Neuronal damage can develop after persistent episodes of hyperglycaemia in diabetes.
Neuronal glucose uptake depends on the extracellular concentration of glucose. Glucose crosses the blood–brain barrier through membrane-bound insulin-independent glucose transporter proteins.
The normal intracellular fate of glucose is phosphorylation of the number-6-position carbon and entry into glycolysis, but in hyperglycaemia glucose is diverted to the polyol (sorbitol) metabolic pathway. This causes sorbitol accumulation and inappropriate osmolarity in cells. In addition, intracellular glucose is oxidized to form free radicals and reactive carbonyls, leading to oxidative and nitrosative stress.
Intracellular signalling cascades are also altered in hyperglycaemia. Mitogen-activated protein kinases, including p38 and Jun N-terminal kinase, are activated by high glucose levels and alter cell phenotype.
Non-enzymatic glycation of proteins by glucose causes the formation of advanced glycation end-products (AGEs). These have altered biochemical properties and can induce cellular changes through RAGE receptors.
The functional consequences of hyperglycaemia include nerve conduction abnormalities, pain and allodynia, and impaired axonal regeneration. Early pharmacological intervention in the chain of glucose-triggered adverse events could help to alleviate the symptoms associated with diabetic neuropathy.
Neurons have a constantly high glucose demand, and unlike muscle cells they cannot accommodate episodic glucose uptake under the influence of insulin. Neuronal glucose uptake depends on the extracellular concentration of glucose, and cellular damage can ensue after persistent episodes of hyperglycaemia — a phenomenon referred to as glucose neurotoxicity. This article reviews the pathophysiological manifestation of raised glucose in neurons and how this can explain the major components of diabetic neuropathy.
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We would like to thank Diabetes UK (formerly The British Diabetic Society) for many years of financial support.
- Postprandial state
The state immediately after feeding during which absorption of glucose from the gastrointestinal tract into the blood occurs; this is the time at which plasma glucose concentrations are at their highest and insulin secretion is maximal in healthy individuals.
- Blood–brain barrier
An anatomical and physiological barrier that selectively transfers solutes from the blood to the cerebrospinal fluid; the barrier is formed by tight junctions of cerebral capillary endothelial cells.
- Non-enzymatic glycation
The addition of glucose (or other saccharides) to macromolecules without the need for enzyme catalysis.
- Schiff base
Named after Hugo Schiff, this is a functional group that contains a carbon–nitrogen double bond with the nitrogen atom connected to an aryl or an alkyl group but not to a hydrogen atom.
- Sural nerve
One of the terminal branches of the sciatic nerve. It runs down the lateral aspect of the calf and ankle and supplies the outer part of the foot. It carries mostly sensory fibres.
- Node of Ranvier
An interruption in the myelin sheath that covers axons. Nodes of Ranvier facilitate the propagation of action potentials by saltatory conduction.
Naturally occuring chemical that when given at an appropriate dose, destroys a large fraction of the insulin-secreting cells of the pancreas, causing non-lethal insulin-deficiency diabetes.
- Myelin loops
The terminal folds of the myelin sheath that adhere to the axonal membrane on either side of the node of Ranvier.
Pain that is evoked by normally innocuous stimuli.
An increased pain response to normally noxious stimuli.
An abnormally high concentration of insulin in the blood, usually generated by feedback-driven inadequacy of glucose removal, which is a common result of insulin insensitivity in type II diabetes.
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Cite this article
Tomlinson, D., Gardiner, N. Glucose neurotoxicity. Nat Rev Neurosci 9, 36–45 (2008). https://doi.org/10.1038/nrn2294
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