New perspectives in diabetic neuropathy

Abstract

Diabetes prevalence continues to climb with the aging population. Type 2 diabetes (T2D), which constitutes most cases, is metabolically acquired. Diabetic peripheral neuropathy (DPN), the most common microvascular complication, is length-dependent damage to peripheral nerves. DPN pathogenesis is complex, but, at its core, it can be viewed as a state of impaired metabolism and bioenergetics failure operating against the backdrop of long peripheral nerve axons supported by glia. This unique peripheral nerve anatomy and the injury consequent to T2D underpins the distal-to-proximal symptomatology of DPN. Earlier work focused on the impact of hyperglycemia on nerve damage and bioenergetics failure, but recent evidence additionally implicates contributions from obesity and dyslipidemia. This review will cover peripheral nerve anatomy, bioenergetics, and glia-axon interactions, building the framework for understanding how hyperglycemia and dyslipidemia induce bioenergetics failure in DPN. DPN and painful DPN still lack disease-modifying therapies, and research on novel mechanism-based approaches is also covered.

Keywords: bioenergetics; diabetes; dyslipidemia; hyperglycemia; metabolic syndrome; mitochondria; obesity; pathophysiology; peripheral neuropathy; prediabetes.

Figure 1.. DPN presentation and PNS structure.

(A) Diabetic peripheral neuropathy (DPN) manifests as nerve injury (red color) in a “stocking-glove” pattern. DPN starts in the feet and progresses proximally towards the calves. At this point, DPN begins in the hands. Intensity of red color indicates extent of damage. DPN mirrors pattern of patient symptomatology of pain, e.g., prickling, burning, electric shock-like sensations. Created in Biorender.com. (B) The peripheral nerve is comprised of bundles of afferent sensory neurons with cell bodies in the dorsal root ganglia and bundles of efferent motor neurons with cell bodies in the ventral horn of the spinal cord. Myelinating Schwann cells (SCs) wrap around a single myelinated sensory axon and areas between intervening SCs are called nodes of Ranvier. Non-myelinating SCs organize multiple small unmyelinated fibers into Remak bundles. Panel B figure adopted, with minor revisions, from Feldman et al. Neuron 2017.

Figure 2.. Bioenergetics in the healthy nerve.

(A) Healthy, bioenergetically active sensory neuron, which requires energy to maintain a membrane potential, propagate signals, and release and reuptake neurotransmitters. (B) Schwann cells (SCs) mainly metabolize glucose (GLU) to generate energy and may reserve fatty acids (FA), imported using fatty acid transporter proteins (FATP), to synthesize myelin. SCs express glucose transporter 1 (GLUT1) to import glucose, which is metabolized to pyruvate (PYR) in the cytoplasm. SCs use lactate dehydrogenase A (LDHA) to convert a fraction of the glycolysis-derived pyruvate to lactate, which is transferred to axons via monocarboxylate transporters 1 and 4 (MCT1, MCT4). SCs can also release extracellular vesicles (EVs), which are taken up by neurons. Neurons import glucose via GLUT3 and catabolize it by glycolysis to pyruvate. Axons receive SC-derived lactate through MCT2, which is converted to pyruvate by lactate dehydrogenase B (LDHB). Neurons prefer glucose as an energy substrate, but also possess FATP and may utilize fatty acids as an energy source. Viable mitochondria (red) are trafficked anterogradely by kinesin and TRAK, to axon termini, where they generate energy to support axonal activity. (C) Mitochondrial bioenergetics: Pyruvate is shuttled into the mitochondrial matrix by mitochondrial pyruvate carrier (MPC), converted to acetyl-CoA by the pyruvate dehydrogenase complex (PDC) and further metabolized via the tricarboxylic acid (TCA) cycle, which feeds substrates into oxidative phosphorylation (OXPHOS) within the inner mitochondrial membrane (IMM), ultimately yielding ATP. Fatty acids are conjugated to coenzyme A (CoA) by long-chain-fatty-acid-CoA ligase (ACSL) and shuttled into mitochondria by carnitine palmitoyltransferase 1 and 2 (CPT1 and CPT2) as acylcarnitine (AC) intermediates across the outer mitochondrial membrane (OMM) and IMM. Acyl-CoA is then broken down by β-oxidation into acetyl-CoA, which is funneled into the TCA cycle followed by OXPHOS. Created in Biorender.com.

Figure 3.. DPN pathophysiology and bioenergetics failure.

(A) Injured sensory neuron in DPN experiences distal-to-proximal axonal loss mirroring bioenergetic failure at distal sites. (B) During DPN, the peripheral nerve develops insulin resistance and SC and axon insulin receptors (IR) cease responding to insulin. Insulin resistance disrupts SC and axon metabolism, e.g., blunted mTORC1 signaling. In SCs, blunted mTORC1 signaling potentially impairs lactate shuttling to axons via monocarboxylate transporters (MCTs). Excess long-chain saturated fatty acids (SFA) increase lipotoxic acylcarnitines in SCs, which may transfer to axons. Hyperglycemia triggers oxidative stress from reactive oxygen species (ROS) and pathologic extracellular vesicle (EV) release from SCs, which accelerate DPN development. In axons, hyperglycemia shunts glycolytic intermediate energy metabolites into polyol and hexosamine pathways. Hyperglycemia and dyslipidemia depolarize mitochondrial membranes (black, nonvital mitochondria), reducing ATP production, and generating ROS. Long-chain SFAs impair mitochondrial trafficking. Lower ATP coupled with fewer mitochondria causes bioenergetic failure, triggering distal-to-proximal nerve damage, which manifests clinically as neuropathy. Created in Biorender.com.

Figure 4.. Painful DPN pathophysiology.

(A) Mechanisms of painful DPN related to channel modification and overactivation (from left to right): Genetic variants (red sphere) in sodium channels Na_v1.7 and Na_v1.8; TRPA1 (transient receptor potential cation channel, subfamily A, member 1) modified by methylglyoxal; TRPV1 (transient receptor potential cation channel, subfamily V, member 1) modified by SUMOylation; overactivation of HCN2 (hyperpolarization-activated and cyclic nucleotide-gated 2) by elevated cyclic AMP (cAMP). (B) Mechanisms of painful DPN related to metabolism and mitochondria (from left to right): High-fat diet (HFD) blocks transcription by liver X receptors (LXR), which regulates cholesterol and fatty acid homeostasis, in dorsal root ganglion neurons, exacerbating endoplasmic reticulum (ER) stress and triggering mechanical pain hypersensitivity; HFD increases calcium (Ca²⁺) signaling and fragments mitochondria in sensory neurons; genetic variants to SLC25A3 (red sphere), encoding a mitochondrial phosphate transporter for ATP production. (C) Unmyelinated sensory neuron in DPN, showing localization of channels at axon termini, with HCN2 in the axon additionally, and metabolic perturbations within the axon and cell body. Created in Biorender.com.