**2.1 Diabetic peripheral neuropathy**

Diabetic peripheral neuropathy (DPN) is considered the cardinal driving force to developing DFU. It is a condition where nerves in the limbs (lower limbs in the case of DFU) are damaged by a variety of conditions such as inflammation, oxidative stress, advanced glycated end-products and a decrease in nitric oxide production [24–26]. The nerve damage renders the diabetic feet insensitive to harmful stimuli such as trauma from stepping on a hot or sharp object or skin injury from wearing ill-fitted shoes. It is reported that over 60% of foot ulcers among the diabetic population is directly linked to the development of DPN [24–26]. An increased activity of aldose reductase and sorbitol dehydrogenase (enzymes involved in the alternate metabolism of glucose under hyperglycemic conditions) leads to the accumulation of sorbitol and fructose [27]. High concentrations of these sugars negatively impact the levels of myoinositol, a carbocyclic sugar that mediates cell signal transduction in response to neurotransmitter and hormones [28, 29]. In DPN, there is reduced nerve innervation of small muscles of the foot as well as a decline in peripheral sensation and vasomotor control of the pedal

## *Association between Diabetic Kidney Disease and Diabetic Foot Ulceration DOI: http://dx.doi.org/10.5772/intechopen.107825*

circulation. This leads to development of wounds in these patients, which progress to ulcers that go unnoticed until observed by someone else [30].

Diabetes mellitus also promotes skin fissuring and dryness (reduced sweating), a situation which makes the skin prone to infections (due to the cracks in the skin acting as a potential portal for entry of bacteria) and poses as a risk factor in the expansion and worsening of DFU [31, 32].

DPN may reduce the production of neuropeptides such as substance P, calcitonin gene-related peptide and nerve growth factor, as these neuropeptides are important for wound healing [33–35]. These changes aid the progression of wounds and ulcers to gangrenes, coupled untimely management (with pharmacological or surgical intervention) ultimately leads to the loss of a limb. Also, the lack of pain sensation exposes the feet of diabetic patients with sensory neuropathy to repeated unnoticed trauma. It is important to note that the lack of pain sensation and impaired temperature sensation, both being components of sensory neuropathy, can make the instant withdrawal of a foot from harmful objects or hot liquid impossible [36, 37]. This creates an ulcer which may become chronic due to constant exposure to obnoxious stimuli. Furthermore, repeated pressure at focal point within the foot leads to the development of foot ulcers. This is partly linked to flexor extension imbalance and muscle atrophy, which develops in some diabetic patients, causing unequal distribution pressure and prominence of the diabetic foot [38, 39]. Thus, DPN creates repeated and unequal distribution pressure in the feet of diabetic patients, leading to development of DFU.
