function in health and disease. We studied the role of sumoylation on Periaxin by generating conditional PLP-CreERT2+/+Ubc9fl/fl mice lacking sumo conjugating enzyme (Ubc9), which is expected to delete sumoylation in Schwann cells and oligodendrocytes. The conditional deletion of Ubc9 in Schwann cells considerably reduced the walking and running behaviour of PLP-CreERT2+/+Ubc9fl/fl mice, which can be considered as early symptoms of onset of peripheral neuropathy. Although our results cannot be generalised to other mouse genotypes, our conditional Ubc9-knock-out mice may be useful for assessing the cell-specific role of sumoylation in myelination and peripheral neuropathies.