Diabetic Peripheral Neuropathy

What is diabetic peripheral neuropathy (DPN)?

Diabetic peripheral neuropathy (DPN) is a type of nerve damage that occurs in individuals with diabetes mellitus. It is one of the most common complications of diabetes and affects the nerves that extend from the brain and spinal cord to the limbs, particularly the legs and feet. DPN typically develops gradually over time, and symptoms may vary widely in severity and presentation.

 

The exact cause of diabetic peripheral neuropathy is not fully understood, but it is thought to involve a combination of metabolic, vascular, and neurotrophic factors associated with diabetes. Chronic hyperglycemia (high blood sugar levels) is considered a primary contributing factor to nerve damage in diabetes.

 

What is the relationship between DPN and oxidative stress?

The relationship between diabetic peripheral neuropathy (DPN) and oxidative stress is well-established, and oxidative stress is considered one of the key mechanisms underlying the development and progression of neuropathic complications in diabetes. Oxidative stress occurs when there’s an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to neutralize them with antioxidants.

 

Several factors contribute to oxidative stress in diabetic peripheral neuropathy:

 

• Hyperglycemia: Chronic hyperglycemia (high blood sugar levels) is a primary contributor to oxidative stress in diabetes. Elevated glucose levels can lead to increased production of ROS through various pathways, including glucose auto-oxidation, advanced glycation end products (AGEs) formation, and activation of protein kinase C (PKC). Excessive ROS production damages nerve cells and impairs nerve function, contributing to the development of DPN.

 

• Mitochondrial Dysfunction: Mitochondria are the primary source of ROS production in cells and play a crucial role in cellular energy metabolism. Dysfunction of mitochondria, such as impaired electron transport chain function or reduced antioxidant defenses, can lead to increased ROS generation and oxidative stress. Mitochondrial dysfunction is implicated in the pathogenesis of DPN and contributes to nerve damage and dysfunction.

 

• Inflammation: Chronic low-grade inflammation is a hallmark of diabetic neuropathy and contributes to oxidative stress. Inflammatory mediators, such as cytokines and chemokines, activate immune cells and stimulate the production of ROS as part of the immune response. In turn, ROS can further activate inflammatory signaling pathways, creating a positive feedback loop that exacerbates tissue damage and inflammation in the nerves.

 

• Polyol Pathway Activation: The polyol pathway is a metabolic pathway that converts glucose to sorbitol and fructose in nerve cells. In diabetes, increased flux through the polyol pathway leads to the accumulation of sorbitol, which depletes cellular NADPH and impairs the regeneration of reduced glutathione (GSH), a key antioxidant. This results in increased susceptibility to oxidative stress and nerve damage in DPN.

 

• Advanced Glycation End Products (AGEs): AGEs are formed through non-enzymatic reactions between sugars and proteins in the presence of elevated glucose levels. AGEs can cross-link and modify proteins in nerve cells, leading to impaired nerve function and increased susceptibility to oxidative stress. AGE-mediated mechanisms contribute to the pathogenesis of DPN.

 

Overall, oxidative stress plays a significant role in the pathogenesis and progression of diabetic peripheral neuropathy by contributing to nerve damage, dysfunction, and degeneration.