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Health Protocols

Neuropathy (Diabetic)

Mechanisms Involved in the Development of Diabetic Neuropathy

The development and progression of diabetic neuropathy is complex. There are a number of metabolic, vascular, and hormonal mechanisms involved (Feldman 2012b).


One key factor involved in the development and progression of diabetic neuropathy is increased glycation, a process in which glucose and other sugars interact with proteins. Glycation causes proteins throughout the body to become dysfunctional. The dysfunctional molecules created by glycation are termed advanced glycation end products (AGEs) (Sugiyama 1996; Ahmed 2007; Sugimoto 2008).

Because people with diabetes have elevated blood glucose levels, they usually also have higher levels of AGEs. These glycation end products have the capacity to destroy cells or disrupt function in many tissues, including nerves (Brownlee 2001; Feldman 2012b; Morales-Vidal 2012). The damage done to nerves by glycation occurs via two different mechanisms. First, the glycation of nerve proteins inhibits their function, which directly affects nerve activity. Second, AGEs can bind to the surfaces of nerve cells and trigger an inflammatory response, further damaging the neurons (Vincent 2011). Increased levels of reactive oxygen species also contribute to the formation of AGEs (Brownlee 2001).


Inflammation also plays a critical role in diabetic neuropathy, as people with both type 1 and type 2 diabetes have higher levels of C-reactive protein and tumor necrosis factor-alpha (TNF-α), which are two chemicals involved in the inflammatory response. Higher levels of TNF-α are associated with diabetic neuropathy (Edwards 2008; Gonzalez-Clemente 2005). All of these different pro-inflammatory chemicals lead to the presence of an increased number of immune cells, called macrophages, around the nerves. These macrophages contribute to neuropathy by several mechanisms, including the production of reactive oxygen species and enzymes that break down myelin, which is a protein that forms a protective coating around nerves (Edwards 2008).

Vascular Dysfunction

Elevated blood glucose levels also cause vascular dysfunction, leading to circulatory problems. High glucose levels activate a protein called protein kinase C, which triggers the constriction of blood vessels; these constricted blood vessels lead to reduced blood flow to neurons (Evcimen 2007; Brownlee 2001; Feldman 2012b). Blood vessels are also damaged by AGEs, further disrupting blood flow (Ahmed 2005; Halushka 2009). This impaired blood flow to neurons deprives them of oxygen, also known as ischemia. Oxygen deprivation can damage and destroy neurons. 

Types of Diabetic Neuropathy

There are multiple types of diabetic neuropathy. The most common form, peripheral neuropathy, tends to affect sensory nerves, and can either cause pain or lack of sensation. A second form is autonomic neuropathy, in which the nerves that govern many involuntary bodily functions, such as digestion, perspiration, heart rate, and blood pressure control are damaged. Proximal neuropathy (also known as lumbosacral radioplexus neurophagy or diabetic amyotrophy) affects the lower body and can cause pain and weakness, usually in the thighs, hips, or buttocks. Focal neuropathy and mononeuropathy affect a specific nerve causing weakness and/or pain to the area supplied by that nerve or signs and symptoms that are characteristic for the nerve affected (Callaghan 2012b; Tesfaye 2010; American Diabetes Association 2013; Merck Manual 2013).

Peripheral neuropathy is the most common form of diabetic neuropathy and the best characterized. Peripheral neuropathy typically affects the hands and feet first, as these are the areas with the longest peripheral nerves, followed by the legs and arms (Callaghan 2012a; Edwards 2008; Mayo Clinic 2012; Morales-Vidal 2012). The neuropathy can affect both large fiber nerves, which transmit information about light touch and pressure sensations, vibration, and body position, as well as small fibers, which transmit information regarding pain and temperature (Bansal 2006; Vinik 2006). Small fibers are more frequently affected than large fibers (Hsieh 2010).