How does diabetes lead to neuropathy?

From the Guidelines

Diabetes leads to neuropathy primarily through prolonged high blood sugar levels that damage nerves throughout the body, and maintaining good blood glucose control is the most effective way to prevent or slow diabetic neuropathy progression. When blood glucose remains elevated over time, it causes chemical changes in nerves, impairs their ability to transmit signals, and damages the blood vessels that supply oxygen and nutrients to nerves. This damage occurs through several mechanisms: excessive glucose converts to sorbitol and fructose which accumulate in nerves causing swelling and damage; advanced glycation end products form when sugar binds to proteins, interfering with normal nerve function; oxidative stress increases as high glucose levels generate harmful free radicals; and inflammation develops as the immune system responds to nerve damage. Additionally, diabetes reduces blood flow to nerves by damaging small blood vessels. These processes collectively lead to nerve fiber degeneration, resulting in symptoms like numbness, tingling, pain, and weakness, typically beginning in the feet and hands before potentially spreading to other areas.

Key Points to Consider

• The early recognition and appropriate management of neuropathy in people with diabetes is important, as up to 50% of diabetic peripheral neuropathy may be asymptomatic 1.
• Optimizing glucose control can prevent or delay the development of neuropathy in patients with type 1 diabetes and slow the progression of neuropathy in patients with type 2 diabetes 1.
• Assessing and treating patients to reduce pain related to diabetic peripheral neuropathy and symptoms of autonomic neuropathy can improve quality of life 1.
• Gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and sodium channel blockers are recommended as initial pharmacologic treatments for neuropathic pain in diabetes 1.

Recommendations for Practice

• All people with diabetes should be assessed for diabetic peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and at least annually thereafter 1.
• Assessment for distal symmetric polyneuropathy should include a careful history and assessment of either temperature or pinprick sensation and vibration sensation using a 128-Hz tuning fork 1.
• Maintaining good blood glucose control through medication, diet, and exercise is crucial to prevent or slow diabetic neuropathy progression 1.

From the Research

Pathophysiology of Diabetic Neuropathy

Diabetic neuropathy is a common complication of diabetes that affects the quality of life in patients with diabetes, with approximately 60-70% of patients suffering from a distal symmetrical form of mild to severe neuropathy 2. The development and progression of diabetic neuropathy are attributed to several mechanisms, including:

• High glucose and oxidative stress-mediated damage in neurons and glial cells
• Neuroinflammation and crosstalk between these disease processes
• Glucose and lipid imbalances and insulin resistance that are interconnected via oxidative stress, inflammation, and altered gene expression 3
• Polyol pathway, hexosamine pathway, protein kinase C, advanced glycation end product formation, polyADP ribose polymerase, and the role of oxidative stress, inflammation, growth factors and lipid abnormalities 4

Mechanisms of Axon Dysfunction

The neuropathy accompanying type 2 diabetes (insulin resistance) and type 1 diabetes (insulin deficiency) appears to differ in terms of structural changes, with the former showing a milder axonal involvement and segmental myelin breakdown, whereas the latter shows a more severe axonal atrophy and axonal loss 5. The disorder does not only involve somatic peripheral nerves but also autonomic and central nerve tracts.

Key Factors Contributing to Diabetic Neuropathy

Key factors contributing to diabetic neuropathy include:

• Persistent hyperglycemic conditions and malfunctioning glia that drive disease progression 2
• Metabolic causes of diabetic neuropathy, including insulin deficiency and hyperglycemia 5
• Oxidative stress, inflammation, and altered gene expression that contribute to neurovascular dysfunctions 3

Current Understanding and Treatment Options

Despite the current understanding of the pathophysiology of diabetic neuropathy, treatment options for this disorder are still limited, highlighting the need for further studies to identify new molecular and therapeutic targets 2, 3, 4. Current treatment strategies focus on preventative care and pain management, with several drugs confirmed by the FDA for painful diabetic neuropathy, including pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch 6.