**2. Diabetic peripheral neuropathy**

Diabetic peripheral neuropathy (DPN) is the most common long-term complication of diabetes and the primary cause of foot ulcers and lower-extremity amputation. Diabetic peripheral neuropathy has significant impact on the quality of life. It may present with the typical feet involvement to a more wide range of symptoms and signs from myelopathy-like to a myopathy-like symptoms to even death. Diabetic neuropathy affects between 23 and 76% of people [10]. The progression of DPN is related to poor glycemic control, aging, long diabetes duration, visceral obesity, hypertension, smoking, hyperinsulinemia, and dyslipidemia [11]. Improved glycemic control, early detection, and preventive care can avoid adverse outcomes.

DPN is a well-known microvascular complication of type 2 diabetes mellitus resulting from chronic hyperglycemia and defined by a peripheral nerve dysfunction in a diabetic patient after other etiologies have been excluded. Neuropathy develops in about 5–10% of diabetic patients in the first year, and 60–70% of diabetic patients experience some type of diabetic peripheral neuropathy after 20 years of duration of diabetes [12, 13].

#### **2.1 Pathogenetic mechanisms**

Peripheral nerve damage in diabetic peripheral neuropathy is caused by a variety of mechanisms; the most important are oxidative stress, inflammation, and mitochondrial dysfunction. Diabetes activates inflammatory molecules, causing a functional nitric monoxide deficit, activation of alternative metabolic pathways, accumulation of glycation end products, oxidative stress, and inflammation. The expression of pro-inflammatory cytokines including C-reactive protein, TNF-, and IL-6 is higher in people with diabetes. Chronic hyperglycemia causes cytokines to infiltrate vascular tissue, which will reduce the body's ability to heal by its own [14].

Chronic hyperglycemia stimulates macrophages, such as cells secrete TNF-, resulting in an increased of cytokine released. TNF- boosts the expression of endothelial cell adhesion molecules, precipitating atherosclerosis. In patients with poorly regulated diabetes, increased TNF development as a result of hyperglycemia is a factor in exacerbating insulin resistance. The effect of TNF- on Schwann cells also explains local demyelination in peripheral neuropathy [15].

Hyperglycemia primarily affects Schwann cells, resulting in cell damage, altered axon integrity, and impaired growth factor signaling [16–18]. Defective inflammatory pathways in axons and Schwann cells, including advanced glycation end product/receptor (AGE/RAGE) signaling, have been observed in diabetic neuropathy in animal models that lead to nerve damage [19].

Sensory neurodegeneration in the chronic stage of diabetes was linked to early damage to the distal axons of both upper and lower limb neurons in a study involving both human and animal models, revealing a pattern that explains the glove and stocking distribution loss of sensation seen in DPN. These changes are accompanied by widespread defects in electrophysiology and gene expression, all of which contribute to a degenerative phenotype [20]. Existing data about the development of DPN, such as increased oxidative and nitric oxide stress, polyol accumulation, microangiopathy, abnormal AGE-RAGE signaling, and/or mitochondrial dysfunction, account for a variety of mRNA modification that modify miRNA expression patterns, resulting in a wide range of DPN phenotypes.

Endothelial nitric oxide synthase (eNOS) dysfunction can play a key role in the pathogenic pathway that leads to diabetic vascular complications, such as DPN. As a result, eNOS is thought to be a potential cause for DPN progression. Hyperglycemia is associated with defects in the vasa nervorum and nerve fiber loss in the early stages of DPN. The ischemia and hypoxia in the nerves of patients with type 2 diabetes mellitus due to microangiopathy of vasa nervorum have always been observed and possibly a pathogenic mechanism of DPN [21–23].
