What are the primary mechanisms of nerve damage due to hyperglycemia?

From the Guidelines

Hyperglycemia damages nerves primarily through four interconnected mechanisms, including the polyol pathway, advanced glycation end products, protein kinase C activation, and increased hexosamine pathway activity, which collectively cause mitochondrial dysfunction, inflammation, reduced blood flow to nerves, and direct damage to nerve fibers. The primary mechanisms of nerve damage due to hyperglycemia can be broken down into the following key points:

• Excess glucose enters the polyol pathway, where it's converted to sorbitol and fructose, depleting NADPH and glutathione, which leads to oxidative stress and nerve damage 1
• Hyperglycemia causes formation of advanced glycation end products (AGEs) that modify proteins and lipids, impairing nerve function and triggering inflammatory responses 1
• Hyperglycemia activates protein kinase C, altering signaling pathways and reducing nerve blood flow
• Increased hexosamine pathway activity leads to abnormal protein modifications that disrupt nerve cell function These mechanisms are supported by studies that demonstrate the importance of maintaining tight glycemic control to prevent and limit nerve damage, as these biochemical pathways become increasingly active when blood glucose levels remain chronically elevated 1. The damage typically begins in the longest nerves (those in the feet and legs), explaining why peripheral neuropathy often presents first as distal sensory loss. Some key points to consider in the context of nerve damage due to hyperglycemia include:
• The role of small fibre neuropathy in the diagnosis of diabetic sensorimotor polyneuropathy 1
• The importance of quantifying intraepidermal nerve fibre density in skin biopsies and corneal nerve morphology using corneal confocal microscopy to assess small fibre dysfunction 1
• The need for early intervention to prevent and limit nerve damage, as IENF loss is an early feature of diabetes and progresses with increasing neuropathic severity 1

From the Research

Mechanisms of Nerve Damage due to Hyperglycemia

The primary mechanisms of nerve damage due to hyperglycemia are complex and multifactorial. Some of the key mechanisms include:

• The polyol pathway, which is activated in response to high blood sugar levels and can lead to the accumulation of toxic metabolites in nerve cells 2
• The formation of advanced glycation end-products (AGEs), which can damage nerve cells and disrupt their function 3, 4
• The activation of protein kinase C, which can lead to the activation of various pro-inflammatory pathways and contribute to nerve damage 2, 5
• Oxidative stress and inflammation, which can damage nerve cells and disrupt their function 2, 5
• The disruption of growth factors and lipid metabolism, which can contribute to nerve damage and dysfunction 2

Role of Advanced Glycation End-Products

Advanced glycation end-products (AGEs) play a key role in the development of diabetic neuropathy. AGEs can:

• Damage nerve cells and disrupt their function 3, 4
• Activate the receptor for AGEs (RAGE), leading to the activation of pro-inflammatory pathways and the production of reactive oxygen species 3, 4
• Contribute to the development of microangiopathy in the peripheral nerve 4

Other Mechanisms

Other mechanisms that may contribute to nerve damage due to hyperglycemia include:

• The disruption of axonal transport and the degradation of axonal cytoskeletal proteins 3
• The impairment of regenerative activity in diabetic neuropathy 3
• The involvement of cellular factors derived from the bone marrow in the development of peripheral nerve pathology 5