|PathophysiologyThe factors leading to the development of peripheral neuropathy in diabetes are not understood completely, and multiple hypotheses have been advanced. It is generally accepted to be a multifactorial process. Important contributing biochemical mechanisms in the development of the more common symmetrical forms of diabetic polyneuropathy likely include the following:Polyol pathway
• Hyperglycemia causes increased levels of intracellular glucose in nerves
• Leads to saturation of the normal glycolytic pathway.
• Extra glucose is shunted into the polyol pathway
• Converted to sorbitol (sugar alcohol) and fructose by the enzymes aldose reductase and sorbitol dehydrogenase.
• Accumulation of sorbitol and fructose
• Lead to reduced nerve myo-inositol, (An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction.)
• Leads to decreased membrane Na+/K+ -ATPase activity, impaired axonal transport, and structural breakdown of nerves, causing abnormal action potential propagation.
• This is the rationale for the use of aldose reductase inhibitors to improve nerve conduction.4
While most cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney, and nervous tissues are insulin-independent, so glucose moves freely across the cell membrane, regardless of the action of insulin. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway.
Advanced glycation end products (AGE)
The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advance glycation end products that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport.5
The increased production of free radicals in diabetes may be detrimental via several mechanisms that are not fully understood. These include direct damage to blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the incomplete understanding of these processes, use of the antioxidant alpha lipoic acid may hold promise for improving neuropathic symptoms.
Main Pathologic features of diabetic neuropathy.
• Loss of myelinated and unmyelinated fibers.
• Myelinated nerve fiber loss may be diffuse or patchy.
• Clusters of regenerating fibers may be abundant.
• Thickening of endoneurial blood vessels.
• Increased durability and rigidity of Schwann cell basal laminae.
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