Copper metabolism dysregulation contributes to mitochondrial damage in diabetic retinopathy (DR). This study investigated whether dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, alleviates DR by regulating copper homeostasis.
Methods
Clinical serum analysis, high glucose-exposed ARPE-19 cells, and diabetic rat models were used. Measurements included copper/ceruloplasmin levels, oxidative stress, mitochondrial function, and mitophagy markers.
Results
Clinical test results show that the levels of ceruloplasmin and copper in the serum of patients with proliferative diabetic retinopathy (PDR) are significantly higher than those of diabetic patients. High glucose induced copper/ceruloplasmin accumulation, downregulated ATP7B/SOD1/COX11/ATP7A/CCS, upregulated SCO1/DMT1, and impaired mitochondrial function in retinal pigment epithelial (RPE) cells. Dulaglutide reversed these effects, reducing oxidative stress and inflammation while restoring mitochondrial integrity. Crucially, it activated PINK1/Parkin-mediated mitophagy. The protective effects were abolished by CuSO4, confirming copper homeostasis as central to its mechanism. In diabetic rats, dulaglutide corrected retinal copper metabolism abnormalities, ameliorated histopathological damage, and enhanced mitophagy, thereby preserving mitochondrial function and alleviating diabetic retinopathy.
Conclusion
Dulaglutide ameliorates DR by correcting copper dysregulation and promoting mitophagy, highlighting copper homeostasis as a potential therapeutic target.
LinJHuangLSongL, et al.Unraveling the diabetic link to osteoporosis: novel insights from integrative bulk and single-cell transcriptomics. J Renin Angiotensin Aldosterone Syst2025; 26: 14703203251405957.
2.
LiangNLiJWangW, et al.PXN+ monocytes accelerate diabetic retinopathy progression and inflammaging via SELPLG-SELL axis-mediated immune chemotaxis and RAS modulation. J Renin Angiotensin Aldosterone Syst2025; 26: 14703203251386803.
3.
XourafaGKorbmacherMRodenM. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat Rev Endocrinol2024; 20: 27–49.
4.
HuangYLiZZhuJ, et al.Construction of a risk prediction model for adverse pregnancy outcomes in primipara with gestational diabetes mellitus combined with pregnancy-induced hypertension syndrome. Clinical and Experimental Hypertension (New York, NY: 1993)2025; 47: 2492621.
5.
HuSYanJYuanQ, et al.The role of miRNAs in podocyte injury in diabetic nephropathy: mechanisms and clinical applications. Curr Mol Pharmacol2024; 17: e18761429363169.
6.
ChandraPSachanNSaraswatN, et al.A detailed review of molecular pathways and mechanisms responsible for the development and aggravation of neuropathy and nephropathy in diabetes. Curr Mol Pharmacol2024; 17: e280323215026.
7.
SunRZuoL. MAPK8 And HDAC6: potential biomarkers related to autophagy in diabetic retinopathy based on bioinformatics analysis. Front Endocrinol (Lausanne)2025; 16: 1487007.
8.
YaoHLiTZhangJ. Inflammatory factors secreted from endothelial cells induced by high glucose impair human retinal pigment epithelial cells. Turkish Journal of Biochemistry2024; 49: 422–429.
9.
Al-ShabraweyMZhangWMcDonaldD. Diabetic retinopathy: mechanism, diagnosis, prevention, and treatment. BioMed Res Int2015; 2015:854593.
10.
NianSMiYRenK, et al.The inhibitory effects of Dulaglutide on cellular senescence against high glucose in human retinal endothelial cells. Hum Cell2022; 35: 995–1004.
ChenZYuJFuL, et al.Unveiling the metal-driven death: ferroptosis and cuproptosis in leukemia. Eur J Med Res2025; 30: 1241.
13.
WangYChenSZhouZ, et al.Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT. Eur J Med Res2025; 30: 394.
14.
DascaluAMAnghelacheAStanaD, et al.Serum levels of copper and zinc in diabetic retinopathy. Potential new therapeutic targets (Review). Experimental and Therapeutic Medicine2022; 23: 324.
15.
UgarteMOsborneNNBrownLA, et al.Iron, zinc, and copper in retinal physiology and disease. Surv Ophthalmol2013; 58: 585–609.
ChuLXiaoLXuB, et al.Dissociation of HKII in retinal epithelial cells induces oxidative stress injury in the retina. Int J Mol Med2019; 44: 1377–1387.
18.
YangYDongCMaX, et al.Advances in cuproptosis harnessing copper-based nanomaterials for cancer therapy. J Mater Chem B2025; 13: 2978–2999.
19.
KavyashreeSHarithpriyaKRamkumarKM. Miro1- a key player in β-cell function and mitochondrial dynamics under diabetes mellitus. Mitochondrion2025; 84: 102039.
20.
WangZLZhangXYTanCY, et al.FXR suppress Müller cell activation by regulating cGAS/STING pathway in diabetic retinopathy. FEBS J2025; 292: 6035–6053.
21.
HuQZhangXHuangJ, et al.The STAT1-SLC31A1 axis: potential regulation of cuproptosis in diabetic retinopathy. Gene2024; 930: 148861.
22.
Pardo LozanoFRubio MarcosACasañ FernándezR, et al.Real-world evaluation of the efficacy and safety of switching from weekly dulaglutide to weekly semaglutide: the SEMA-SWITCH study. Endocrinologia, Diabetes y Nutricion2025; 72: 501574.
23.
AttiaSMAlshamraniAAAhmadSF, et al.Dulaglutide reduces oxidative DNA damage and hypermethylation in the somatic cells of mice fed a high-energy diet by restoring redox balance, inflammatory responses, and DNA repair gene expressions. J Biochem Mol Toxicol2024; 38: e23764.
24.
ZhangQSunCWuJ, et al.Pharmacokinetic similarity study comparing the biosimilar candidate, LY05008, with its reference product dulaglutide in healthy Chinese male subjects. Expert Opin Biol Ther2023; 23: 727–735.
25.
LiuLChengZWangL, et al.Efficacy and safety of dulaglutide biosimilar ly05008 versus the reference product dulaglutide (trulicity) in Chinese adults with type 2 diabetes mellitus: a randomized, open-label, active comparator study. J Diabetes2025; 17: e70077.
26.
SinghHNattNKNimDK. Association between glucagon-like peptide-1 agonists and risk of diabetic retinopathy: a disproportionality analysis using FDA adverse event reporting system data. Expert Rev Endocrinol Metab2025; 20: 147–152.
27.
YoshidaYJoshiPBarriS, et al.Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes - A systematic review and meta-analysis. J Diabetes Complications2022; 36: 108255.
28.
LakhaniMKwanATMihalacheA, et al.Association of glucagon-like peptide-1 receptor agonists with optic nerve and retinal adverse events: a population-based observational study across 180 countries. Am J Ophthalmol2025; 277: 148–168.
29.
NiNYangLPLinX, et al.Studies on the mechanism of energy metabolism via AMPK/PGC-1α signaling pathway induced by compatibility of Ligusticum chuanxiong Hort and Gastrodia. Phytother Res2024; 38: 4835–4854.
30.
GaoYLiSZhangS, et al.Atractylenolide-I attenuates MPTP/MPP(+)-mediated oxidative stress in Parkinson's disease through SIRT1/PGC-1α/Nrf2 axis. Neurochem Res2024; 50: 18.
31.
ZhangXJiangQSuY, et al.AMPK Phosphorylates and stabilises copper transporter 1 to synergise metformin and copper chelator for breast cancer therapy. Br J Cancer2023; 128: 1452–1465.
32.
PanZDengCShuiL, et al.Copper deficiency induces oxidative stress in liver of mice by blocking the Nrf(2) pathway. Biol Trace Elem Res2024; 202: 1603–1611.
33.
GungorHKaraH. Effects of selenium, zinc, insulin and metallothionein on cadmium-induced oxidative stress and metallothionein gene expression levels in diabetic rats. J Basic Clin Physiol Pharmacol2020; 31: 20190198.
34.
XieSZhangMShiW, et al.Long-term activation of glucagon-like peptide-1 receptor by dulaglutide prevents diabetic heart failure and metabolic remodeling in type 2 diabetes. J Am Heart Assoc2022; 11: e026728.
35.
MeiXLiYWuJ, et al.Dulaglutide restores endothelial progenitor cell levels in diabetic mice and mitigates high glucose-induced endothelial injury through SIRT1-mediated mitochondrial fission. Biochem Biophys Res Commun2024; 716: 150002.
36.
WangRWangNHanY, et al.Dulaglutide alleviates LPS-induced injury in cardiomyocytes. ACS Omega2021; 6: 8271–8278.
37.
ChazotteB. Labeling mitochondria with JC-1. Cold Spring Harb Protoc2011; 6: 1103–1104.
38.
LiHYWangJXiaoT, et al.STING Immune activation of microglia aggravating neurovascular unit damage in diabetic retinopathy. Free Radical Biol Med2025; 233: 86–101.
39.
MahapadiAAShirsathVPundgeA. Non-proliferative diabetic retinopathy detection using rosmarus quagga optimized explainable generative meta learning based deep convolutional neural network model. Int Ophthalmol2025; 45: 178.
40.
MishraNSaxenaSShuklaRK, et al.Advanced glycation end products are biomolecular biomarkers for proliferative diabetic retinopathy. Indian J Ophthalmol2025; 73: 906–911.
41.
BehlTKotwaniA. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. Pharmacol Res2015; 99: 137–148.
42.
SongSQiuDLuoF, et al.Knockdown of NLRP3 alleviates high glucose or TGFB1-induced EMT in human renal tubular cells. J Mol Endocrinol2018; 61: 101–113.
43.
ChenJTengYYangM. Role of inflammatory regulatory factors in neovascularization of diabetic retinopathy. Internation Eye Sci [Chinese]2021; 21: 1390–1393.
44.
LiTHQiuCJYuXJ, et al.Increased serum pigment epithelium-derived factor in women with gestational diabetes is associated with type 2 diabetes. Int J Endocrinol2015; 2015: 346938.
45.
SongEDongYHanLN, et al.Diabetic retinopathy: VEGF, bFGF and retinal vascular pathology. Chin Med J2004; 117: 247–251.
46.
LiZDKangSLiH, et al.Absence of astrocytic ceruloplasmin reverses the senescence process with aging of learning and memory abilities. Redox Biol2025; 82: 103611.
47.
DmitrievOYPatryJ. Structure and mechanism of the human copper transporting ATPases: fitting the pieces into a moving puzzle. Biochim Biophys Acta Biomembr2024; 1866: 184306.
48.
ChenYLiCLiM, et al.Roles of copper transport systems members in breast cancer. Cancer Med2024; 13: e70498.
49.
VanišováMBurskáDKřížováJ, et al.Stable COX17 downregulation leads to alterations in mitochondrial ultrastructure, decreased copper content and impaired cytochrome c oxidase biogenesis in HEK293 cells. Folia Biol2019; 65: 181–187.
50.
TianZJiangSZhouJ, et al.Copper homeostasis and cuproptosis in mitochondria. Life Sci2023; 334: 122223.
51.
ChenLMinJWangF. Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Therap2022; 7: 378.
52.
ZhangYXiXMeiY, et al.High-glucose induces retinal pigment epithelium mitochondrial pathways of apoptosis and inhibits mitophagy by regulating ROS/PINK1/Parkin signal pathway. Biomed Pharmacother2019; 111: 1315–1325.
53.
YeDZhuJSuS, et al.Natural small molecules regulating the mitophagy pathway counteract the pathogenesis of diabetes and chronic complications. Front Pharmacol2025; 16: 1571767.
54.
HuXLvJZhaoY, et al.Important regulatory role of mitophagy in diabetic microvascular complications. J Transl Med2025; 23: 269.
55.
MadhuriYSaifullahQPandeyM, et al.An overview of recent developments in clinical trials of anti-diabetic drugs. Panminerva Med2025; 67: 87–100.
56.
De MarinisYZSalehiAWardCE, et al.GLP-1 inhibits and Adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2 + channel-dependent exocytosis. Cell Metab2010; 11: 543–553.
57.
KimuraROkouchiMFujiokaH, et al.Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3 K/Akt/mTOR/GCLc/redox signaling pathway. Neuroscience2009; 162: 1212–1219.
