# Neurovascular Impairment in Type 2 Diabetes Mellitus: The Role of Adipocyte-Derived Exosomes **Authors:** Harshal Sawant, Ji Chen Bihl PMC · DOI: 10.3390/biom16020233 · Biomolecules · 2026-02-03 ## TL;DR This paper reviews how fat cell exosomes in type 2 diabetes contribute to brain blood vessel problems and cognitive decline. ## Contribution The paper highlights novel insights into how adipocyte-derived exosomes mediate neurovascular impairment in T2DM. ## Key findings - Adipocyte-derived exosomes contribute to cerebrovascular complications via oxidative stress and blood-brain barrier disruption. - These exosomes are linked to neuroinflammation and mitochondrial dysfunction in brain microvascular endothelial cells. - Ad-EXs show potential as biomarkers and therapeutic targets for diabetes-related cerebrovascular diseases. ## Abstract Type 2 diabetes mellitus (T2DM) is a major metabolic disorder characterized by chronic hyperglycemia with far-reaching morbidities. Among these, diabetes-related cerebrovascular complications such as ischemic and hemorrhagic stroke, cerebral blood vessel disease, and vascular dementia are significant contributors to morbidity and mortality. Adipose tissue is a metabolically active endocrine organ that becomes dysfunctional in T2DM and communicates with distant tissues via secreted factors, including extracellular vesicles such as exosomes (EXs), phospholipid bilayer-enclosed nanosized particles. These adipocyte-derived exosomes (Ad-EXs) carry bioactive cargo, including lipids, proteins, and microRNAs that influence the function of distant organs, including the brain. Evidence indicates that Ad-EXs in T2DM are a significant risk factor for cerebrovascular complications via neurovascular impairment either directly through the adipose tissue–brain axis or indirectly by other organs. This review provides an overview of current knowledge on how Ad-EXs from different adipocyte populations contribute to cerebrovascular complications through oxidative stress, blood–brain barrier disruption, neuroinflammation, and mitochondrial dysfunction. Particular emphasis is placed on recent findings and gaps in knowledge linking diabetic Ad-EXs with brain microvascular endothelial cells that mediate neurovascular crosstalk, contributing to stroke susceptibility and cognitive decline. We also discuss the potential of Ad-EXs as biomarkers and therapeutic targets for cerebrovascular complications of T2DM. ## Linked entities - **Diseases:** Type 2 diabetes mellitus (MONDO:0005148), vascular dementia (MONDO:0004648), ischemic stroke (MONDO:1060198), hemorrhagic stroke (MONDO:1060199) ## Full-text entities - **Genes:** MIR27B (microRNA 27b) [NCBI Gene 407019] {aka MIR-27b, MIRN27B, miRNA27B}, MIR132 (microRNA 132) [NCBI Gene 406921] {aka MIRN132, miRNA132, mir-132}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, SIRT1 (sirtuin 1) [NCBI Gene 23411] {aka SIR2, SIR2L1, SIR2alpha}, CLDN5 (claudin 5) [NCBI Gene 7122] {aka AWAL, BEC1, CPETRL1, TMDVCF, TMVCF}, P2RX5 (purinergic receptor P2X 5) [NCBI Gene 5026] {aka LRH-1, P2X5, P2X5R}, Mmp9 (matrix metallopeptidase 9) [NCBI Gene 17395] {aka B/MMP9, Clg4b, Gel B, MMP-9, pro-MMP-9}, TOMM20 (translocase of outer mitochondrial membrane 20) [NCBI Gene 9804] {aka MAS20, MOM19, TOM20}, NR1H3 (nuclear receptor subfamily 1 group H member 3) [NCBI Gene 10062] {aka LXR-a, LXRA, RLD-1}, IRS1 (insulin receptor substrate 1) [NCBI Gene 3667] {aka HIRS-1}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, Tjp1 (tight junction protein 1) [NCBI Gene 21872] {aka ZO1}, Ptch1 (patched 1) [NCBI Gene 19206] {aka A230106A15Rik, Ptc, Ptc1, Ptch, mes, wig}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, AK2 (adenylate kinase 2) [NCBI Gene 204] {aka ADK2}, CYCS (cytochrome c, somatic) [NCBI Gene 54205] {aka CYC, HCS, THC4}, MIR210 (microRNA 210) [NCBI Gene 406992] {aka MIRN210, mir-210}, PPARGC1A (PPARG coactivator 1 alpha) [NCBI Gene 10891] {aka LEM6, PGC-1(alpha), PGC-1alpha, PGC-1v, PGC1, PGC1A}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, TRAF3 (TNF receptor associated factor 3) [NCBI Gene 7187] {aka CAP-1, CD40bp, CRAF1, IIAE5, IMD132A, IMD132B}, Vcam1 (vascular cell adhesion molecule 1) [NCBI Gene 22329] {aka CD106, Vcam-1}, Cldn5 (claudin 5) [NCBI Gene 12741] {aka MBEC1, Tmvcf}, MIR155 (microRNA 155) [NCBI Gene 406947] {aka MIRN155, miRNA155, mir-155}, ATP5MC1 (ATP synthase membrane subunit c locus 1) [NCBI Gene 516] {aka ATP5A, ATP5G, ATP5G1}, BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, Mmp2 (matrix metallopeptidase 2) [NCBI Gene 17390] {aka Clg4a, GelA, MMP-2}, SLC36A2 (solute carrier family 36 member 2) [NCBI Gene 153201] {aka PAT2, TRAMD1}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CD81 (CD81 molecule) [NCBI Gene 975] {aka CVID6, S5.7, TAPA1, TSPAN28}, MIR143 (microRNA 143) [NCBI Gene 406935] {aka MIRN143, mir-143}, MSR1 (macrophage scavenger receptor 1) [NCBI Gene 4481] {aka CD204, SCARA1, SR-A, SR-AI, SR-AII, SR-AIII}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Icam1 (intercellular adhesion molecule 1) [NCBI Gene 15894] {aka CD54, Icam-1, Ly-47, MALA-2}, HSPD1 (heat shock protein family D (Hsp60) member 1) [NCBI Gene 3329] {aka CPN60, GROEL, HLD4, HSP-60, HSP60, HSP65}, Mmp3 (matrix metallopeptidase 3) [NCBI Gene 17392] {aka EMS-2, MMP-3, SL-1, SLN-1, SLN1, STR-1}, KLF4 (KLF transcription factor 4) [NCBI Gene 9314] {aka EZF, GKLF}, CAV1 (caveolin 1) [NCBI Gene 857] {aka BSCL3, CGL3, LCCNS, MSTP085, PPH3, VIP21}, MIR29B1 (microRNA 29b-1) [NCBI Gene 407024] {aka MIRN29B1, miR-29b, miRNA29B1, mir-29b-1}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, TSG101 (tumor susceptibility 101) [NCBI Gene 7251] {aka TSG10, VPS23}, Adipoq (adiponectin, C1Q and collagen domain containing) [NCBI Gene 11450] {aka 30kDa, APN, Acdc, Acrp30, Ad, Adid}, FTMT (ferritin mitochondrial) [NCBI Gene 94033] {aka MTF}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, OCLN (occludin) [NCBI Gene 100506658] {aka BLCPMG, PPP1R115, PTORCH1}, Pparg (peroxisome proliferator activated receptor gamma) [NCBI Gene 19016] {aka Nr1c3, PPAR-gamma, PPAR-gamma2, PPARgamma, PPARgamma2}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, CD63 (CD63 molecule) [NCBI Gene 967] {aka AD1, HOP-26, ME491, MLA1, OMA81H, Pltgp40}, FABP4 (fatty acid binding protein 4) [NCBI Gene 2167] {aka A-FABP, AFABP, ALBP, HEL-S-104, aP2}, MIR33A (microRNA 33a) [NCBI Gene 407039] {aka MIR33, MIRN33, MIRN33A, hsa-mir-33, hsa-mir-33a, miR-33}, CD9 (CD9 molecule) [NCBI Gene 928] {aka BTCC-1, DRAP-27, MIC3, MRP-1, TSPAN-29, TSPAN29}, HSPA4 (heat shock protein family A (Hsp70) member 4) [NCBI Gene 3308] {aka APG-2, HEL-S-5a, HS24/P52, HSPH2, RY, hsp70}, 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}, FIS1 (fission, mitochondrial 1) [NCBI Gene 51024] {aka CGI-135, TTC11}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Ocln (occludin) [NCBI Gene 18260] {aka Ocl}, NOX4 (NADPH oxidase 4) [NCBI Gene 50507] {aka KOX, KOX-1, RENOX}, RETN (resistin) [NCBI Gene 56729] {aka ADSF, FIZZ3, RENT, RETN1, RSTN, XCP1}, MTHFD1L (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like) [NCBI Gene 25902] {aka FTHFSDC1, MTC1THFS, dJ292B18.2}, TJP1 (tight junction protein 1) [NCBI Gene 7082] {aka ZO-1} - **Diseases:** synaptic loss (MESH:D012183), hypoxia (MESH:D000860), ischemia (MESH:D007511), neurological deficits (MESH:D009461), metabolic dysregulation (MESH:D021081), metabolic abnormalities (MESH:D008659), cerebral small vessel disease (MESH:D059345), Stroke (MESH:D020521), vascular complications (MESH:D003925), cerebral blood vessel disease (MESH:D009383), multi-organ injury (MESH:D009102), obese (MESH:D009765), hemorrhagic (MESH:D006470), white matter lesions (MESH:D056784), CNS diseases (MESH:D002493), hemorrhagic stroke (MESH:D000083302), Neuroinflammation (MESH:D000090862), gastrointestinal, pancreatic, and hepatic disorders (MESH:D010195), traumatic brain injury (MESH:D000070642), Diabetic (MESH:D003920), vascular rupture (MESH:D012421), endothelial dysfunction (MESH:D014652), ischemic (MESH:D002545), cancer (MESH:D009369), AD (MESH:D000544), aMCI (MESH:D060825), NAFLD (MESH:D065626), Lewis lung cancer (MESH:D008175), Mitochondrial Dysfunction (MESH:D028361), dyslipidemia (MESH:D050171), loss of vision (MESH:D014786), hyperlipidemia (MESH:D006949), cerebral hypoperfusion (MESH:D002547), impaired nerve conduction (MESH:D019955), hematoma (MESH:D006406), Chronic hyperglycemia (MESH:D006943), metabolic syndrome (MESH:D024821), injury to (MESH:D014947), neurodegeneration (MESH:D019636), complications (MESH:D008107), Fatty (MESH:D008067), Inflammation (MESH:D007249), memory impairment (MESH:D008569), neuropathy (MESH:D009422), Cognitive Decline (MESH:D003072), glucose intolerance (MESH:D018149), amyloid (MESH:C000718787), Dementia (MESH:D003704), systemic (MESH:D015619), coronary artery disease (MESH:D003324), infarct (MESH:D007238), Adipose (MESH:D018205), impaired kidney function (MESH:D007674), peripheral arterial disease (MESH:D058729), T2DM (MESH:D003924), transient ischemic attack (MESH:D002546), IR (MESH:D007333), Cerebrovascular complications (MESH:D002561), endothelial injury (MESH:D057772), Neurovascular Impairment (MESH:D013901) - **Chemicals:** Ceramides (MESH:D002518), cholesterol (MESH:D002784), NO (MESH:D009569), 4-hydroxy-2-nonenal (MESH:C027576), free fatty acids (MESH:D005230), phospholipid (MESH:D010743), triglycerides (MESH:D014280), MDA (MESH:D015104), PI (MESH:D010716), fat (MESH:D005223), calcium (MESH:D002118), ROS (MESH:D017382), glucose (MESH:D005947), diacylglycerols (MESH:D004075), sphingolipids (MESH:D013107), Lipid (MESH:D008055), PS (MESH:D010718), PC (MESH:D010713), Malondialdehyde (MESH:D008315), SM (MESH:D013109), PE (MESH:C483858), superoxide (MESH:D013481), 4-hydroxyneonal (-), hydrogen peroxide (MESH:D006861) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116] - **Cell lines:** RAW 264.7 — Mus musculus (Mouse), Mouse leukemia, Cancer cell line (CVCL_0493), 3T3-L1 — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0123), Ad-EXs — Homo sapiens (Human), Telomerase immortalized cell line (CVCL_VU20), HTR8/SVneo — Homo sapiens (Human), Transformed cell line (CVCL_7162), MAECs — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_U411), MC38 — Mus musculus (Mouse), Mouse colon adenocarcinoma, Cancer cell line (CVCL_B288), HUVECs — Homo sapiens (Human), Finite cell line (CVCL_3722) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12937626/full.md ## Figures 5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12937626/full.md ## References 124 references — full list in the complete paper: https://tomesphere.com/paper/PMC12937626/full.md --- Source: https://tomesphere.com/paper/PMC12937626