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Role of miRNAs in diabetic neuropathy: mechanisms and possible interventions

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Abstract

Accelerating cases of diabetes worldwide have given rise to higher incidences of diabetic complications. MiRNAs, a much-explored class of non-coding RNAs, play a significant role in the pathogenesis of diabetes mellitus by affecting insulin release, β-cell proliferation, and dysfunction. Besides, disrupted miRNAs contribute to various complications, diabetic retinopathy, nephropathy, and neuropathy as well as severe conditions like diabetic foot. MiRNAs regulate various processes involved in diabetic complications like angiogenesis, vascularization, inflammations, and various signaling pathways like PI3K, MAPK, SMAD, and NF-KB signaling pathways. Diabetic neuropathy is the most common diabetic complication, characterized mainly by pain and numbness, especially in the legs and feet. MiRNAs implicated in diabetic neuropathy include mir-9, mir-106a, mir-146a, mir-182, miR-23a and b, miR-34a, and miR-503. The diabetic foot is the most common diabetic neuropathy, often leading to amputations. Mir-203, miR-23c, miR-145, miR-29b and c, miR-126, miR-23a and b, miR-503, and miR-34a are associated with diabetic foot. This review has been compiled to summarize miRNA involved in initiation, progression, and miRNAs affecting various signaling pathways involved in diabetic neuropathy including the diabetic foot. Besides, potential applications of miRNAs as biomarkers and therapeutic targets in this microvascular complication will also be discussed.

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Abbreviations

DM:

Diabetes mellitus

CHD:

Coronary heart disease

CVAs:

Cerebrovascular accidents

BMR:

Basal metabolic rate

IRAK1:

Interleukin-1 receptor-activated kinase

RAF6:

Tumor necrosis factor receptor-associated factor-6

PDN:

Painful diabetic neuropathy

CALHM1:

Calcium homeostasis modulator 1

KCC2:

K + Cl- cotransporter 2

GABA:

Gamma-aminobutyric acid

CCI:

Chronic constriction sciatic nerve injury

NP:

Neuropathic pain

STAT3:

Signal transducer and activator of transcription 3

SOCS1:

Suppressor of cytokine signaling 1

HMGB1:

High-mobility group box 1

MDA:

Malondialdehyde

VCAM-1:

Vascular cell adhesion molecule-1

GPX:

Glutathione peroxidase

SOD:

Superoxide dismutase

MDT:

Maggot debridement therapy

SDF-1α:

Stromal cell-derived factor-1α

FBN1:

Fibrillin 1

DFU:

Diabetic foot ulcer

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Funding

 Council of Scientific and Industrial Research (CSIR), New Delhi, is acknowledged for Senior Research Fellowship (SRF) to P.K. for Ph.D. Declarations. DST-FIST grant (SR/FST/LS-I/2017/49) to department of Human Genetics and Molecular Medicine, Central University of Punjab is acknowledged with thanks.

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Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India

    Prabhsimran Kaur, Sandeep Singh & Anjana Munshi

  2. Max Endocrinology, Diabetes and Obesity Care Centre, Max Superspeciality Hospital, Bathinda, 151001, India

    Sushil Kotru

Authors
  1. Prabhsimran Kaur
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  2. Sushil Kotru
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  3. Sandeep Singh
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  4. Anjana Munshi
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Contributions

The idea of the article was framed by PK, SK, SS, and AM. Literature was searched by PK and AM, and data analysis was done by PK, SK, and SS. The draft was jointly prepared by PK, SK, SS, and AM. It was critically revised by AM and SS.

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Correspondence to Anjana Munshi.

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Key Points

(a) Diabetic neuropathy is the most common microvascular complication affecting at least 50% of diabetic patients.

(b) MiRNAs have been reported to play a key role in vascularization, angiogenesis, inflammation, various signaling cascades, and other mechanisms that contribute to oxidative and nitrative stress and, thus, diabetic neuropathy.

(c) With promising findings and lesser side effects, miRNA can be investigated as a therapeutic target for the complication.

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Kaur, P., Kotru, S., Singh, S. et al. Role of miRNAs in diabetic neuropathy: mechanisms and possible interventions. Mol Neurobiol 59, 1836–1849 (2022). https://doi.org/10.1007/s12035-021-02662-w

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