Potential mechanisms linking metabolic, vascular, and neural defects in diabetic neuropathy

Initiator	Metabolic defect	Metabolic mediator	Functional mediator	Consequence
↑ Glucose	Glycation/AGE	Protein cross-linking	Matrix defects	Endoneurial fibrosis ↓ Neurotrophic SAM
		Protein inactivation	Receptor-ligand defects	↓ Neurotrophism
		NO quenching	Vasoconstriction	Ischemia/hypoxia
		Macrophage activation	Cytokines, ↑ TGF	Cytotoxicity* Endoneurial fibrosis
		Free radical formation	Oxidative stress	Cytotoxicity
	Autooxidation	Free radical formation	Oxidative stress	Cytotoxicity*
	↑ Sorbitol pathway	↓ NADPH	Oxidative stress ↓ NO synthesis	Cytotoxicity* Ischemia/hypoxia
		NADH/lactate	Pseudohypoxia	Cytotoxicity*
		↑ Glycation	(See above)	(See above)
		↓ Taurine	Oxidative stress	Cytotoxicity*
		↓ MI/↓ PI/↓ PKC	Signal transduction Eicosanoid defects	↓ Neurotrophism Ischemia/hypoxia
	↑ DAG	↑ PKC	Signal transduction	Ischemia
FA defects	↑ Free FA	↑ Long-chain acyl-Co's	Mitochondrial defects	Cytotoxicity
FA defects	↓ 3-β-dehydrog	↓ GLA	Eicosanoid defects	Ischemia/hypoxia
↓ Insulin	?↓ GF expression	?IGF/NGF/BDNF/NT3	Neurotrophic factors	↓ Neurotrophism

AGE: advanced glycosylation end-products; BDNF: brain-derived neurotrophic factor; DAG: diacylglycerol; FA: fatty acid; GLA: gamma linoleic acid; IGF: insulin-like growth factors; MI: myoinositol; NO: nitric oxide; PI: phosphoinositide; PKC: protein kinase C; NT3: neurotrophin-3; SAM: substrate adhesion molecules; TGF: transforming growth factor.
* Cytotoxicity of neural, glial, and vascular components of peripheral nerve.

Adapted from: Stevens MJ, Feldman EL, Greene DA. The aetiology of diabetic neuropathy: the combined roles of metabolic and vascular defects. Diabet Med 1995; 12:566.

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