Polineuropatia Diabetica, Pasado, Presente y Futuro

Caspian Journal of Internal Medicine 2023 (Spring); 14(2): 153-169
DOI: 10.22088/cjim.14.2.153
Narrative Review
Diabetic neuropathy: Past, present, and future

Juan Quiroz-Aldave (MD) 1
María Durand-Vásquez (MD) 2 Abstract
Elman Gamarra-Osorio (MD) 3 Background: A sedentary lifestyle and an unhealthy diet have considerably increased the
Jacsel Suarez-Rojas (MD) 4 incidence of diabetes mellitus worldwide in recent decades, which has generated a high rate
Pela Jantine Roseboom (MD) 5
of associated chronic complications.
Rosa Alcalá-Mendoza (MD) 6
Julia Coronado-Arroyo (MD) 7
Methods: A narrative review was performed in MEDLINE, EMBASES and SciELO
Francisca Zavaleta-Gutiérrez (PhD) 8 databases, including 162 articles.
Luis Concepción-Urteaga (PhD) 9 Results: Diabetic neuropathy (DN) is the most common of these complications, mainly
Marcio Concepción-Zavaleta (MD) 10 * producing two types of involvement: sensorimotor neuropathy, whose most common form
is symmetric distal polyneuropathy, and autonomic neuropathies, affecting the
cardiovascular, gastrointestinal, and urogenital system. Although hyperglycemia is the main
1. Division of Medicine, Hospital de
Apoyo Chepén, Chepén, Peru
metabolic alteration involved in its genesis, the presents of obesity, dyslipidemia, arterial
2. Division of Family Medicine. hypertension, and smoking, play an additional role in its appearance. In the pathophysiology,
Hospital de Apoyo Chepén, Chepén, three main phenomena stand out: oxidative stress, the formation of advanced glycosylation
Peru end-products, and microvasculature damage. Diagnosis is clinical, and it is recommended to
3. Division of Endocrinology, Hospital use a 10 g monofilament and a 128 Hz tuning fork as screening tools. Glycemic control and
Víctor Lazarte Echegaray, Trujillo, Peru
non-pharmacological interventions constitute the mainstay of DN treatment, although there
4. Universidad Científica del Sur, Lima,
Peru
are currently investigations in antioxidant therapies, in addition to pain management.
5. Division of Emergency Medicine, Conclusions: Diabetes mellitus causes damage to peripheral nerves, being the most common
Hospital Regional Docente de Trujillo, form of this, distal symmetric polyneuropathy. Control of glycemia and comorbidities
Trujillo, Peru contribute to prevent, postpone, and reduce its severity. Pharmacological interventions are
6. Division of Physical Medicine and intended to relieve pain.
Rehabilitation, Hospital Víctor Lazarte
Keywords: Diabetic Neuropathy, Diabetes Mellitus, Complication, Treatment, Glycemic
Echegaray, Trujillo, Peru
7. Division of Obstetrics and
Control, HbA1c
Gynecology, Hospital Nacional Edgardo
Rebagliati Martins, Lima, Peru Citation:
8. Division of Neonatology, Hospital Quiroz-Aldave J, Durand-Vásquez M, Gamarra-Osorio E, et al. Diabetic neuropathy. Past,
Belén de Trujillo, Trujillo, Peru present, and future. Caspian J Intern Med 2023; 14(2): 153-169.
9. School of Medicine, Universidad
Nacional de Trujillo, Trujillo, Peru
10. Division of Endocrinology, Hospital
Jorge Voto Bernales, Lima, Peru F rom the ancient age in which observations on DN began until the present, there has
been notable progress in the description of this pathology and the understanding of its
underlying pathological mechanisms and treatments. Based on Skljarevski (1) and Boulton
* Correspondence: (2) Figure 1 depicts diabetic neuropathy historically, up to the present. Last decades, the
Marcio Concepción-Zavaleta,
acquisition of inadequate lifestyles has caused a large increase worldwide in components of
Division of Endocrinology,
Hospital Jorge Voto Bernales, the metabolic syndrome, including diabetes mellitus (DM) (3–5). The combination of
Lima, Peru genetic susceptibility and other factors such as a sedentary lifestyle and overeating are
responsible for the appearance of DM. Prevention of the development of DM and its
E-mail: complications is essential to reduce the high morbidity and mortality it causes (4, 6, 7).
[email protected] Neuropathy as a complication of DM is associated with large social and health costs, in
Tel: +51951223318
addition to a decrease in the quality of life (8–11). About half of the cases of neuropathy are
secondary to DM (12). Diabetic neuropathy (DN) affects 30-50% of people with DM. The
Received: 27 June 2022 prevalence of DN in newly diagnosed diabetics is 8%, reaching more than 50% in those with
Revised: 3 Aug 2022 long-standing DM (10, 13-16).
Accepted: 6 Sep 2022
© The Author(s) Publisher: Babol University of Medical Sciences
154 Quiroz-Aldave J, et al.
It is interesting that, although the incidence of neuropathy density lipoproteins) are also associated with DN in patients
in people with type 2 DM (T2DM) is higher than in those with with T2DM and in some patients with T1DM (24, 25, 30).
type 1 DM (T1DM), its prevalence is similar, which is Other risk factors involved are smoking, alcoholism, tall
probably due to differences in age of onset and its stature, and advanced age (31). The role of genetics in the
pathophysiology (17–22). DM is the main risk factor involved development of DN is not yet fully understood, so more
in the genesis of neuropathy, and its main predictors are the research is required for future applications (32). The goal of
duration of DM and hemoglobin A1C (HbA1c) levels (22). this review is to describe the pathophysiology, clinical
Several epidemiological studies have shown that obesity is the manifestations, diagnosis, and treatment of DN, and mention
second most important risk factor for the development of DN the current advances and future perspectives on its
(23–29). The other components of the metabolic syndrome management.
(hypertriglyceridemia, hypertension, and low levels of high-
Figure 1. Diabetic neuropathy research timeline
Methods were included. The investigation was limited to articles

Search strategy: MEDLINE, EMBASES and SciELO related to human beings, so that exclusion criteria were non-
Electronic databases were searched for completed studies of human studies. Case reports, case series, letters to the editor
any design except case reports, case series, letters to the editor, and conference proceedings were also excluded.
and conference proceedings from database inception between Screening: Identified citations were exported to Endnote. A
2005 and 2022. The Medical Subject Heading (MeSH) used total of 16873 citations were identified; 2105 duplicates were
was "diabetic neuropathies" and includes the following removed; 14768 titles and abstracts were screened against
concepts: diabetic autonomic neuropathy, diabetic neuralgia, eligibility criteria. No grey literature was included. 14607
symmetric diabetic proximal motor neuropathy, asymmetric titles were excluded at the title and abstract screen, 162
diabetic proximal motor neuropathy, diabetic asymmetric eligible full text papers met the inclusion criteria. This process
polyneuropathy, diabetic mononeuropathy, diabetic is summarized in Figure 2 Data extraction and synthesis:
amyotrophy, and diabetic polyneuropathy. Results from the included papers were extracted to a table and
Inclusion and exclusion criteria: Inclusion criteria were include physiopathology, diagnosis, management, and
studies published in English or Spanish, involving patients of therapies under study.
any age. Systematic reviews, clinical trials, prospective cohort Quality assessment: The quality of our narrative review was
studies, cross-sectional and retrospective studies, and evaluated using the SANRA scale, which included the
narrative reviews related to the objective of this manuscript following items: explanation of the importance of the review,
Diabetic neuropathy. An update 155
statement of the objectives of the review, description of the This narrative review has the endorsement of the Ethics
bibliographic search, references, scientific reasoning, and Committee of the Faculty of Medicine of the National
appropriate presentation of information (33). University of Trujillo.
Figure 2. Flowchart of narrative review process
Results dorsal root ganglia (DRG) to undergo β-oxidation, one

Physiopathology molecule of acetyl-CoA is formed in each cycle, and it enters
DN is a degenerative problem of the nervous system that the tricarboxylic acid cycle for the formation of reduced
mainly affects sensory and autonomic axons, and nicotinamide adenine dinucleotide (NADH) and reduced
progressively, to a lesser degree, motor axons. The exact flavin adenine dinucleotide (FADH2). DM has an overload of
mechanism by which DM targets sensory neurons remains substrates that saturate the transport system, converting
unknown. DN develops progressively and involves the acetyl-CoA molecules into acylcarnitine. Accumulated
retraction and death of terminal sensory axons in the acylcarnitine which is toxic to the Schwann cells and DRG
periphery, with relative preservation of the soma. Initially, the neurons, is released from Schwann cells and can induce
longest sensory axons are damaged, so the manifestations are axonal degeneration, by mitochondrial dysfunction and
first distal, developing to proximal. For this reason, DN is maladaptation to stress, adding the nervous system injury (37,
considered to be a length-dependent neuropathy (34). Chronic 38).
hyperglycemia causes damage to the Schwann cells, leading NADH and FADH2 enter the mitochondria by complexes
to demyelination in the most severe cases of DN. Given the I-IV to produce ATP through oxidative phosphorylation. This
interaction and mutual support between the axons and the process generates reactive oxygen species (ROS) as by-
Schwann cells, the damage of the latter would also lead to products, but in small quantities, which are easily neutralized
various alterations in the axons (35, 36). by cellular antioxidants such as superoxide dismutase,
Role of hyperglycemia and hyperlipidemia glutathione, and catalase (39, 40). Excessive substrate in DM
The difference in the way of energy production in the leads to oxidative phosphorylation failure, decreased ATP
peripheral nervous system of people with DM is the basis for production, and increased ROS levels, producing
understanding the pathogenesis of DN. When long-chain fatty mitochondrial failure and metabolic and oxidative damage to
acids are transported to Schwann cells and their axons in the Schwann cells and neurons. Of the DRGs (41–43).
Dysfunctional mitochondria do not produce enough energy lipoproteins, mainly low-density lipoproteins (LDL), are
and lose their normal capacity for transit through the axons, oxidized by ROS and bind to oxidized LDL receptor 1
worsening axonal disruption and damage (44). These alternate (LOX1), toll-like receptor 4 (TLR4) and PFGA (52–54). The
routes to process the excess of glucose, as the polyol pathway binding of oxidized LDL to these receptors activates a series
and the hexosamine pathway, produce an excess of free fatty of signaling cascades, including the activation of caspase 3
acids catabolized by β-oxidation causing damage to Schwann and the degradation of nuclear DNA, producing additional
cells, through ROS and inflammation produced by the inflammation and the accumulation of ROS, thus contributing
activation of macrophages and subsequent production of to progression of neuropathy (54, 55). Sphingolipid
cytokines and chemokines. (45–47) Additionally, metabolism in people with T2DM is also altered, resulting in
hyperglycemia leads to the glycation of structural and the formation of atypical deoxysphingolipids, which are toxic
functional proteins, generating advanced glycation end- to neurons and pancreatic beta cells (56, 57). The level of
products (APGPs), which alter or decrease protein function deoxysphingolipids not only is elevated in people with
and interact with specific PFGA receptors, modifying gene metabolic syndrome or T1DM but much more in those with
expression and intracellular signaling. (34) They also promote T2DM. Of the latter, those with DN present the highest levels
the release of pro-inflammatory molecules and free radicals. (58, 59). Excess of glucose and fatty acids and their relation
(48) Furthermore, in neurons, excess cholesterol is oxidized to inflammation and tissue damage.
to oxysterols, which cause tissue damage (40, 49–51). Plasma
Figure 3. Relationship of the glucose and fatty acid metabolism with DN. (a) The normal metabolism of glucose and fatty acids, which,
through a series of complementary mechanisms, end in the production of ATP. (b) The effects of DM on the normal metabolism of glucose and fatty acids,
overloading the transport system and causing failure of oxidative phosphorylation. (c) The effects of an excess of glucose and fatty acids and their relation to
inflammation and tissue damage. (34)
Role of dysfunction in the microcirculation In addition, hyperglycemia increases the expression of

Poor blood supply to peripheral nerves is another possible glyoxal, a reactive metabolite that forms PFGA by modifying
pathological mechanism involved in DN. Microcirculatory ion channel cellular proteins, altering their function (76.77).
dysfunction is associated with peripheral nerve dysfunction, In DN, there is an increased influx of spontaneously active
leading to further nerve damage. DM patients exhibit higher nociceptors into the spinal cord, which enhances synaptic
capillary density in the endometrium, probably influenced by transmission, further amplifying nociceptive signaling in a
DM-induced nerve ischemia (60). The basement membrane of process called central sensitization. Microglia exhibit a
blood vessels undergoes thickening and is also associated with proinflammatory phenotype, although the exact form is
nerve damage (61). DM also decreases vascular formation unknown. These cells can release factors, such as brain-
mediators such as insulin-like growth factors, vascular derived neurotrophic factor, that amplify nociceptive synaptic
endothelial growth factor (VEGF), nerve growth factor signaling within the spinal cord and contribute to mechanical
(NGF), and angiopoietins (62). pain-related hypersensitivity (78.79).
Role of insulin resistance Sensory-motor neuropathy
Normally, insulin acts as a growth factor for sensory Several clinical syndromes of DN have been described,
neurons, allowing the growth of neuronal processes. Insulin very different from each other, although often coexisting.
receptors are expressed in the sensory neurons of the DRGs Sensorimotor neuropathy includes distal sensory
and axons, especially in the nodes of Ranvier (63, 64). polyneuropathy, acute mononeuropathies, multiple
Glycemic control with insulin has little effect on neuropathy mononeuropathies, and radiculopathies (80). Distal sensory
in patients with T2DM given the insulin resistance developed polyneuropathy is the most frequent form and in more than
by the neurons, similar to that of the muscle and adipose 50% of cases, it generates symptoms like burning pain,
tissue. In contrast, in T1DM, the benefit on neuropathy is electrical or stabbing sensations, paresthesia, and
notorious (65, 66). hyperesthesia, which are usually worse at night and reduce the
Mechanisms of neuropathic pain ability to perform daily activities (81, 82).
Nearly half of DN patients develop neuropathic pain, In the examination of the lower extremities, loss of
frequently manifested as a spontaneous burning pain in the sensitivity to vibration, pressure pain, and temperature is
feet (67). Allodynia, paresthesia, and loss of sensitivity have usually found, as well as decreased or absent osteotendinous
also been reported. The presence or absence of neuropathic reflexes. When there is muscle weakness, it is usually mild
pain is probably due to a complex interaction of genetic (81, 83). Some patients develop early neuropathy, not
factors, somatosensory circuitry, and psychological factors necessarily associated with the use of insulin or oral
(68). hypoglycemic agents, and manifest only pain and paresthesia,
Being female increases the risk of painful DN. The which corresponds to another entity called insulin neuritis
severity of the neuropathy, poor glycemic control, renal (84). In order of frequency, the most common acute
dysfunction, and a higher body mass index are risk factors for mononeuropathies are paralysis of the oculomotor nerve and
neuropathic pain and are associated with neuropathy those of the trochlear and facial nerves (84). They are usually
progression (69, 70). associated with nerve ischemia and generally appear during a
Damaged sensory neurons present hyperexcitability, and transition period in DM, such as after an episode of
generate spontaneous activity by action potentials in the hyperglycemia or hypoglycemia, when the insulin therapy
absence of a stimulus and an altered response. This aberrant regimen is started or adjusted, or when there is rapid weight
activity is what initiates and allows the continuation of loss (83).
neuropathic pain (71, 72). The pathogenesis of neuropathic Multiple mononeuropathies are unilateral or asymmetric
pain also involves genetic variations of ion channels and painful neuropathies that start abruptly in one nerve and then
alterations in their expression, trafficking, and post- sequentially or irregularly affect other nerves (80). These
translational modifications, such as an increased expression of radicular-plexopathies present sub-acutely with pain followed
the Nav1.8 subunit of the channel, voltage-gated sodium in by weakness, and mainly affect older people with mild or
sensory neurons, which contributes to hyperexcitability of undiagnosed DM. The main forms are cervical, thoracic, and
DRG neurons (73-75). lumbosacral radicular-plexopathy, and they can present
separately or simultaneously (85). Of these, lumbosacral extremities and anterior abdomen, culminating in global
radicular-plexopathy is the one that produces the greatest anhidrosis. In some cases, it causes hyperhidrosis (97).
morbidity, with intense pain that begins in the waist or hips Diagnosis
and extends to the thigh and knee on one side, associated with DN presents in a heterogeneous manner and on many
kneeling and might be more intense at night. Pain is the main occasions without a correlation with glycemia figures,
discomfort at the beginning, but gradually weakness and possibly, being it not impossible to go together with renal DM
atrophy become the biggest problem, mainly affecting the complications, which lowers the blood sugar level. So,
pelvic girdle and the thighs, and progressively it may spread defining it accurately and, even more, classifying it is
more distally. Due to the above, it is also known as diabetic sometimes controversial. For a better understanding of its
amyotrophy (83–85). manifestations, it is usually classified into two groups, being
Autonomic neuropathies generalized symmetrical polyneuropathy which includes the
Autonomic neuropathies can affect cholinergic, adrenergic, acute sensory, chronic sensory-motor, and autonomic form,
and peptidergic fibers, and can be sub-clinically detected with and the focal and multifocal neuropathy. The last group
tests or become evident with signs and symptoms (86). includes the list of cranial, truncal, focalized in one extremity,
Cardiovascular autonomic neuropathy arises as a result of proximal motor or neuropathy amyotrophic, and chronic
the interaction between glycemic control, duration of DM, inflammatory demyelinating polyneuropathy forms (80, 81,
age-related neuronal wear, and blood pressure (86). Its 98). The diagnosis of DN is clinical, based on an adequate
manifestations include altered heart rate variability, anamnesis and physical examination, restricting objective
tachycardia at rest, exercise intolerance, blood pressure confirmatory tests mainly to the field of research or in the case
dysregulation, and orthostatic hypotension (87, 88). Although of atypical clinical presentations (10.88). The heterogeneous
symptoms appear years after DM onset, subclinical presentations like tingling, together with lancinating pain,
involvement can be detected as early as 1 year after T2DM accompanied by weakness and instability in the extremities,
diagnosis and 2 years after T1DM diagnosis. This form of from distal to proximal onset, occur in most patients and are
neuropathy is associated with the highest morbidity and the necessary elements for diagnosis (10, 80, 88). The signs
mortality (88, 89). and symptoms (99) together with the systemic manifestations
Gastrointestinal autonomic neuropathy is usually a (81) are summarized in Table 1, which are easy to identify in
diagnosis of exclusion due to the difficulty in evaluating a clinical evaluation.
gastrointestinal function in humans. It affects up to 75% of The great variety of signs and symptoms can be organized
people with DM (87, 88). It produces nausea, bloating, into a series of scales that can help us to formalize the
abdominal pain, diarrhea, constipation, and delayed gastric diagnosis. Despite the passage of time, the Toronto Clinical
emptying, altering the absorption of medications, hindering Neuropathy Score is still used due to its easy application and
glycemic control, and producing malnutrition and a poor high reproducibility in any medium. This scale considers the
quality of life (87, 90). Another type of autonomic neuropathy symptoms of foot pain, numbness, tingling, weakness, ataxia,
is erectile dysfunction, which affects more than 50% of men and upper limb symptoms, as well as knee and ankle reflexes,
with DM and is caused by neuropathy and endothelial finishing with the sensory tests using a monofilament,
dysfunction. Given its close relationship with endothelial temperature perception, vibration, position, and light touch. It
dysfunction, erectile dysfunction is an early marker of offers a total score from 0 to 19, where a higher score reflects
cardiovascular risk (91-93). Bladder dysfunction occurs due greater nerve damage (100,101). If a patient with pain,
to involvement of autonomic and sensory nerve fibers (94, paresthesia, and/or weakness complains of atypical sub-
95). The first thing that is altered is the sensitivity in the acutely or acutely characteristics, or presents a heterogeneous
bladder, producing delayed urinary reflexes, increased distribution, an objective diagnostic laboratory test is
bladder capacity, and urinary retention (88, 95). This can necessary (99,102) to rule out vitamin B12 deficiency,
happen asymptomatically, becoming the dysfunction evident especially if the patient is a long-term metformin user (103),
when a urinary tract infection occurs secondary to the increase as well as thyroid function control, even screening for
in residual urine volume (96). Besides, autonomic neuropathy autoimmune diseases. Rarely, a biopsy of the sural or radial
initially produces loss of thermoregulatory sweating in the nerve is necessary (10, 98, 104).
Table 1. Common systemic signs and symptoms of Diabetic neuropathy
Skin and
Cardiovascular Gastrointestinal Genitourinary Nervous
appendages
Intolerance to Erectile
Nausea, early Paresthesia, Intolerance to
exercise, dysfunction,
Symptom satiety, hyperalgesia, heat or cold,
weakness, vaginal
abdominal pain allodynia blurred vision
fatigue dryness
Reduced Anhidrosis,
Urinary
Postural sensation to hyperhidrosis,
Diarrhea, retention,
Signs syncope, painful and inability to
constipation. urinary
hypotension. non-painful adapt to
incontinence.
stimuli. ambient light.
Differential diagnosis Association, as well as the American Academy of Neurology,

As has been noted, there are different forms of presentation recommend screening for ND at diagnosis and annually for
of DN, with distal-onset generalized symmetric patients with T2DM, and 5 years after diagnosis and annually
polyneuropathy being the most frequent form. However, it thereafter for patients with T1DM (10,105).
must be taken into account that not all diabetic patients have Prevention
neuropathy secondary to DM. In fact, in approximately 1 in In both T1DM and T2DM, the base harm is hyperglycemia,
10 diabetics with neuropathy, DM is not the responsible so evidently, glycemic control is the base of DN prevention,
entity, but rather some other cause is involved (34,105). however, the outcome does not seem to be the same in the
That is why it is necessary to assess other etiologies that different types of DM, since the incidence decreases very
can generate neuropathy such as alcohol abuse, genetic slightly in patients with T2DM compared to patients with
alterations, neoplasms, medications like chemotherapy and T1DM, making us know that the pathophysiological
HIV treatments, and amyloidosis. An adequate clinical history mechanism of each type of DM plays a crucial role in this
is essential to know what type of patient should have a more complication (107,108). In not many years we will be able to
exhaustive search for another cause. (10.34) have adequate studies at hand to take a position on other types
Screening of interventions such as metabolic surgeries, which help in the
All screening tests must be easy and fast to apply, and their remission of DM2, but we still cannot adequately distinguish
results reliable, so the arsenal of tests used for DN screening what role they play in complications such as DN.
is very small. The 10-gram monofilament together with the Management
128 Hz tuning fork have similar screening power, compared The management of DN includes 4 main strategies:
with other more expensive and difficult-to-apply methods to glycemic control, intervention in diet and lifestyles, therapies
discriminate DN (10,34,105–107). The American Diabetes aimed at the pathogenesis of the disease, and symptomatic
relief of neuropathic pain (109). The latter being perhaps the should have a positive impact on the complications of DN, so
main objective sought by the patient but which the clinician on ND. Within the range of possibilities, the total vegetarian
must always consider within the global management or vegan diet can have a beneficial effect on the symptomatic
mentioned. control of DN (124). Another option that has shown a benefit
Glycemic control in the control of metabolic diseases is the Mediterranean diet,
The DCCT study showed that intensive glycemic control having as its main characteristic the high consumption of fats
can delay the onset of DN in patients with T1DM. After 6.5 from vegetable oils and proteins from fish meat. This has not
years of follow-up, the intensive glycemic control group with generated direct evidence so far in the improvement of DN
a mean HbA1c of 7.4% had an increase in frequency of DN symptoms, but in the progression of the disease and in
from 7% to 9% compared to the conventional glycemic inflammatory mechanisms that are related to the pain
control group with a mean HbA1c of 9.1% what presented an pathways, which can reduce symptoms this way (125-127).
increase from 5% to 17% in the frequency of DN (110). Very low-calorie diets, between 200-500 kcal/day, could have
Glycemic control is less effective in preventing the a beneficial effect by reducing insulin resistance and
progression of DN in patients with DM2. The UKPDS study improving glycemic control figures, but given the possibility
did not show a significant difference in the frequency of DN of an increase in ketone bodies, there is no clear picture(128).
between the conventional and intensive glycemic control Nutrient deficiencies might be an additional risk in time.
groups with sulfonylureas or insulin (111). These data should Obesity control and weight reduction to a normal MIC can
not lead us to suppose that glycemic control is less relevant in improve the structure and function of peripheral nerves (129).
T2DM as it affects also other organs and physiological Metabolic surgery in DM to generate greater and faster
pathways, such as the nervous system, and must be controlled weight loss is approved by health securities in some countries.
(109, 112). The previously mentioned studies involve a large Ketogenic diets and Dietary-Approaches-to-Stop-
international population and assessed the intensity of Hypertension (DASH) diets have only shown clear benefits in
glycemic control by a trimestral HbA1c, which proved to be the management of arterial hypertension.
an important tool in disease management. The result of the Mild to moderate-intense physical exercise can have a
HbA1c value has to be considered not to be completely beneficial impact on neuropathic pain reduction and DN
adequate in patients with hemoglobin alterations, like in any control (130) not only because of the control effect on
anemia, iron deficiencies, chronic kidney disease, hyperglycemia itself but also because it influences plasticity
polycythemia, and related clinical conditions. In addition, the mechanisms that can improve symptoms (131).
high glycemic variability that a patient with frequent dietary Disease-modifying therapies
transgressions can present can only be distinguished in daily Two drugs that are approved for the treatment of DN in
continuous glucose monitoring. This is why numerous studies multiple countries, stand out: alpha-lipoic acid, which reduces
have appeared in recent years that attempt to assess whether oxidative stress, and benfotiamine, which inhibits the
glycemic variability plays a role in the progression of accumulation of PFGA (132,133).
complications, finding that it does play a role as an Several randomized clinical trials have shown the efficacy
independent factor in the development and progression of DN and safety of alpha-lipoic acid 600 mg daily in reducing
in T1DM as well in T2DM; therefore, the use of continuous neuropathic symptoms, intravenously after 3 weeks and orally
glycemic monitoring systems may become more relevant after 5 weeks of treatment (134–137). Benfotiamine is a pro-
(113–116). *** The most recent studies have been drug of thiamin (vitamin B1). The BENDIP (Benfotiamine in
summarized in Table 2. Diabetic Polyneuropathy) clinical trial showed a significant
*** References 117–123 are in Table 2. improvement in neuropathic symptoms after 6 weeks of
Diet and lifestyle treatment with a dose of 300 mg every 12 hours, which proved
Evaluating the impact of diet itself in the treatment of DN, to be the optimal effective and safe dose (138).
we have not found strong evidence of direct benefit, however, More large-scale studies are needed before these drugs can
it is deduced that an adequate diet that allows glycemic control be recommended in the clinical practice.
Table 2. Impact of the glycemic variability on Diabetic neuropathy

Study Populación and type Result
Oyibo SO et al. 2002. Randomized clinical trial in 20 T1DM It was found that the mean glycemic variability was higher
(117) patients. in painful DN, but without statistical significance.
Kwai NC et al. 2016. Randomized clinical trial in 17 T1DM In patients with higher glycemic variability, greater neuronal
(118) patients. excitability was found.
Randomized clinical trials in 13 and 27
Akaza M et al. 2018. Glycemic variability was independently associated with an
T1DM and T2DM patients,
(119) increased risk of medial plantar neuropathy.
respectively.
The perception of vibrations measured in Hertz was
Dahlin LB et al. Randomized clinical trial in 159 T1DM
evaluated, finding fewer vibrations in patients with better
2020. (120) patients.
glycemic control.
A significant association of painful DN was found with
Mizokami-Stout KR Retrospective cohort in 5936 T1DM
those patients who presented acute diabetic complications
et al. 2020. (121) patients.
during follow-up.
A significant correlation was found between time in the
Feng ZQ et al. 2021. Randomized clinical trial in 95 T1DM
glycemic range and HbA1c-independent sudomotor
(122) patients.
dysfunction.
Yang J et al. 2021. Cross-sectional study in 364 T2DM Time in range correlated with painful DN and stands out as a
(123) patients. valuable clinical assessment measure.
Pain management treatment with duloxetine (141). While for the phenotype of
Pain relief in patients with DN has been a great challenge pain with paroxysms, treatment with high doses of
and its adequate approach must take into account multiple pregabaline is recommended (142). Both drugs are recognized
factors. Despite the high prevalence of DN, only 40% of as first-line drugs in DN. Regarding the approach according
patients receive a treatment considered first or second line in to comorbidities, the use of duloxetine is recommended in
the treatment of DN. A similar percentage does not receive patients with depression. In patients with anxiety or sleep
any treatment (139). There are more than 30 drugs disorders, it is preferred to initiate treatment with pregabalin.
recommended for the treatment of DN, with different efficacy, In the absence of improvement, tricyclic antidepressants could
safety, and level of evidence. Therapeutic efficacy is be added as second-line therapy (133), always emphasizing to
considered with a significant reduction in symptoms, the patient that the symptomatic relief of pain is not
approximately 50% on pain scales. But none of them has been instantaneous and that the dose should be titrated according to
shown to achieve complete pain relief. In clinical practice, each patient and based on the doses accepted until now. The
two approaches to pain management stand out. The first drugs are described in table 3 with the recommended dose,
focused on the DN phenotype and neuropathic pain and the additionally, the time in weeks on average that it must have
second approach focused on the presence of comorbidities, been administrated to show an effect (112). *** Finally, the
including anxiety, depression, sleep disorders, chronic treatment must be evaluated and valued by the patient,
complications of DM, cardiovascular diseases, among currently existing various scales such as the Diabetes Quality
others(140). of Life (DQOL) or the Diabetes-Specific Quality of Life Scale
Two DN phenotypes have been described: a paresthesia- (DSQOLS) (151), which attempt to assess objectively the
like pain phenotype and a paroxysmal pain phenotype. For the improvement or deterioration in the quality of life (152).
paresthesia-like pain phenotype, it is recommended to start *** References 143–150 are in Table 2.
Table 3. Drugs involved in the treatment of Diabetic neuropathy

Drug Intervention Goal Dose (mg/d) Effect (weeks)
Duloxetine (143) First-line Anti-depressive SNRIs 40-60 10-12
Pregabalin (144) First-line Anti-convulsant α2-δ ligand 300-600 8-12
Alfa-lipoic acid (145) First-line Neuromodulator NF-κB, ROS, TRPV1 600-1800 4-6
Benfotiamine (146) First-line Neuromodulator Hexosamine pathway 100-300 4-6
Amitriptyline (147) Second-line Anti-depressant SNRIs 25-100 2-4
Valproic acid (148) Second-line Anticonvulsant GABA 1000-1200 4-12
Gabapentin (149) Second-line Anti-convulsant GABA 900-3600 4-6
Carbamazepine (150) Second-line Sodium channels 400-800 8-12

GABA: gamma-aminobutyric acid; NF-κB: Nuclear factor kappa B; ROS: reactive oxygen species; SNRI: Serotonin–norepinephrine
reuptake inhibitor; TRPV1: transient receptor potential vanilloid 1
Therapies under study glycemia, blood pressure, and other components of the
There is a lot of interest in therapeutic agents focused on metabolic syndrome contribute to prevent or postpone it, as in
other points within the pathophysiology of DN, which is why other cases, stopping the progression of this condition or in
new drugs are under study (153,154). Desensitization of the the worse cases, reducing its severity. Intervention in
temperature-sensitive transient receptor potential channel in lifestyles such as an appropriate diet and exercise also provide
nociceptive neurons has been proposed as an interesting benefits in its management.
therapeutic option considering the pain pathways, through the Pharmacological interventions may be aimed at relieving
application of topical capsaicin, which is still only approved pain, but there is considerable progress made in disease-
for the management of painful DN in feet (155). The use of modifying therapies. There are many aspects of this disease
low-voltage electrical current stimulation of the spinal cord that are still being investigated to improve its prevention and
with success in some studies is also under investigation treatment.
(156,157).
Mutations in voltage-gated sodium channels such as
Nav1.7 have been implicated in painful DN, and are the target Acknowledgments
of antagonists such as the drug Xenon402, which is useful in None to declare
erythromelalgia and has the potential to be used in other types
of neuropathic pain (158,159). The intrathecal administration
of drugs such as morphine and ziconotide allows direct release Funding: None to declare
into the cerebrospinal fluid, with fewer side effects than Conflict of Interests: None to declare
systemic administration; however, their use in DN has not Authors’ contribution: Concepción-Zavaleta M and Quiroz-
been evaluated, and this could be complicated by the difficulty Aldave J designed the outline of this article review. Quiroz-
in healing of wounds that people with DM are prone to Aldave J, Durand-Vásquez M, Gamarra -Osorio E, Suarez-
(160,161). Rojas J and Alcalá-Mendoza R were the main writers and
The benefit of topical application of O2 and CO2 performed literature review. Roseboom P, Concepción-
nanobubbles for the treatment of DN symptoms is also being Urteaga L, and Concepción-Zavaleta M were reviewers and
studied in more than 50% of patients with success so far (162). prepared the manuscript. Roseboom P, Coronado-Arroyo J
In conclusion, Diabetes mellitus causes damage to peripheral and Zavaleta-Gutiérrez F were translators and interpreters,
nerves, with a variety of clinical manifestations. The most and performed written contribution to the text body. All
common form is distal symmetric polyneuropathy. Control of authors have read and approved the final manuscript.
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Polineuropatia Diabetica, Pasado, Presente y Futuro

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Caspian Journal of Internal Medicine 2023 (Spring); 14(2): 153-169

Diabetic neuropathy: Past, present, and future

Figure 1. Diabetic neuropathy research timeline

Methods were included. The investigation was limited to articles

Figure 2. Flowchart of narrative review process

Results dorsal root ganglia (DRG) to undergo β-oxidation, one

Role of dysfunction in the microcirculation In addition, hyperglycemia increases the expression of

Table 1. Common systemic signs and symptoms of Diabetic neuropathy

Differential diagnosis Association, as well as the American Academy of Neurology,

Table 2. Impact of the glycemic variability on Diabetic neuropathy

Table 3. Drugs involved in the treatment of Diabetic neuropathy

Carbamazepine (150) Second-line Sodium channels 400-800 8-12

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