[1]

GBD 2021 Diabetes Collaborators. 2023. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 402:203−234

doi: 10.1016/S0140-6736(23)01301-6
[2]

Zhang X, Zhang F, Xu X. 2024. Single-cell RNA sequencing in exploring the pathogenesis of diabetic retinopathy. Clinical and Translational Medicine 14:e1751

doi: 10.1002/ctm2.1751
[3]

Zhang L, Xu F, Hou L. 2024. IL-6 and diabetic kidney disease. Frontiers in Immunology 15:1465625

doi: 10.3389/fimmu.2024.1465625
[4]

Luo X, Xu Q, Wang Z, Huang C, Liu C, et al. 2025. A lesion-fusion neural network for multi-view diabetic retinopathy grading. IEEE Journal of Biomedical and Health Informatics 29:3184−3193

doi: 10.1109/JBHI.2024.3384251
[5]

Jansson Sigfrids F, Dahlström EH, Forsblom C, Sandholm N, Harjutsalo V, et al. 2021. Remnant cholesterol predicts progression of diabetic nephropathy and retinopathy in type 1 diabetes. Journal of Internal Medicine 290:632−645

doi: 10.1111/joim.13298
[6]

Gamez M, Elhegni HE, Fawaz S, Ho KH, Campbell NW, et al. 2024. Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes. Cardiovascular Diabetology 23:50

doi: 10.1186/s12933-024-02133-1
[7]

Li K, Wang YJ, Chen C, Wang XJ, Li W. 2025. Targeting pyroptosis: a novel strategy of ginseng for the treatment of diabetes and its chronic complications. Phytomedicine 138:156430

doi: 10.1016/j.phymed.2025.156430
[8]

Liu M, Lim ST, Song W, Coffman TM, Wang X. 2026. Beyond lipids: fenofibrate in diabetic retinopathy and nephropathy. Trends in Pharmacological Sciences 47:325−341

doi: 10.1016/j.tips.2025.07.014
[9]

He F, Ng Yin Ling C, Nusinovici S, Cheng CY, Wong TY, et al. 2024. Development and external validation of machine learning models for diabetic microvascular complications: cross-sectional study with metabolites. Journal of Medical Internet Research 26:e41065

doi: 10.2196/41065
[10]

Zhao L, Hu H, Zhang L, Liu Z, Huang Y, et al. 2024. Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions. MedComm 5:e516

doi: 10.1002/mco2.516
[11]

Dilworth L, Stennett D, Facey A, Omoruyi F, Mohansingh S, et al. 2024. Diabetes and the associated complications: the role of antioxidants in diabetes therapy and care. Biomedicine & Pharmacotherapy 181:117641

doi: 10.1016/j.biopha.2024.117641
[12]

Fu S, Sun W, Liu L, Xiao J, Xiong J, et al. 2024. Müller cells harboring exosomal lncRNA OGRU modulate microglia polarization in diabetic retinopathy by serving as miRNA sponges. Diabetes 73:1919−1934

doi: 10.2337/db23-1015
[13]

Cao L, Ding L, Xia Q, Zhang Z, Li M, et al. 2025. Macrophage polarization in diabetic vascular complications: mechanistic insights and therapeutic targets. Journal of Translational Medicine 23:1050

doi: 10.1186/s12967-025-07075-0
[14]

Li ZH, Sun ZJ, Tang SCW, Zhao MH, Chen M, et al. 2025. Finerenone alleviates over-activation of complement C5a-C5aR1 axis of macrophages by regulating G protein subunit alpha i2 to improve diabetic nephropathy. Cells 14:337

doi: 10.3390/cells14050337
[15]

Li Z, Wang W, Zhu L, Wang Z, Liu C, et al. 2025. Reprogramming retinal microglia polarization by efferocytosis-mimicking nanoparticles for ameliorating diabetic retinopathy. ACS Applied Materials & Interfaces 17:29210−29223

doi: 10.1021/acsami.5c03170
[16]

Sang W, Zhang X, Hu Q, Jiang B, Guan J, et al. 2025. Inhibition of Dectin-1 alleviates inflammation in early diabetic retinopathy by regulating microglia phenotype. Gene 963:149572

doi: 10.1016/j.gene.2025.149572
[17]

Shi J, Wei X, Zou G, Liu X, An J, et al. 2025. Exploring the protective role of DDIT4/mTOR in podocyte integrity through macrophage polarization in diabetic kidney disease. Renal Failure 47:2546623

doi: 10.1080/0886022X.2025.2546623
[18]

Li J, Chen K, Li X, Zhang X, Zhang L, et al. 2023. Mechanistic insights into the alterations and regulation of the AKT signaling pathway in diabetic retinopathy. Cell Death Discovery 9:418

doi: 10.1038/s41420-023-01717-2
[19]

Tong Y, Li X, Zhu Y, Liao X, Zhang L. 2025. Modified Zn-MOF multifunctional nanoparticles for combination therapy of DN and exploratory study of the nephroprotective effect. Biomedicine & Pharmacotherapy 192:118713

doi: 10.1016/j.biopha.2025.118713
[20]

Pearce A, Redfern-Nichols T, Wills E, Rosa M, Manulak I, et al. 2025. Quantitative approaches for studying G protein-coupled receptor signalling and pharmacology. Journal of Cell Science 138:JCS263434

doi: 10.1242/jcs.263434
[21]

Singh A, Shadangi S, Rana S. 2025. G-protein coupled receptors in neuroinflammation, neuropharmacology, and therapeutics. Biochemical Pharmacology 242:117301

doi: 10.1016/j.bcp.2025.117301
[22]

Olaniru OE, Persaud SJ. 2019. Adhesion G-protein coupled receptors: implications for metabolic function. Pharmacology & Therapeutics 198:123−134

doi: 10.1016/j.pharmthera.2019.02.012
[23]

Strassheim D, Sullivan T, Irwin DC, Gerasimovskaya E, Lahm T, et al. 2021. Metabolite G-protein coupled receptors in cardio-metabolic diseases. Cells 10:3347

doi: 10.3390/cells10123347
[24]

Chen L, Zhang H, Zhang Y, Li X, Wang M, et al. 2024. Ganglion cell-derived LysoPS induces retinal neovascularisation by activating the microglial GPR34-PI3K-AKT-NINJ1 axis. Journal of Neuroinflammation 21:278

doi: 10.1186/s12974-024-03265-7
[25]

Tang H, Li K, Shi Z, Wu J. 2025. G-protein-coupled receptors in chronic kidney disease induced by hypertension and diabetes. Cells 14:729

doi: 10.3390/cells14100729
[26]

Sun P, Liu J, Chen G, Guo Y. 2025. The role of G protein-coupled receptors in the regulation of orthopaedic diseases by gut microbiota. Nutrients 17:1702

doi: 10.3390/nu17101702
[27]

Hansen W, Loser K, Westendorf AM, Bruder D, Pfoertner S, et al. 2006. G protein-coupled receptor 83 overexpression in naive CD4+CD25− T cells leads to the induction of Foxp3+ regulatory T cells in vivo. Journal of Immunology 177:209−215

doi: 10.4049/jimmunol.177.1.209
[28]

Zhang Y, Xiao Y, Zhu Y, Yan L, Cheng N, et al. 2025. GPR83 protects cochlear hair cells against ibrutinib-induced hearing loss through AKT signaling pathways. Frontiers in Medicine 12:1579285

doi: 10.3389/fmed.2025.1579285
[29]

Consonni A, Morara S, Codazzi F, Grohovaz F, Zacchetti D. 2011. Inhibition of lipopolysaccharide-induced microglia activation by calcitonin gene related peptide and adrenomedullin. Molecular and Cellular Neuroscience 48:151−160

doi: 10.1016/j.mcn.2011.07.006
[30]

Sun J, Qian P, Kang Y, Dai HB, Wang FZ, et al. 2021. Adrenomedullin 2 attenuates LPS-induced inflammation in microglia cells by receptor-mediated cAMP-PKA pathway. Neuropeptides 85:102109

doi: 10.1016/j.npep.2020.102109
[31]

Wang F, Kong L, Wang W, Shi L, Wang M, et al. 2021. Adrenomedullin 2 improves bone regeneration in type 1 diabetic rats by restoring imbalanced macrophage polarization and impaired osteogenesis. Stem Cell Research & Therapy 12:288

doi: 10.1186/s13287-021-02368-9
[32]

Liu K, Shi R, Wang S, Liu Q, Zhang H, et al. 2021. Intermedin inhibits the ox-LDL–induced inflammation in RAW264.7 cells by affecting fatty acid–binding protein 4 through the PKA pathway. Frontiers in Pharmacology 12:724777

doi: 10.3389/fphar.2021.724777
[33]

Wang Y, Tian J, Mi Y, Ren X, Lian S, et al. 2021. Experimental study on renoprotective effect of intermedin on diabetic nephropathy. Molecular and Cellular Endocrinology 528:111224

doi: 10.1016/j.mce.2021.111224
[34]

Kakihara S, Matsuda Y, Hirabayashi K, Imai A, Iesato Y, et al. 2023. Role of adrenomedullin 2/intermedin in the pathogenesis of neovascular age-related macular degeneration. Laboratory Investigation 103:100038

doi: 10.1016/j.labinv.2022.100038
[35]

Massimini M, Bachetti B, Dalle Vedove E, Benvenga A, Di Pierro F, et al. 2022. A set of dysregulated target genes to reduce neuroinflammation at molecular level. International Journal of Molecular Sciences 23:7175

doi: 10.3390/ijms23137175
[36]

Guan R, Kang Z, Li L, Yan X, Gao T. 2024. PIK3CA regulates development of diabetes retinopathy through the PI3K/Akt/mTOR pathway. PLoS One 19:e0295813

doi: 10.1371/journal.pone.0295813
[37]

Zang L, Saitoh S, Katayama K, Zhou W, Nishimura N, et al. 2024. A zebrafish model of diabetic nephropathy shows hyperglycemia, proteinuria and activation of the PI3K/Akt pathway. Disease Models & Mechanisms 17:dmm050438

doi: 10.1242/dmm.050438
[38]

Hansen W, Westendorf AM, Toepfer T, Mauel S, Geffers R, et al. 2010. Inflammation in vivo is modulated by GPR83 isoform-4 but not GPR83 isoform-1 expression in regulatory T cells. Genes & Immunity 11:357−361

doi: 10.1038/gene.2010.5
[39]

Tu C, Wang L, Wei L. 2022. The role of PKM2 in diabetic microangiopathy. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 15:1405−1412

doi: 10.2147/dmso.s366403
[40]

Pang Y, Li Y, Lv Y, Sun L, Zhang S, et al. 2016. Intermedin restores hyperhomocysteinemia-induced macrophage polarization and improves insulin resistance in mice. Journal of Biological Chemistry 291:12336−12345

doi: 10.1074/jbc.M115.702654
[41]

Li L, Ma P, Liu Y, Huang C, Wai-sum O, et al. 2013. Intermedin attenuates LPS-induced inflammation in the rat testis. PLoS One 8:e65278

doi: 10.1371/journal.pone.0065278
[42]

Hong Y, Hay DL, Quirion R, Poyner DR. 2012. The pharmacology of adrenomedullin 2/intermedin. British Journal of Pharmacology 166:110−120

doi: 10.1111/j.1476-5381.2011.01530.x
[43]

Sak K. 2024. GPCRs as targets for flavonoids in cancer cells: new options for intervention. Exploration of Targeted Anti-Tumor Therapy 5:1155−1167

doi: 10.37349/etat.2024.00268
[44]

Yang Y, Wang Y, Yu XY, Lian LH. 2018. Clinical observation on effects of Zishen Jianpi Huayu pills combined with laser treatment on retinal thickness of macular area, NOS, VEGF and IL-6 in diabetic macular edema patients. China Journal of Chinese Ophthalmology 28:159−162 (in Chinese)

doi: 10.13444/j.cnki.zgzyykzz.2018.03.008
[45]

Teng Y, Zeng XT, Luo YZ, Liu H, Yang Y, et al. 2022. Study on the effect of oral Zishen Jianpi Huayu Tablets combined with anti-VEGF therapy on cytokines in aqueous humor of diabetic retinopathy patients. China Journal of Chinese Ophthalmology 32:767−772 (in Chinese)

doi: 10.13444/j.cnki.zgzyykzz.2022.10.003
[46]

Feng H, Qi YL, Feng YW, Zhou J, Luo YZ, et al. 2024. Exploring the intervention mechanism of Zishen Jianpi Huayu Tablets on diabetic retinopathy based on network pharmacology, molecular docking an experimental validation. Traditional Chinese Drug Research & Clinical Pharmacology 35:1197−1205 (in Chinese)

doi: 10.19378/j.issn.1003-9783.2024.08.011
[47]

Lu C, Lan Q, Song Q, Yu X. 2024. Identification and validation of ferroptosis-related genes for diabetic retinopathy. Cellular Signalling 113:110955

doi: 10.1016/j.cellsig.2023.110955
[48]

Li Q, Wan XG, Liu SL, Liu M. 2020. Clinical observation of Zi-Shen-Jian-Pi-Hua-Yu Tablets in treating early diabetic nephropathy with Qi-Yin deficiency and blood stasis syndrome. Journal of Guangzhou University of Traditional Chinese Medicine 37:1224−1228 (in Chinese)

doi: 10.13359/j.cnki.gzxbtcm.2020.07.004
[49]

Li KM, Xu ZP, Tian N, Dong Y, Liu H, et al. 2020. Zi-Shen-Jian-Pi-Hua-Yu Tablets ameliorate diabetic retinopathy in rats by inhibiting the AGEs/RAGE/NF-κB pathway. Traditional Chinese Drug Research & Clinical Pharmacology 31:1147−1152 (in Chinese)

doi: 10.19378/j.issn.1003-9783.2020.10.003
[50]

Ortiz-Martínez M, González-González M, Martagón AJ, Hlavinka V, Willson RC, et al. 2022. Recent developments in biomarkers for diagnosis and screening of type 2 diabetes mellitus. Current Diabetes Reports 22:95−115

doi: 10.1007/s11892-022-01453-4
[51]

Serban D, Dascalu AM. 2024. New diagnostic and therapeutic approaches in diabetic microvascular complications. Biomedicines 12:1858

doi: 10.3390/biomedicines12081858
[52]

Zhou H, Mu L, Yang Z, Shi Y. 2023. Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy. Frontiers in Immunology 14:1113212

doi: 10.3389/fimmu.2023.1113212
[53]

Wang L, Su J, Liu Z, Ding S, Li Y, et al. 2024. Identification of immune-associated biomarkers of diabetes nephropathy tubulointerstitial injury based on machine learning: a bioinformatics multi-chip integrated analysis. BioData Mining 17:20

doi: 10.1186/s13040-024-00369-x
[54]

Liu W, Tong B, Xiong J, Zhu Y, Lu H, et al. 2025. Identification of macrophage polarisation and mitochondria-related biomarkers in diabetic retinopathy. Journal of Translational Medicine 23:23

doi: 10.1186/s12967-024-06038-1
[55]

Luo J, Guo X, Zheng Y, Yang Z, Pei SY, et al. 2025. Integration of multi-omics data and machine learning to identify antioxidant biomarkers in type 1 diabetes. Free Radical Biology and Medicine 236:41−56

doi: 10.1016/j.freeradbiomed.2025.05.385
[56]

Asnaghi L, White DT, Key N, Choi J, Mahale A, et al. 2019. ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma. Oncogene 38:2056−2075

doi: 10.1038/s41388-018-0543-2
[57]

Adam RC, Pryce DS, Lee JS, Zhao Y, Mintah IJ, et al. 2023. Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice. Proceedings of the National Academy of Sciences of the United States of America 120:e2309967120

doi: 10.1073/pnas.2309967120
[58]

Wu J, Li K, Peng W, Li H, Li Q, et al. 2019. Autoinducer-2 of Fusobacterium nucleatum promotes macrophage M1 polarization via TNFSF9/IL-1β signaling. International Immunopharmacology 74:105724

doi: 10.1016/j.intimp.2019.105724
[59]

Urabe F, Kosaka N, Sawa Y, Yamamoto Y, Ito K, et al. 2020. miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4, and CHORDC1. Science Advances 6:eaay3051

doi: 10.1126/sciadv.aay3051
[60]

Wang Z, Wang K, Yu X, Chen M, Du Y. 2022. Comprehensive analysis of expression signature and immune microenvironment signature of biomarker Endothelin Receptor Type A in stomach adenocarcinoma. Journal of Cancer 13:2086−2104

doi: 10.7150/jca.68673
[61]

Tao Y, Xiong M, Peng Y, Yao L, Zhu H, et al. 2025. Machine learning-based identification and validation of immune-related biomarkers for early diagnosis and targeted therapy in diabetic retinopathy. Gene 934:149015

doi: 10.1016/j.gene.2024.149015
[62]

Udler MS, McCarthy MI, Florez JC, Mahajan A. 2019. Genetic risk scores for diabetes diagnosis and precision medicine. Endocrine Reviews 40:1500−1520

doi: 10.1210/er.2019-00088