# Protective Role of Physical Exercise and Exercise‐Induced FNDC5/Irisin in Combating Diabetes‐Related Cognitive Impairment and Autonomic and Peripheral Neuropathies: A Comprehensive Review **Authors:** Sepideh Poshtdar, Hosein Ataei-Goujani, Amirali Ahrabi PMC · DOI: 10.1155/jdr/5552311 · Journal of Diabetes Research · 2026-02-18 ## TL;DR Physical exercise and the exercise-induced protein irisin may help protect against diabetes-related brain and nerve damage. ## Contribution This review highlights the novel role of FNDC5/irisin in mediating the protective effects of exercise against diabetes-related cognitive and neuropathic complications. ## Key findings - Physical exercise reduces cognitive impairments and diabetic neuropathies. - FNDC5/irisin is a key mediator in the protective effects of exercise. - Aerobic, resistance, and multimodal training all show benefits in experimental and clinical studies. ## Abstract The rising prevalence of diabetes has been closely linked to increased mortality and morbidity, particularly as its complications become more widespread. Among the most challenging of these complications are cognitive impairments and diabetic neuropathies, which are neurodegenerative conditions that significantly diminish the quality of life in the diabetic population. Beyond its well‐established benefits for improving glycemic control and preventing cardiovascular complications, physical exercise has also been shown to mitigate central and peripheral neurodegenerative complications of diabetes, including cognitive decline, peripheral neuropathies, and autonomic neuropathies. Emerging research suggests that fibronectin type III domain‐containing protein 5 (FNDC5), later converted into irisin, an exercise‐induced myokine, plays a key role in mediating these protective effects. This narrative review thoroughly examines the protective impact of various forms of physical exercise—including aerobic, resistance, and multimodal training—on diabetic neuropathies and cognitive decline, while also exploring the involvement of FNDC5/irisin in these beneficial outcomes across experimental animal studies, cross‐sectional analyses, and controlled trials. ## Linked entities - **Genes:** FNDC5 (fibronectin type III domain containing 5) [NCBI Gene 252995] - **Proteins:** FNDC5 (fibronectin type III domain containing 5) - **Diseases:** diabetes (MONDO:0005015), peripheral neuropathies (MONDO:0003620) ## Full-text entities - **Genes:** App (amyloid beta precursor protein) [NCBI Gene 54226] {aka Abeta}, Casp3 (caspase 3) [NCBI Gene 25402] {aka CPP32-beta, Lice, Yama}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, FNDC5 (fibronectin type III domain containing 5) [NCBI Gene 252995] {aka FRCP2, irisin}, UCP1 (uncoupling protein 1) [NCBI Gene 7350] {aka SLC25A7, UCP}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, RENBP (renin binding protein) [NCBI Gene 5973] {aka RBP, RNBP}, Ptgs2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 29527] {aka COX-2, Cox2, PGHS-2, PHS II, Pghs2}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, FGF21 (fibroblast growth factor 21) [NCBI Gene 26291], CASP1 (caspase 1) [NCBI Gene 834] {aka ICE, IL1BC, P45}, NTF3 (neurotrophin 3) [NCBI Gene 4908] {aka HDNF, NGF-2, NGF2, NT-3, NT3}, Gfap (glial fibrillary acidic protein) [NCBI Gene 14580], Cybb (cytochrome b-245 beta chain) [NCBI Gene 66021] {aka Gp91-phox, Nox2}, MYOG (myogenin) [NCBI Gene 4656] {aka MYF4, bHLHc3, myf-4}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, NUP62 (nucleoporin 62) [NCBI Gene 23636] {aka IBSN, SNDI, p62}, ACSL4 (acyl-CoA synthetase long chain family member 4) [NCBI Gene 2182] {aka ACS4, FACL4, LACS4, MRX63, MRX68, XLID63}, TPSG1 (tryptase gamma 1) [NCBI Gene 25823] {aka PRSS31, TMT, trpA}, NTRK1 (neurotrophic receptor tyrosine kinase 1) [NCBI Gene 4914] {aka MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, CTSB (cathepsin B) [NCBI Gene 1508] {aka APPS, CPSB, KWE, RECEUP}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Akt1 (AKT serine/threonine kinase 1) [NCBI Gene 24185] {aka Akt}, Sirt1 (sirtuin 1) [NCBI Gene 93759] {aka SIR2L1, Sir2, Sir2a, Sir2alpha}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, NEFL (neurofilament light chain) [NCBI Gene 4747] {aka CMT1F, CMT2E, CMTDIG, NF-L, NF68, NFL}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, Bax (BCL2 associated X, apoptosis regulator) [NCBI Gene 24887], IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, MAP1LC3A (microtubule associated protein 1 light chain 3 alpha) [NCBI Gene 84557] {aka ATG8E, LC3, LC3A, MAP1ALC3, MAP1BLC3}, Bdnf (brain derived neurotrophic factor) [NCBI Gene 12064], Bdnf (brain-derived neurotrophic factor) [NCBI Gene 24225], Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Ppargc1a (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha) [NCBI Gene 19017] {aka A830037N07Rik, Gm11133, PGC-1, PPARGC-1-alpha, Pgc-1alpha, Pgc1}, Fndc5 (fibronectin type III domain containing 5) [NCBI Gene 384061] {aka 1500001L03Rik, PeP, Pxp}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, MDNS (Mammary-digital-nail syndrome) [NCBI Gene 100529148], PPARGC1A (PPARG coactivator 1 alpha) [NCBI Gene 10891] {aka LEM6, PGC-1(alpha), PGC-1alpha, PGC-1v, PGC1, PGC1A}, BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, SYN1 (synapsin I) [NCBI Gene 6853] {aka EPILX, EPILX1, MRX50, SYN1a, SYN1b, SYNI}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, PINK1 (PTEN induced kinase 1) [NCBI Gene 65018] {aka BRPK, PARK6}, Dcx (doublecortin) [NCBI Gene 13193] {aka Dbct}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, Gfap (glial fibrillary acidic protein) [NCBI Gene 24387], SLC25A19 (solute carrier family 25 member 19) [NCBI Gene 60386] {aka DNC, MCPHA, MTPPT, MUP1, THMD3, THMD4}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, PRKN (parkin RBR E3 ubiquitin protein ligase) [NCBI Gene 5071] {aka AR-JP, LPRS2, PARK2, PDJ}, Il1b (interleukin 1 beta) [NCBI Gene 24494] {aka IL-1F2} - **Diseases:** allodynia (MESH:D006930), ketoacidosis (MESH:D007662), RADL (MESH:D002313), foot ulcers (MESH:D016523), multiple sclerosis (MESH:D009103), glucose intolerance (MESH:D018149), Charcot-Marie-Tooth joint deformities (MESH:D002607), memory deficit (MESH:D008569), Cognitive decline (MESH:D003072), hyperosmotic coma (MESH:D003128), Autonomic neuropathies (MESH:D009422), depression (MESH:D003866), nephropathy (MESH:D007674), heart failure (MESH:D006333), sciatic tissue damage (MESH:D020426), Neuropathic pain (MESH:D009437), neuronal injury (MESH:D009410), T2D (MESH:D003924), sensory loss (MESH:C580162), CAN (MESH:D006331), T1D (MESH:D003922), amyloid (MESH:C000718787), dementia (MESH:D003704), paresthesia (MESH:D010292), DPN (MESH:D010523), muscle function deterioration (MESH:D009135), orthostatic hypotension (MESH:D007024), hypoglycemia (MESH:D007003), Diabetic Neuropathy (MESH:D003929), foot infections (MESH:D007239), cardiovascular complications (MESH:D002318), myocardial infarction (MESH:D009203), dizziness (MESH:D004244), insulin resistance (MESH:D007333), NCV (MESH:C564269), diastole and systole (MESH:D006337), weight loss (MESH:D015431), vascular dysfunction (MESH:D002561), loss of sensation (MESH:D006987), cerebral ischemia reperfusion injury (MESH:D015427), cerebral microvascular dysfunction (MESH:D017566), diabetic foot ulcers (MESH:D017719), resting tachyarrhythmia (MESH:D014202), death (MESH:D003643), Diabetes Complications (MESH:D048909), hyperglycemic (MESH:D006944), hypertension (MESH:D006973), demyelination (MESH:D003711), ischemia (MESH:D007511), synaptic (MESH:D012183), hypoxia (MESH:D000860), ANS dysfunction (MESH:D001342), bradycardia (MESH:D001919), HIIT (MESH:D000095027), burn (MESH:D002056), obese (MESH:D009765), hypoxic (MESH:D002534), cardiac arrhythmia (MESH:D001145), gestational diabetes (MESH:D016640), impairment of language, memory, thinking, (MESH:D007806) - **Chemicals:** TBARS (MESH:D017392), ROS (MESH:D017382), glucose (MESH:D005947), GSH (MESH:D005978), lipid (MESH:D008055), Annona muricata extract (-), AGEs (MESH:D017127), STZ (MESH:D013311), iron (MESH:D007501), kynurenic acid (MESH:D007736), fat (MESH:D005223), sugar (MESH:D000073893) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090] - **Cell lines:** C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU), HT22 — Mus musculus (Mouse), Transformed cell line (CVCL_0321), C57BL/6J — Mus musculus (Mouse), Transformed cell line (CVCL_C0MW) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12914223/full.md ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12914223/full.md ## References 181 references — full list in the complete paper: https://tomesphere.com/paper/PMC12914223/full.md --- Source: https://tomesphere.com/paper/PMC12914223