Novel pathogenic pathways in diabetic neuropathy

•Glial cells play a critical role in maintenance of axonal integrity and function. •Diabetes mellitus modifies axon–glia interactions at nodal areas of PNS nerves. •Axonal energy metabolism and ion conductance are particularly affected. •These observations provide a basis for novel therapeutic and diagnostic approaches. Diabetic peripheral neuropathy (DPN) is a common complication affecting more than one third of diabetes mellitus (DM) patients. Although all cellular components participating in peripheral nerve function are exposed to and affected by the metabolic consequences of DM, nodal regions, areas of intense interactions between Schwann cells and axons, may be particularly sensitive to DM-induced alterations. Nodes are enriched in insulin receptors, glucose transporters, Na+ and K+ channels, and mitochondria, all implicated in the development and progression of DPN. Latest results particularly reinforce the idea that changes in ion-channel function and energy metabolism, both of which depend on axon–glia crosstalk, are among the important contributors to DPN. These insights provide a basis for new therapeutic approaches aimed at delaying or reversing DPN. Diabetic peripheral neuropathy (DPN) is a common complication affecting more than one third of diabetes mellitus (DM) patients. Although all cellular components participating in peripheral nerve function are exposed to and affected by the metabolic consequences of DM, nodal regions, areas of intense interactions between Schwann cells and axons, may be particularly sensitive to DM-induced alterations. Nodes are enriched in insulin receptors, glucose transporters, Na+ and K+ channels, and mitochondria, all implicated in the development and progression of DPN. Latest results particularly reinforce the idea that changes in ion-channel function and energy metabolism, both of which depend on axon–glia crosstalk, are among the important contributors to DPN. These insights provide a basis for new therapeutic approaches aimed at delaying or reversing DPN. a change in the resting membrane potential of excitable cells due to the successive opening of voltage-gated Nav and Kv channels. It consists of three phases: de-, re-, and hyperpolarization. a process producing ATP which can be divided into three steps: cytosolic glycolysis, the mitochondrial citric acid cycle, and electron transport chain/oxidative phosphorylation. glucose is metabolized to amino sugars, for example UDP-N-acetylglucosamine, via the hexosamine pathway. This pathway is particularly increased during hyperglycemia. the inability of peripheral tissues (e.g., muscle, adipocytes, liver, and peripheral nerves as outlined here) to respond to circulating insulin. region under the myelin sheath adjacent to the paranode; highly enriched in Kv1 channels which are important for AP repolarization and nerve excitability. monocarboxylate transporters, present in the plasma membrane and mitochondria of both glial and neurons, are involved in the transportation of pyruvate and lactate. a group of metabolic disorders, including predominantly obesity, hyperglycemia, dysinsulinemia, dyslipidemia, and hypertension, that raise the risk for cardiovascular diseases and DM. methylglyoxal is a byproduct of glycolysis that is highly enriched under DM. It promotes the formation of AGEs and is suggested to impair mitochondrial function. ATP-dependent ion pump maintaining resting membrane potential by extruding three Na+ ions against two K+ ions for each ATP molecule consumed. This represents one of the most energy-demanding subcellular processes. the generic term to describe distinct domains between two internodal segments of Schwann cell myelin, composed of the node of Ranvier, paranode, and juxtaparanode. unmyelinated gap of ∼1 μm between two myelin segments of peripheral nerves that is covered by Schwann cell microvilli. An area of AP generation due to a high accumulation of Nav channels. It also contains Kv channels. situation in a cell if there are more oxidants (e.g., superoxide, peroxynitrite) than antioxidants, potentially leading to cell damage. region between the node of Ranvier and juxtaparanode characterized by close axon–glial interactions. Schwann cell paranodal loops serve as a diffusion barrier between internode and node. inability to produce adequate amounts of insulin as a consequence of an autoimmune reaction against pancreatic β cells (affects ∼10% of DM patients). the most common form of DM (affects ∼90% of DM patients) initially caused by a defective response of target tissues to secreted insulin.