DPN is considered a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvascular alterations due to chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates (13, 19). A simpler definition for clinical practice can be ‘the presence of symptoms and/or signs of neuropathy that develops in the context of prediabetes or diabetes after the exclusion of other causes of peripheral neuropathy (20–22).

DPN progresses gradually with increasing duration of diabetes and in relation to glycemic control in both T1D and T2D (23, 24). Notably, while the prevalence of DPN is considered to be rather low within the first five years of disease onset in T1D, slowing of nerve conduction velocity may be one of the earliest neuropathic abnormalities in T2D, often present at diagnosis (23, 24). Hence, DPN should be suspected in all patients with prediabetes and T2D and those who have had T1D for more than five years (24, 25).

Although the exact pathophysiology of DPN remains unknown, the role of various signaling cascades has been proposed such as advanced glycation end-product (AGE) pathway, polyol pathway, protein kinase C (PKC) pathway, hexosamine pathway and poly (ADP ribose) polymerase (PARP) pathway (9, 26–29). Endothelial health is compromised by multiple factors such as glycosylation, hyperlipidemias, hyperhomocysteinemia, hypertension, excessive platelet activity, reduced nitric oxide and excessive generation of reactive oxygen species (ROS) (30, 31).

Nonetheless, chronic hyperglycemia is the main underlying cause of DPN, which leads to damage at the vascular level and the free passage of glucose to neurons and Schwann cells, resulting in an imbalance between nerve damage and nerve fiber repair (20, 32). All the proposed pathways in pathogenesis are activated with hyperglycemia, and they can directly or indirectly impair the redox capacity of the cell and increase the production of ROS (9, 26–29). With the accumulation of ROS (oxygen free radicals such as superoxide anion radical and hydroxyl radical), the endogenous antioxidant defense system (i.e., superoxide dismutase, catalase, glutathione ascorbate) fails to counteract ROS generation, resulting in an increase in oxidative stress (28, 33). The increased oxidative stress leads to impaired neural function, gradually heading to apoptosis in neurons and supporting glial cells (i.e., Schwann cells and satellite glial cells) of the peripheral nervous system (9, 26–29).

The causes of DPN are thought to be a multi-factorial metabolic process that increasingly deteriorates tissues. Hyperglycemia, increased sorbitol and protein kinase C, elevated homocysteine, reduced nitric oxide and excessive Reactive Oxygen Species (ROS) damage endothelial tissue and produce a rheological change that increases vascular resistance and reduces blood flow to the nerve

Diabetes is the strongest risk factor for DPN, along with certain disease characteristics such as diabetes duration and poor glycemic control in terms of fasting blood glucose (FBG), glycated hemoglobin (HbA1c; >7%), postprandial hyperglycemia and the glycemic variability (4, 7, 25, 34–39). Poor glycemic control is the most critical and principal modifiable risk factor for DPN (4, 5, 7, 25). Presence of symptoms and/or signs of distal symmetric polyneuropathy have also been reported in prediabetes although prevalence is variable among studies (40–42). A growing body of evidence supports an association between prediabetes and early small-fiber symptoms and the likelihood of neuropathy to be already developed in the prediabetic stage (7, 12). Given the stronger association of neuropathy with impaired glucose tolerance (IGT) rather than the impaired fasting glucose (IFG), post-load hyperglycemia seems to be the key mechanism for inducing increased oxidative stress, endothelial dysfunction, and activation of both PKC and the polyol pathway, leading to impaired neuronal metabolism and DNA damage in prediabetic stage (37, 43).

Other risk factors increasing the prevalence of DPN include the non-modifiable risk factors such as older age (>50 years), height (directly related to the length of the axon), female gender (particularly for painful DPN), comorbid diabetic retinopathy/nephropathy and positive HLA-DR3/4 genotype, and the modifiable risk factors including the hypertension, dyslipidemia, smoking, alcohol use, obesity, and vitamin D deficiency, vitamin B12 deficiency and low C-peptide levels (4, 7, 25, 32–37, 44–49) ( Table 1 ). The recognition of risk factors is of critical importance in the timely identification of subclinical/early DPN for effective disease control and prevention of hazards (i.e., ulcer, gangrene, and amputation) and social burden (2, 32, 50).

DPN usually manifests as a length-dependent, distal-symmetrical, sensorimotor polyneuropathy (22, 51). Its onset is generally insidious, and the course is chronic and progressive without treatment (23). Symptoms at presentation can be either “positive”, including neuropathic pain (described as deep aching, burning, and sharp stabbing sensations), paresthesia and hyperesthesia, or “negative”, including loss of sensations (hypoesthesia), including different sensory modalities relating to small fiber (temperature, pain) and large fiber (touch, pressure, vibration, position) functions and ataxic gait (6, 20, 22, 52, 53).

Alternatively, some patients may be completely asymptomatic, and signs may be only revealed by a detailed neurological examination (6, 22, 23), while some others may present with rare, atypical diabetic neuropathies with distinct features and underlying mechanisms, as well as with neuropathies attributed to causes other than diabetes (6, 54).

In accordance with the higher vulnerability of lower-limb long axons to injury, DPN usually develops first in the feet and then progresses proximally involving the upper limbs (dying-back type of axonal degeneration), and patients typically present with a “stocking-glove” like distribution of neuronal dysfunction (20, 22, 51).

Overall, up to 50% of affected subjects do not report symptoms, and up to one fourth of patients develop painful DPN which is particularly associated with physical and psychosocial impairment, disability, and reduced health-related quality of life (20–22, 24, 25, 55).

Most patients show a “mixed” neuropathy with both large and small nerve fiber damage and all patients with DPN are considered to be at increased risk of neuropathic complications such as foot ulceration and Charcot’s neuroarthropathy as well as the falls and fractures (20, 23–25).

Despite its major impact on morbidity and mortality, DPN is frequently underdiagnosed and underestimated in clinical practice (22, 23, 56, 57). The factors considered responsible for the challenges in recognition and timely diagnosis of DPN include:

DPN is a diagnosis by exclusion, and its recognition is mainly based on clinical suspicion and the effort put into finding it (22, 23). However, there is insufficient physician awareness regarding the recognition of DPN, even when the neuropathy is symptomatic (22, 23, 30, 57, 58). The population-based studies reported that painful DPN and painless DPN were previously undiagnosed in almost 60% and 80% of T2D patients, respectively (59–61).

The current practice of DPN care is also considered inadequate in terms of patient journey which includes multiple visits to different clinicians having no specialist training to assess the level of risk, to provide advice, or to appropriately refer the patients for further investigation and appropriate interventions (62, 63).

Accordingly, the participating experts consider the suspicion of the disease by clinicians as the key factor, emphasizing the awareness of the disease during the patient journey by the first-admission or referring physicians. In this regard, improved awareness of DPN among internal medicine, family medicine and physical medicine and rehabilitation specialists besides the neurology and endocrinology specialists as the most consulted specialists, seems to be the key factor in consideration of DPN in differential diagnosis of patients presenting with suspected neuropathic symptoms. Increase in familiarity of non-specialist physicians with recognition of DPN seems also important to reduce the unnecessary referrals among several different specialists before a correct diagnosis is reached.

DPN is considered to appear in approximately half of all diabetic individuals at some stage in their lives, emphasizing the utility of screening in early diagnosis of DPN (9, 64). Data from the MONICA/KORA Augsburg Surveys from Germany revealed the varying prevalence of DPN and painful DPN across the spectrum of diabetes, pre-diabetic states and normoglycemia, including known diabetes (28% and 13%, respectively), IGT (13% and 9%), IFG (11% and 4%) and normal glucose tolerance (NGT; 7% and 1%) (40, 65).

In a multicenter study with 1,113 diabetic patients from Turkey, the prevalence of DPN was found to be 40.4% based on the clinical examination alone and increased to 62.2% by combining nerve conduction studies with clinical examination, while the neuropathic pain prevalence was 14.0% (66). In another study from Turkey in 100 newly diagnosed prediabetic individuals who were screened for microvascular and macrovascular diabetic complications, microvascular complications were found in 12% of the participants (neuropathy: 4%, nephropathy: 8%) and 19% had macrovascular complications (67).

Accordingly, given the accumulating evidence on the increasing risk of DPN in patients with prediabetes and with the duration of the disease in those with known diabetes (40, 65, 68), early screening for DPN in the setting of prediabetes and diabetes is important to prevent and delay the occurrence of DPN (20, 22, 34). Screening for early detection and subsequent follow-up of progression is also important given that DPN is already well-established by the time its symptoms and/or clinical signs develop, impeding the benefits of intensified multifactorial intervention at an early stage of disease trajectory (3, 63, 69, 70).

The newly updated “American Diabetes Association (ADA) Standard of Care in Diabetes 2024” for Neuropathy Screening Guidelines states that patients with T2D at the time of diagnosis and those with T1D five years after diagnosis should be evaluated for DPN by obtaining a careful medical history and physical examination (sensory assessment and foot examination), and subsequently they should be evaluated every year (71).

In addition, given the likely association between different microvascular complications, as well as between micro and macrovascular complications of diabetes, when a patient is diagnosed to have one diabetes complication, it is important to screen for others (72, 73).

Clinical history and examination are the mainstays of clinical diagnosis, and when medical history and basic neurological examination (simple semi-quantitative bedside instruments and inspection of feet) reveals the corresponding neuropathic symptoms and/or signs in the absence of other potential causes of distal symmetric peripheral neuropathy, this supports the diagnosis of DPN (4, 6, 7, 23, 74).

Accordingly, in most cases, the diagnosis of DPN is made by ruling out other potential causes of distal symmetric peripheral neuropathy, such as alcohol use, nutritional deficiencies (i.e., vitamins B6, B12, and E, thiamine, folate, copper, phosphate), hypothyroidism/hyperthyroidism, autoimmune diseases (i.e., systemic lupus erythematosus, rheumatoid arthritis), malignancy (i.e., multiple myeloma), infections (HIV/AIDS, Lyme disease), chemotherapy and toxin exposure (4, 11, 20, 49, 72). This necessitates a careful medical history and a screening laboratory test for complete blood count, comprehensive metabolic profile, fasting blood glucose, thyroid-stimulating hormone, and vitamin B12 levels, as well as the serum protein electrophoresis with immunofixation to exclude other causes of peripheral neuropathy (6, 20, 22, 25, 56, 63, 75, 76).

Neuropathic symptoms include the pain (characteristically described as burning, painful cold, lancinating, tingling, stabbing or shooting) and the non-painful neuropathic symptoms such as paresthesias (tingling, prickling or ant-like sensations), dysesthesias (unpleasant abnormal sensation whether spontaneous or evoked), sensory ataxia (ataxic gait) or numbness (often described as “wrapped in wool” or like “walking on thick socks”) (20, 22) ( Table 2 ; Figure 1 ).

Neuropathic signs detected on basic neurological examination including bedside sensory tests and foot inspection include (a) sensory deficit in large nerve fiber (via 128 Hz tuning fork for vibration sensation, 1 and 10 g monofilament for pressure sensation and wisp of cotton for light touch sensation), (b) sensory deficit in small nerve fiber (via neurotips for pain-pinprick sensation) and cold tuning fork for cold sensation), (c) allodynia (pain triggered by normally non-painful stimuli such as the contact of socks, shoes, or bedclothes), (d) hyperalgesia (exaggerated response to painful stimuli), (e) motor weakness (extension of the big toe, ankle dorsiflexion, and walking on heels), (f) absence of reflexes (ankle and patellar deep tendon reflexes), (g) balance and fall risk (Romberg test, normal gait, and tandem gait), and (h) inspection of feet (for deformities, ulcers, fungal infection, muscle wasting, hair distribution or loss, and the presence or absence of pulses) (20, 22, 23) ( Table 2 ; Figure 1 ).

Small and large nerve fiber damage most frequently coexist in DPN, and thus testing small and large nerve fiber function with appropriate semi-quantitative bedside tests is equally important (22, 51). In the painful DPN, intensity of pain is evaluated via numeric rating scale [NRS] or a visual analogue scale [VAS]), while the pain typically worsens at night and may interfere with daily activities and reduce the quality of life and sleep and characteristics (20, 22, 23).

The ADA definition does not require an abnormal electrodiagnostic test for clinical neuropathy diagnosis, as also supported by studies indicating that electrodiagnostic tests rarely change the etiology and/or management of patients meeting a clinical DPN definition (3, 77, 78). However, when evaluating a person with diabetes and signs and/or symptoms of neuropathy, it is important to remember that DPN is not the only possible cause of these signs and/or symptoms and that rare diabetic neuropathies or even neuropathies of other etiologies may be present (6, 24). Hence, the confirmatory testing (detailed neurological work-up) is not usually needed for clinical diagnosis but is used in clinical research and is helpful in the diagnosis of patients with atypical presentations (6, 7). These tests include the large fiber nerve injury tests (electrodiagnostic tests: nerve conduction tests and electromyography) and the small fiber nerve injury (intraepidermal nerve fiber density) (6, 7, 74) ( Figure 1 ).

The atypical presentations that should alert the physician to consider non-diabetic causes of neuropathy via referral for a detailed neurological work-up (confirmatory tests) include: (1) asymmetry and rapid progression of the symptoms, (2) predominant motor weakness over sensory loss, (3) mononeuropathy or cranial nerve involvement, (4) progression of the neuropathy despite optimal glycemic control, (5) symptoms from the upper limbs, (6) family history of nondiabetic neuropathy, (7) severe painful symptoms in the feet whilst clinical examination is normal, 8) diagnosis of DPN cannot be ascertained by clinical examination with the semi-quantitative bedside tests (6–8, 20, 22, 74) ( Figure 1 ).

Accordingly, the present expert panel suggests that DPN should be considered in a patient with prediabetes or diabetes who presents with neuropathic symptoms (involve both sides symmetrically) and/or signs of neuropathy in the presence of DPN risk factors (i.e., advancing age, obesity, hypertension, dyslipidemia, poor glycemic control), with careful consideration of laboratory testing to rule out other causes of distal symmetric peripheral neuropathy and referral for a detailed neurological work-up for a confirmative test of either small or large nerve fiber dysfunction only in atypical cases. The proposed “screening and diagnostic” algorithm is provided in Figure 1 .

Upstream inhibition of key glycolytic enzymes by oxidative stress activates major pathways (polyol, hexosamine, PKC, PARP and AGE) implicated in the development of DPN (22, 128). Ideally, a targeted intervention is expected to address the underlying pathogenetic mechanisms and to alter the natural trajectory of the disease (97). Several compounds are available which target these major pathways implicated in the pathogenesis of DPN, such as aldose reductase inhibitors (sorbinil, tolrestat, ponalrestat, fidarestat, epalrestat, zenarestat) acting on polyol pathway, PKC inhibitors (ruboxiastaurin), benfotiamine acting on hexosamine pathway, agents acting on AGE pathway (minocycline, aminoguanidine), actovegin acting as PARP inhibitor and ROS inhibitors (alpha-lipoic acid, coenzyme Q10, nicotinamide, resveratrol, taurine) (52, 128).

Amongst them, alpha-lipoic acid (ALA) has a special place in the current DPN treatment paradigm, given that it is licensed as a drug for the treatment of DPN in many countries. Thus, its unique and wide-range antioxidant effects as a favorable agent aimed at the pathogenesis of DPN have been extensively investigated in countries where ALA is widely used, such as Germany, Eastern Europe and Far East (28, 31, 52, 99, 129).