Tropomyosin receptor kinase B-mediated signaling in integration of neuropathic pain and obesity in diabetic polyneuropathy

There is increasing evidence that psychosocial factors may be involved in the pathophysiology of chronic diabetic neuropathic pain. Individuals with diabetic polyneuropathy exhibit significantly higher rates of axis I psychiatric disorders, and worsening neuropathic symptoms correlate with worsened psychiatric illness. This association exists even when social-support and quality-of-life measures are controlled. Aberrant supraspinal structures and neuronal networks in diabetic neuropathy mimic those found in other psychiatric illnesses. Response to standard medications and therapeutic approaches remains unsatisfactory, and antidepressants continue to serve as first-line treatment for diabetic neuropathy. The exact interplay between neuropathic pain and psychiatric illness remains unclear and may have a common pathophysiological focus. This area of study needs to be revisited and psychological interventions must be explored as possible treatment options for diabetic neuropathy.

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Inhibition of MicroRNA-15a/16 Expression Alleviates Neuropathic Pain Development through Upregulation of G Protein-Coupled Receptor Kinase 2

Biomolecules & Therapeutics ◽

10.4062/biomolther.2018.073 ◽

2019 ◽

Vol 27 (4) ◽

pp. 414-422 ◽

Cited By ~ 2

Author(s):

Tao Li ◽

Yingchun Wan ◽

Lijuan Sun ◽

Shoujun Tao ◽

Peng Chen ◽

...

Keyword(s):

Neuropathic Pain ◽

G Protein ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Tapentadol prolonged release in the treatment of neuropathic pain related to diabetic polyneuropathy

The Lancet Neurology ◽

10.1016/s1474-4422(15)00059-9 ◽

2015 ◽

Vol 14 (7) ◽

pp. 684-685 ◽

Cited By ~ 5

Author(s):

Christian Elling ◽

Maja Galic ◽

Ilona Steigerwald

Keyword(s):

Neuropathic Pain ◽

Diabetic Polyneuropathy ◽

Prolonged Release

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Analysis of Macrophages and Peptidergic Fibers in the Skin of Patients With Painful Diabetic Polyneuropathy

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001111 ◽

2021 ◽

Vol 9 (1) ◽

pp. e1111

Author(s):

Sandra Sif Gylfadottir ◽

Mustapha Itani ◽

Alexander Gramm Kristensen ◽

Hatice Tankisi ◽

Troels Staehelin Jensen ◽

...

Keyword(s):

Neuropathic Pain ◽

Diabetic Polyneuropathy ◽

Healthy Controls ◽

Cross Sectional ◽

Macrophage Density ◽

Calcitonin Gene ◽

Skin Biopsies ◽

Male Patients ◽

The Difference ◽

Age And Sex

Background and ObjectivesThe mechanisms of pain in patients with diabetic polyneuropathy are unknown. Studies have suggested a role of inflammation and increased neuropeptides peripherally in pain generation. This study examined the possible skin markers of painful diabetic polyneuropathy (P-DPN): macrophages, substance P (SP), and calcitonin gene-related peptide (CGRP).MethodsThe participants were included from a large Danish cross-sectional clinical study of type 2 diabetes. We diagnosed definite diabetic polyneuropathy using the Toronto criteria and used the Neuropathic Pain Special Interest Group classification for defining P-DPN. We included 60 skin biopsies from patients with diabetic polyneuropathy—30 with P-DPN and 30 with nonpainful diabetic polyneuropathy (NP-DPN)—and 30 biopsies from healthy controls of similar age and sex. The biopsies were stained using PGP 9.5, IbA1, and SP and CGRP primary markers.ResultsThere was increased macrophage density in patients with P-DPN (8.0%) compared with that in patients with NP-DPN (5.1%, p < 0.001), and there was increased macrophage density in patients with NP-DPN (5.1%) compared with that in healthy controls (3.1%, p < 0.001). When controlling for neuropathy severity, body mass index, age, and sex, there was still a difference in macrophage density between patients with P-DPN and patients with NP-DPN. Patients with P-DPN had higher median nerve fiber length density (274.5 and 155 mm−2 for SP and CGRP, respectively) compared with patients with NP-DPN (176 and 121 mm−2 for SP and CGRP, respectively, p = 0.009 and 0.04) and healthy controls (185.5 and 121.5 mm−2 for SP and CGRP, respectively), whereas there was no difference between patients with NP-DPN and controls without diabetes (p = 0.64 and 0.49, respectively). The difference between P-DPN and NP-DPN for SP and CGRP was significant only in female patients, although a trend was seen in male patients.DiscussionThe findings point to a possible involvement of the innate immune system in the pathogenesis of neuropathic pain in patients with DPN, although markers of activated macrophages were not measured in this study.

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Treatment of neurological complications in patients with type 2 diabetes mellitus at the stage of rehabilitation after COVID-19

INTERNATIONAL JOURNAL OF ENDOCRINOLOGY ◽

10.22141/2224-0721.17.6.2021.243214 ◽

2021 ◽

Vol 17 (6) ◽

pp. 491-495

Author(s):

V.I. Pankiv

Keyword(s):

Neuropathic Pain ◽

Folic Acid ◽

Side Effects ◽

Nerve Regeneration ◽

Vitamin B1 ◽

Diabetic Polyneuropathy ◽

Neurological Complications ◽

Nerve Fibers ◽

Peripheral Neuropathic Pain ◽

Uridine Monophosphate

Although the predominant clinical manifestation of COVID-19 is a respiratory disease, various neurological symptoms are increasingly being diagnosed, in particular, diabetic polyneuropathy is diagnosed in most patients with diabetes, affecting large and small nerve fibers. Drugs that are traditionally used for neuropathic pain (tricyclic antidepressants, gabapentinoids, etc.), despite their positive effect in eliminating the symptoms of polyneuropathy, often cause side effects and do not impact nerve regeneration. Over the last decade, a group of nucleotides has been used quite actively. Additional information on the effects of this group of drugs was accumulated and there is a gradual transformation, including their compositions. Thus, recently the attention of researchers has been devoted to the study of the effectiveness of the combination of uridine, choline, vitamins B1, B6, B12, and folic acid, which is characterized by a fairly high safety profile and regenerative potential. The review highlights the mechanisms of action and results of clinical use of this combination. Uridine monophosphate, B vitamins, folic acid are involved in metabolic processes, enhancing nerve regeneration. This contributes to the development of indirect (secondary) analgesic effect. In addition, the data of new studies indicate the ability of uridine monophosphate derivatives to impact purinergic P2Y receptors, which causes a direct analgesic and direct regenerative effect. Studies have demonstrated the clinical efficacy of this combination in the main types of peripheral neuropathic pain. The combination did not cause side effects and was well tolerated. There was a reduction or complete withdrawal of concomitant analgesics against the background of improving the quality of life of patients. The combination of uridine, choline, vitamin B1, vitamin B6, vitamin B12, and folic acid is a very effective addition to the standard therapy of peripheral neuropathic pain of various genesis and rehabilitation after COVID-19.

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Neuropathic pain: mechanisms of development, principles of diagnostics and treatment

Pain medicine ◽

10.31636/pmjua.v4i2.1 ◽

2019 ◽

Vol 4 (2) ◽

pp. 4-32

Author(s):

Dmytro Dmytriiev ◽

Pylyp Prudius ◽

Olesia Zaletskaya ◽

Yevhen Lisak ◽

Yurii Rudnitsky ◽

...

Keyword(s):

Nervous System ◽

Neuropathic Pain ◽

Pain Syndrome ◽

Diabetic Polyneuropathy ◽

Pain Mechanisms ◽

Peripheral Neuropathic Pain ◽

Pain Pathways ◽

Mechanisms Of Development ◽

Somatosensory Nervous System ◽

Cause Of Pain

Neuropathic pain is a pain caused by a disease or focal damage to the somatosensory nervous system. The prevalence of chronic pain with neuropathic features in different countries is estimated at 7–10 %. Damages to the nervous system can occur at the level of peripheral nerves, plexus and dorsal roots (peripheral neuropathic pain) or spinal cord and brain (central neuropathic pain). Neuropathic pain is based on pathological activation of pain pathways. Neuropathic pain occurs with diabetic polyneuropathy more often than with all polyneuropathies of another etiology. Hyperglycemia is the major cause of chronic diabetes mellitus and its progression. Since the cause of pain can rarely be cured, treatment is usually symptomatic. Neuropathic pain is generally poorly controlled by analgesics. NB management is started with conservative pharmacotherapy before applying invasive analgesia. Although there are many drugs that can be used in patients with DPN, monotherapy can not always stop pain syndrome. In addition, the patient may not tolerate the full therapeutic dose of the drug. All this dictates the need for combination therapy.

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Metabolic factors, lifestyle habits, and possible polyneuropathy in early type 2 diabetes: A nationwide study of 5,249 patients in the Danish DD2 cohort

10.2337/dc20-1234/suppl.12006117 ◽

2020 ◽

Author(s):

Diana H. Christensen ◽

Søren T. Knudsen ◽

Sandra S. Gylfadottir ◽

Lotte B. Christensen ◽

Jens S. Nielsen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Neuropathic Pain ◽

Diabetic Polyneuropathy ◽

Prevalence Ratio ◽

Hdl Cholesterol ◽

Diabetes Diagnosis ◽

Early Type ◽

Metabolic Factors ◽

Lifestyle Habits

OBJECTIVE:To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes. RESEARCH DESIGN AND METHODS: We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4-score ≥3). RESULTS: Among 5,249 patients with data on both DPN and pain, 17.9% (n=938) had possible DPN, including 7.4% (n=386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-hip ratio, and waist-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L: adjusted prevalence ratio (aPR) 1.36 (1.17; 1.59), decreased HDL cholesterol <1.0/1.2 mmol/L (male/female): aPR 1.35 (1.12; 1.62), high-sensitive CRP ≥3.0 mg/L: aPR 1.66 (1.42; 1.94), C-peptide ≥1,550 pmol/L: aPR 1.72 (1.43; 2.07), HbA1c ≥78 mmol/mol: aPR 1.42 (1.06; 1.88), and antihypertensive drug use: aPR 1.34 (1.16; 1.55). Smoking: aPR 1.50 (1.24; 1.81) and lack of physical activity (0 vs ≥3 days/week): aPR 1.61 (1.39; 1.85) were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain. CONCLUSIONS:Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.

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