American Diabetes, A. Diagnosis and classification of diabetes mellitus. Diabetes Care 34, S62–S69 (2011).
Google Scholar
Collaboration, N. C. D. R. F. Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants. Lancet 404, 2077–2093 (2024).
Google Scholar
Collaborators, G. B. D. D. 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 (2023).
Google Scholar
Chan, J. C. N. et al. The Lancet Commission on diabetes: using data to transform diabetes care and patient lives. Lancet 396, 2019–2082 (2021).
Google Scholar
Zhang, X., Zhang, J., Ren, Y., Sun, R. & Zhai, X. Unveiling the pathogenesis and therapeutic approaches for diabetic nephropathy: insights from panvascular diseases. Front Endocrinol.15, 1368481 (2024).
Google Scholar
Yu, M. G. et al. Protective factors and the pathogenesis of complications in diabetes. Endocr. Rev. 45, 227–252 (2024).
Google Scholar
Jia, W. et al. Standards of medical care for type 2 diabetes in China 2019. Diabetes Metab. Res Rev. 35, e3158 (2019).
Google Scholar
American Diabetes Association Professional Practice Diagnosis and classification of diabetes: standards of care in diabetes-2024. Diabetes Care 47, S20–S42 (2024).
Google Scholar
Cole, J. B. & Florez, J. C. Genetics of diabetes mellitus and diabetes complications. Nat. Rev. Nephrol. 16, 377–390 (2020).
Google Scholar
Abel, E. D. et al. Diabetes mellitus-Progress and opportunities in the evolving epidemic. Cell 187, 3789–3820 (2024).
Google Scholar
Hsu, P. D., Lander, E. S. & Zhang, F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 157, 1262–1278 (2014).
Google Scholar
Gerace, D. et al. CRISPR-targeted genome editing of mesenchymal stem cell-derived therapies for type 1 diabetes: a path to clinical success?. Stem Cell Res Ther. 8, 62 (2017).
Google Scholar
El Nahas, R., Al-Aghbar, M. A., Herrero, L., van Panhuys, N. & Espino-Guarch, M. Applications of genome-editing technologies for type 1 diabetes. Int. J. Mol. Sci. 25, (2023).
Xu, Y. et al. LINC MIR503HG Controls SC-beta Cell differentiation and insulin production by targeting CDH1 and HES1. Adv. Sci. 11, e2305631 (2024).
Google Scholar
Ma, Q. et al. ZnT8 loss-of-function accelerates functional maturation of hESC-derived beta cells and resists metabolic stress in diabetes. Nat. Commun. 13, 4142 (2022).
Google Scholar
Defronzo, R. A. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58, 773–795 (2009).
Google Scholar
Forbes, J. M. & Cooper, M. E. Mechanisms of diabetic complications. Physiol. Rev. 93, 137–188 (2013).
Google Scholar
Yazdani, S. et al. Dynamic glucose uptake, storage, and release by human microvascular endothelial cells. Mol. Biol. Cell 33, ar106 (2022).
Google Scholar
Zhang, Z. Y. et al. Molecular mechanisms of glucose fluctuations on diabetic complications. Front Endocrinol.10, 640 (2019).
Google Scholar
Srivastava, S. P. et al. Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys. iScience 24, 102390 (2021).
Google Scholar
Hou, Y. et al. Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney. Cell Mol. Life Sci. 81, 23 (2024).
Google Scholar
Liao, Y. L., Fang, Y. F., Sun, J. X. & Dou, G. R. Senescent endothelial cells: a potential target for diabetic retinopathy. Angiogenesis 27, 663–679 (2024).
Google Scholar
Liu, Y. et al. Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment. Cell Death Discov. 10, 148 (2024).
Google Scholar
Zhang, Y. et al. Synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles. Cell Death Discov. 9, 51 (2023).
Google Scholar
Zhao, W. B. & Sheng, R. The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca(2+) transport in the pathogenesis of diseases. Acta Pharm. Sin. 46, 271–291 (2025).
Google Scholar
Kelley, N., Jeltema, D., Duan, Y. & He, Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 20, 3328 (2019).
Tai, G. J. et al. NLRP3 inflammasome-mediated premature immunosenescence drives diabetic vascular aging dependent on the induction of perivascular adipose tissue dysfunction. Cardiovasc Res 121, 77–96 (2025).
Google Scholar
Wu, M. et al. Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy. Metabolism 118, 154748 (2021).
Google Scholar
Lv, D. et al. Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing. Cell Rep. Med 4, 101129 (2023).
Google Scholar
Li, C. et al. Macrophage M1 regulatory diabetic nephropathy is mediated by m6A methylation modification of lncRNA expression. Mol. Immunol. 144, 16–25 (2022).
Google Scholar
Schiffrin, E. L. & Pollock, D. M. Endothelin system in hypertension and chronic kidney disease. Hypertension 81, 691–701 (2024).
Google Scholar
Davenport, A. P. et al. Endothelin. Pharm. Rev. 68, 357–418 (2016).
Google Scholar
van Raalte, D. H. et al. Combination therapy for kidney disease in people with diabetes mellitus. Nat. Rev. Nephrol. 20, 433–446 (2024).
Google Scholar
Bonner, R., Albajrami, O., Hudspeth, J. & Upadhyay, A. Diabetic kidney disease. Prim. Care 47, 645–659 (2020).
Google Scholar
Cortinovis, M., Perico, N., Ruggenenti, P., Remuzzi, A. & Remuzzi, G. Glomerular hyperfiltration. Nat. Rev. Nephrol. 18, 435–451 (2022).
Google Scholar
Vallon, V. & Thomson, S. C. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat. Rev. Nephrol. 16, 317–336 (2020).
Google Scholar
Stefansson, V. T. N. et al. Molecular programs associated with glomerular hyperfiltration in early diabetic kidney disease. Kidney Int. 102, 1345–1358 (2022).
Google Scholar
Yao, X. et al. Klotho Ameliorates Podocyte Injury through Targeting TRPC6 Channel in Diabetic Nephropathy. J. Diabetes Res. 2022, 1329380 (2022).
Google Scholar
Qi, C. et al. Increased dishevelled associated activator of morphogenesis 2, a new podocyte-associated protein, in diabetic nephropathy. Nephrol. Dial. Transpl. 36, 1006–1016 (2021).
Google Scholar
Akhtar, M., Taha, N. M., Nauman, A., Mujeeb, I. B. & Al-Nabet, A. Diabetic kidney disease: past and present. Adv. Anat. Pathol. 27, 87–97 (2020).
Google Scholar
Susztak, K., Raff, A. C., Schiffer, M. & Bottinger, E. P. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55, 225–233 (2006).
Google Scholar
Ducasa, G. M. et al. ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes. J. Clin. Invest 129, 3387–3400 (2019).
Google Scholar
Zhang, J. et al. ABCA1 deficiency-mediated glomerular cholesterol accumulation exacerbates glomerular endothelial injury and dysfunction in diabetic kidney disease. Metabolism 139, 155377 (2023).
Google Scholar
Mohandes, S. et al. Molecular pathways that drive diabetic kidney disease. J. Clin. Investig. 133, e165654 (2023).
Wei, Y. et al. To target cellular senescence in diabetic kidney disease: the known and the unknown. Clin. Sci.138, 991–1007 (2024).
Google Scholar
Liang, D. et al. Metformin improves the senescence of renal tubular epithelial cells in a high-glucose state through E2F1. Front Pharm. 13, 926211 (2022).
Google Scholar
Eleftheriadis, T. et al. Dapagliflozin prevents high-glucose-induced cellular senescence in renal tubular epithelial cells. Int. J. Mol. Sci. 23, 16107 (2022).
Nian, S. et al. The inhibitory effects of Dulaglutide on cellular senescence against high glucose in human retinal endothelial cells. Hum. Cell 35, 995–1004 (2022).
Google Scholar
Sugita, E., Hayashi, K., Hishikawa, A. & Itoh, H. Epigenetic alterations in podocytes in diabetic nephropathy. Front Pharm. 12, 759299 (2021).
Google Scholar
Fu, J., Lee, K., Chuang, P. Y., Liu, Z. & He, J. C. Glomerular endothelial cell injury and cross talk in diabetic kidney disease. Am. J. Physiol. Ren. Physiol. 308, F287–F297 (2015).
Google Scholar
Tanabe, K., Wada, J. & Sato, Y. Targeting angiogenesis and lymphangiogenesis in kidney disease. Nat. Rev. Nephrol. 16, 289–303 (2020).
Google Scholar
Schwager, S. & Detmar, M. Inflammation and Lymphatic Function. Front Immunol. 10, 308 (2019).
Google Scholar
Sandholm, N. et al. Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease. Diabetologia 65, 1495–1509 (2022).
Google Scholar
Yao, L. et al. Mitochondrial dysfunction in diabetic tubulopathy. Metabolism 131, 155195 (2022).
Google Scholar
Kanbay, M. et al. Proximal tubule hypertrophy and hyperfunction: a novel pathophysiological feature in disease states. Clin. Kidney J. 17, sfae195 (2024).
Google Scholar
Juszczak, F., Caron, N., Mathew, A. V. & Decleves, A. E. Critical role for AMPK in metabolic disease-induced chronic kidney disease. Int. J. Mol. Sci. 21, 7994 (2020).
Google Scholar
Hong, Q. et al. Modulation of transforming growth factor-beta-induced kidney fibrosis by leucine-rich α-2 glycoprotein-1. Kidney Int 101, 299–314 (2022).
Google Scholar
Tang, S. C. W. & Yiu, W. H. Innate immunity in diabetic kidney disease. Nat. Rev. Nephrol. 16, 206–222 (2020).
Google Scholar
Yang, M. & Zhang, C. The role of innate immunity in diabetic nephropathy and their therapeutic consequences. J. Pharm. Anal. 14, 39–51 (2024).
Google Scholar
Braga, T. T. et al. MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages. Mol. Med 18, 1231–1239 (2012).
Google Scholar
Sierra-Mondragon, E. et al. All-trans retinoic acid ameliorates inflammatory response mediated by TLR4/NF-kappaB during initiation of diabetic nephropathy. J. Nutr. Biochem 60, 47–60 (2018).
Google Scholar
Zhao, W. et al. Metabolic Dysfunction in the Regulation of the NLRP3 Inflammasome Activation: A Potential Target for Diabetic Nephropathy. J. Diabetes Res 2022, 2193768 (2022).
Google Scholar
Lu, Q. et al. Complement factor B in high glucose-induced podocyte injury and diabetic kidney disease. JCI Insight. 6, e147716 (2021).
Duan, S. et al. Association of glomerular complement C4c deposition with the progression of diabetic kidney disease in patients with type 2 diabetes. Front. Immunol. 11, 2073 (2020).
Google Scholar
Sircar, M. et al. Complement 7 is up-regulated in human early diabetic kidney disease. Am. J. Pathol. 188, 2147–2154 (2018).
Google Scholar
Trambas, I. A., Coughlan, M. T. & Tan, S. M. Therapeutic potential of targeting complement C5a receptors in diabetic kidney disease. Int. J. Mol. Sci. 24, 8758 (2023).
Google Scholar
Satoskar, A. A. et al. Characterization of glomerular diseases using proteomic analysis of laser capture microdissected glomeruli. Mod. Pathol. 25, 709–721 (2012).
Google Scholar
Li, L. et al. C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/beta-catenin signaling pathway in diabetic kidney disease. Metabolism 64, 597–610 (2015).
Google Scholar
Xu, Z., Tao, L. & Su, H. The complement system in metabolic-associated kidney diseases. Front. Immunol. 13, 902063 (2022).
Google Scholar
Flyvbjerg, A. The role of the complement system in diabetic nephropathy. Nat. Rev. Nephrol. 13, 311–318 (2017).
Google Scholar
Rayego-Mateos, S. et al. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int. 103, 282–296 (2023).
Google Scholar
Yang, T. et al. An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory. Mol. Med. 30, 71 (2024).
Google Scholar
Kato, M. & Natarajan, R. Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Nat. Rev. Nephrol. 15, 327–345 (2019).
Google Scholar
Yoshimoto, N. et al. Significance of podocyte DNA damage and glomerular DNA methylation in CKD patients with proteinuria. Hypertens. Res. 46, 1000–1008 (2023).
Google Scholar
Gu, X. et al. N6-methyladenosine demethylase FTO promotes M1 and M2 macrophage activation. Cell Signal 69, 109553 (2020).
Google Scholar
Ma, C. X. et al. Cardiovascular disease in type 2 diabetes mellitus: progress toward personalized management. Cardiovasc. Diabetol. 21, 74 (2022).
Google Scholar
Kozakova, M., Morizzo, C., Fraser, A. G. & Palombo, C. Impact of glycemic control on aortic stiffness, left ventricular mass and diastolic longitudinal function in type 2 diabetes mellitus. Cardiovasc. Diabetol. 16, 78 (2017).
Google Scholar
Medina-Leyte, D. J. et al. Endothelial dysfunction, inflammation and coronary artery disease: potential biomarkers and promising therapeutical approaches. Int. J. Mol. Sci. 22, 3850 (2021).
Google Scholar
Saenz-Medina, J. et al. Endothelial dysfunction: an intermediate clinical feature between urolithiasis and cardiovascular diseases. Int. J. Mol. Sci. 23, 912 (2022).
Google Scholar
Montanaro, R. et al. Hydrogen sulfide donor AP123 restores endothelial nitric oxide-dependent vascular function in hyperglycemia via a CREB-dependent pathway. Redox Biol. 62, 102657 (2023).
Google Scholar
Zhang, X. et al. Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment. Cardiovasc. Diabetol. 23, 150 (2024).
Google Scholar
Yao, Y. et al. Endothelial cell metabolic memory causes cardiovascular dysfunction in diabetes. Cardiovasc. Res. 118, 196–211 (2022).
Google Scholar
Huang, Q. et al. Uncovering endothelial to mesenchymal transition drivers in atherosclerosis via multi-omics analysis. BMC Cardiovasc. Disord. 25, 104 (2025).
Google Scholar
Zhao, G. et al. Endothelial KLF11 is a novel protector against diabetic atherosclerosis. Cardiovasc. Diabetol. 23, 381 (2024).
Google Scholar
Liu, L. et al. Bone marrow mesenchymal stem cell-derived extracellular vesicles alleviate diabetes-exacerbated atherosclerosis via AMPK/mTOR pathway-mediated autophagy-related macrophage polarization. Cardiovasc. Diabetol. 24, 48 (2025).
Google Scholar
Bai, X. et al. CAV1-CAVIN1-LC3B-mediated autophagy regulates high glucose-stimulated LDL transcytosis. Autophagy 16, 1111–1129 (2020).
Google Scholar
Zhang, Z. et al. USF1 transcriptionally activates USP14 to drive atherosclerosis by promoting EndMT through NLRC5/Smad2/3 axis. Mol. Med. 30, 32 (2024).
Google Scholar
Cheng, C. K. et al. SOX4 is a novel phenotypic regulator of endothelial cells in atherosclerosis revealed by single-cell analysis. J. Adv. Res 43, 187–203 (2023).
Google Scholar
Supinski, G. S., Schroder, E. A. & Callahan, L. A. Mitochondria and critical illness. Chest 157, 310–322 (2020).
Google Scholar
Zhang, Y. et al. Liraglutide prevents high glucose induced HUVECs dysfunction via inhibition of PINK1/Parkin-dependent mitophagy. Mol. Cell Endocrinol. 545, 111560 (2022).
Google Scholar
Heather, L. C., Gopal, K., Srnic, N. & Ussher, J. R. Redefining diabetic cardiomyopathy: perturbations in substrate metabolism at the heart of its pathology. Diabetes 73, 659–670 (2024).
Google Scholar
Zhang, Y., Zhang, Z., Tu, C., Chen, X. & He, R. Advanced glycation end products in disease development and potential interventions. Antioxidants14, 492 (2025).
Google Scholar
Bansal, S., Burman, A. & Tripathi, A. K. Advanced glycation end products: key mediator and therapeutic target of cardiovascular complications in diabetes. World J. Diabetes 14, 1146–1162 (2023).
Google Scholar
Souders, C. A., Bowers, S. L. & Baudino, T. A. Cardiac fibroblast: the renaissance cell. Circ. Res 105, 1164–1176 (2009).
Google Scholar
Ndumele, C. E. et al. A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association. Circulation 148, 1636–1664 (2023).
Google Scholar
Meng, L. et al. METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA. Cell Death Dis. 13, 38 (2022).
Google Scholar
Maisch, B., Alter, P. & Pankuweit, S. Diabetic cardiomyopathy–fact or fiction?. Herz 36, 102–115 (2011).
Google Scholar
Falcao-Pires, I. & Leite-Moreira, A. F. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail. Rev. 17, 325–344 (2012).
Google Scholar
Sun, Q., Karwi, Q. G., Wong, N. & Lopaschuk, G. D. Advances in myocardial energy metabolism: metabolic remodelling in heart failure and beyond. Cardiovasc. Res. 120, 1996–2016 (2024).
Google Scholar
McDonagh, T. A. et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 42, 3599–3726 (2021).
Google Scholar
Gladden, J. D., Chaanine, A. H. & Redfield, M. M. Heart failure with preserved ejection fraction. Annu. Rev. Med. 69, 65–79 (2018).
Google Scholar
Dia, M. et al. Effect of metformin on T2D-induced MAM Ca(2+) uncoupling and contractile dysfunction in an early mouse model of diabetic HFpEF. Int. J. Mol. Sci. 23, 3569 (2022).
Google Scholar
Lazo, M. et al. Soluble receptor for advanced glycation end products and the risk for incident heart failure: the atherosclerosis risk in communities study. Am. Heart J. 170, 961–967 (2015).
Google Scholar
Ren, J., Wu, N. N., Wang, S., Sowers, J. R. & Zhang, Y. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications. Physiol. Rev. 101, 1745–1807 (2021).
Google Scholar
Nagayach, A. et al. Advancing the understanding of diabetic encephalopathy through unravelling pathogenesis and exploring future treatment perspectives. Ageing Res. Rev. 100, 102450 (2024).
Google Scholar
Nie, S. D. et al. High glucose forces a positive feedback loop connecting ErbB4 expression and mTOR/S6K pathway to aggravate the formation of tau hyperphosphorylation in differentiated SH-SY5Y cells. Neurobiol. Aging 67, 171–180 (2018).
Google Scholar
Yang, Y. et al. The imbalance of PGD2-DPs pathway is involved in the type 2 diabetes brain injury by regulating autophagy. Int. J. Biol. Sci. 17, 3993–4004 (2021).
Google Scholar
Taile, J., Arcambal, A., Clerc, P., Gauvin-Bialecki, A. & Gonthier, M. P. Medicinal plant polyphenols attenuate oxidative stress and improve inflammatory and vasoactive markers in cerebral endothelial cells during hyperglycemic condition. Antioxidants9, 573 (2020).
Google Scholar
Lee, K. S. et al. Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming. J. Neuroinflamm. 21, 137 (2024).
Google Scholar
Ge, X. et al. Electroacupuncture improves cognitive impairment in diabetic cognitive dysfunction rats by regulating the mitochondrial autophagy pathway. J. Physiol. Sci. 72, 29 (2022).
Google Scholar
Zhao, H. et al. Hydrogen sulfide plays an important role by regulating endoplasmic reticulum stress in diabetes-related diseases. Int. J. Mol. Sci. 23, 7170 (2022).
Google Scholar
Sousa, L., Oliveira, M. M., Pessoa, M. T. C. & Barbosa, L. A. Iron overload: effects on cellular biochemistry. Clin. Chim. Acta 504, 180–189 (2020).
Google Scholar
Swain, S. K., Chandra Dash, U. & Sahoo, A. K. Hydrolea zeylanica improves cognitive impairment in high-fat diet fed-streptozotocin-induced diabetic encephalopathy in rats via regulating oxidative stress, neuroinflammation, and neurotransmission in brain. Heliyon 8, e11301 (2022).
Google Scholar
Golledge, J. Update on the pathophysiology and medical treatment of peripheral artery disease. Nat. Rev. Cardiol. 19, 456–474 (2022).
Google Scholar
Jude, E. B., Oyibo, S. O., Chalmers, N. & Boulton, A. J. Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care 24, 1433–1437 (2001).
Google Scholar
Mozes, G. et al. Atherosclerosis in amputated legs of patients with and without diabetes mellitus. Int. Angiol. 17, 282–286 (1998).
Google Scholar
Nikolajevic, J. & Sabovic, M. Inflammatory, metabolic, and coagulation effects on medial arterial calcification in patients with peripheral arterial disease. Int. J. Mol. Sci. 24, 3132 (2023).
Zayed, M. G. et al. Diabetic retinopathy and quality of life: a systematic review and meta-analysis. JAMA Ophthalmol. 142, 199–207 (2024).
Google Scholar
Ling, F., Zhang, C., Zhao, X., Xin, X. & Zhao, S. Identification of key genes modules linking diabetic retinopathy and circadian rhythm. Front. Immunol. 14, 1260350 (2023).
Google Scholar
Wong, T. Y., Cheung, C. M., Larsen, M., Sharma, S. & Simo, R. Diabetic retinopathy. Nat. Rev. Dis. Prim. 2, 16012 (2016).
Google Scholar
Hassan, J. W. & Bhatwadekar, A. D. Senolytics in the treatment of diabetic retinopathy. Front. Pharm. 13, 896907 (2022).
Google Scholar
Han, X. Y. et al. Targeting endothelial glycolytic reprogramming by tsRNA-1599 for ocular anti-angiogenesis therapy. Theranostics 14, 3509–3525 (2024).
Google Scholar
Yu, F. et al. Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis. Cell Discov. 8, 40 (2022).
Google Scholar
Zhang, J., Qiu, Q., Wang, H., Chen, C. & Luo, D. TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination. Exp. Cell Res. 407, 112800 (2021).
Google Scholar
Gu, C. et al. miR-590-3p inhibits pyroptosis in diabetic retinopathy by targeting NLRP1 and inactivating the NOX4 signaling pathway. Investig. Ophthalmol. Vis. Sci. 60, 4215–4223 (2019).
Google Scholar
Wang, Q. et al. Poly (ADP-ribose) polymerase 1 mediated arginase II activation is responsible for oxidized LDL-induced endothelial dysfunction. Front Pharm. 9, 882 (2018).
Google Scholar
Oshitari, T. Neurovascular cell death and therapeutic strategies for diabetic retinopathy. Int. J. Mol. Sci. 24, 12919 (2023).
Li, L. et al. Ferroptosis: new insight into the mechanisms of diabetic nephropathy and retinopathy. Front Endocrinol. (Lausanne) 14, 1215292 (2023).
Google Scholar
Wolf, J. et al. Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo. Cell 186, 4868–4884.e4812 (2023).
Google Scholar
Yao, Y. et al. Macrophage/microglia polarization for the treatment of diabetic retinopathy. Front Endocrinology14, 1276225 (2023).
Google Scholar
Lv, K. et al. Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy. Front. Immunol. 13, 942768 (2022).
Google Scholar
Ben, S. et al. Microglia-endothelial cross-talk regulates diabetes-induced retinal vascular dysfunction through remodeling inflammatory microenvironment. iScience 27, 109145 (2024).
Google Scholar
Xu, Y. et al. Single-cell transcriptomes reveal a molecular link between diabetic kidney and retinal lesions. Commun. Biol. 6, 912 (2023).
Google Scholar
He, C. et al. A specific RIP3(+) subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism. Proc. Natl Acad. Sci. USA 118, e2023290118 (2021).
Google Scholar
Binet, F. et al. Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy. Science 369, eaay5356 (2020).
Google Scholar
Zhang, X., Zhang, F. & Xu, X. Single-cell RNA sequencing in exploring the pathogenesis of diabetic retinopathy. Clin. Transl. Med. 14, e1751 (2024).
Google Scholar
Van Hove, I. et al. Single-cell transcriptome analysis of the Akimba mouse retina reveals cell-type-specific insights into the pathobiology of diabetic retinopathy. Diabetologia 63, 2235–2248 (2020).
Google Scholar
Zhang, X. et al. Association of plasma osteopontin with diabetic retinopathy in Asians with type 2 diabetes. Mol. Vis. 24, 165–173 (2018).
Google Scholar
Bai, C. W. et al. G protein subunit alpha i2 pivotal role in angiogenesis. Theranostics 14, 2190–2209 (2024).
Google Scholar
Younossi, Z. M. et al. The global epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among patients with type 2 diabetes. Clin. Gastroenterol. Hepatol. 22, 1999–2010.e1998 (2024).
Google Scholar
Chen, Y. et al. Effect of Moderate and vigorous aerobic exercise on incident diabetes in adults with obesity: a 10-year follow-up of a randomized clinical trial. JAMA Intern Med 183, 272–275 (2023).
Google Scholar
Badmus, O. O., Hillhouse, S. A., Anderson, C. D., Hinds, T. D. & Stec, D. E. Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways. Clin. Sci. 136, 1347–1366 (2022).
Google Scholar
Al-Sofiani, M. E., Ganji, S. S. & Kalyani, R. R. Body composition changes in diabetes and aging. J. Diabetes Complic. 33, 451–459 (2019).
Google Scholar
Bassi-Dibai, D. et al. Rehabilitation of individuals with diabetes mellitus: focus on diabetic myopathy. Front Endocrinol.13, 869921 (2022).
Google Scholar
Hernandez-Ochoa, E. O. & Vanegas, C. Diabetic myopathy and mechanisms of disease. Biochem. Pharm.4, e179 (2015).
Bahn, Y. J. et al. CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism. J. Clin. Investig. 133, e162479 (2023).
Google Scholar
Castillo, I. M. P., Argiles, J. M., Rueda, R., Ramirez, M. & Pedrosa, J. M. L. Skeletal muscle atrophy and dysfunction in obesity and type-2 diabetes mellitus: Myocellular mechanisms involved. Rev. Endocr. Metab. Disord. (2025). Online ahead of print. https://doi.org/10.1007/s11154-025-09954-9.
Espino-Gonzalez, E. et al. Impaired skeletal muscle regeneration in diabetes: from cellular and molecular mechanisms to novel treatments. Cell Metab. 36, 1204–1236 (2024).
Google Scholar
Rebelos, E., Anastasiou, I. A., Tentolouris, A., Papanas, N. & Jude, E. What is new on diabetic neuropathy? Insights from the 2023 ADA and EASD conferences. Int. J. Low. Extrem Wounds 28, 15347346241233938 (2024).
Google Scholar
Hong, T. et al. The prevalence of cardiovascular disease in adults with type 2 diabetes in China: results from the cross-sectional CAPTURE study. Diabetes Ther. 13, 969–981 (2022).
Google Scholar
Gordois, A., Scuffham, P., Shearer, A., Oglesby, A. & Tobian, J. A. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 26, 1790–1795 (2003).
Google Scholar
Lee, C. G. et al. Prevalence of distal symmetrical polyneuropathy by diabetes prevention program treatment group, diabetes status, duration of diabetes, and cumulative glycemic exposure. Diabetes Care 47, 810–817 (2024).
Google Scholar
Boulton, A. J. M. A brief overview of the diabetic neuropathies. Diabetes Res Clin. Pr. 206, 110758 (2023).
Google Scholar
Pop-Busui, R. et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 40, 136–154 (2017).
Google Scholar
Yorek, M. Treatment for diabetic peripheral neuropathy: what have we learned from animal models?. Curr. Diabetes Rev. 18, e040521193121 (2022).
Google Scholar
Eid, S. A. et al. New perspectives in diabetic neuropathy. Neuron 111, 2623–2641 (2023).
Google Scholar
Elafros, M. A. et al. Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments. Lancet Neurol. 21, 922–936 (2022).
Google Scholar
Wang, L. et al. Exosomes derived from schwann cells ameliorate peripheral neuropathy in type 2 diabetic mice. Diabetes 69, 749–759 (2020).
Google Scholar
Gonzalez-Alvarez, M. E., Sanchez-Romero, E. A., Turroni, S., Fernandez-Carnero, J. & Villafane, J. H. Correlation between the altered gut microbiome and lifestyle interventions in chronic widespread pain patients: a systematic review. Medicines59, 256 (2023).
Google Scholar
Yang, J. et al. Gut microbiota modulate distal symmetric polyneuropathy in patients with diabetes. Cell Metab. 35, 1548–1562.e1547 (2023).
Google Scholar
Li, W. et al. Identification of immune infiltration and the potential biomarkers in diabetic peripheral neuropathy through bioinformatics and machine learning methods. Biomolecules 13, 39 (2022).
Google Scholar
Lan, Z., Wei, Y., Yue, K., He, R. & Jiang, Z. Genetically predicted immune cells mediate the association between gut microbiota and neuropathy pain. Inflammopharmacology 32, 3357–3373 (2024).
Google Scholar
Fu, X. L. et al. Global recurrence rates in diabetic foot ulcers: a systematic review and meta-analysis. Diabetes Metab. Res Rev. 35, e3160 (2019).
Google Scholar
Deng, H. et al. Mechanisms of diabetic foot ulceration: a review. J. Diabetes 15, 299–312 (2023).
Google Scholar
Soyoye, D. O., Abiodun, O. O., Ikem, R. T., Kolawole, B. A. & Akintomide, A. O. Diabetes and peripheral artery disease: a review. World J. Diabetes 12, 827–838 (2021).
Google Scholar
Edmonds, M., Manu, C. & Vas, P. The current burden of diabetic foot disease. J. Clin. Orthop. Trauma 17, 88–93 (2021).
Google Scholar
Villa, F. et al. Anaerobes in diabetic foot infections: pathophysiology, epidemiology, virulence, and management. Clin. Microbiol. Rev. 37, e0014323 (2024).
Google Scholar
Bashir, H., Multani, H. & Aleem, S. Bacteriological profile and antimicrobial sensitivity pattern of isolates from diabetic foot of patients attending a teaching hospital in Northern India. Asian J. Med. Sci. 12, 83–87 (2021).
Google Scholar
Yadav, R. K., Mishra, A. & Sharma, R. Assessment of microbial profile in the patients with diabetic foot: a Microbiological Study. J. Adv. Med. Dent. Sci. Res. 4, 105–108 (2016).
Xourafa, G., Korbmacher, M. & Roden, M. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 20, 27–49 (2024).
Google Scholar
Pereira, S., Cline, D. L., Glavas, M. M., Covey, S. D. & Kieffer, T. J. Tissue-specific effects of leptin on glucose and lipid metabolism. Endocr. Rev. 42, 1–28 (2021).
Google Scholar
Wang, X., Jia, J. & Huang, T. Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis. BMJ Open Diabetes Res Care 8, e001140 (2020).
Google Scholar
Perry, R. J. & Shulman, G. I. The role of leptin in maintaining plasma glucose during starvation. Postdoc J. 6, 3–19 (2018).
Google Scholar
Metz, M. et al. Leptin increases hepatic triglyceride export via a vagal mechanism in humans. Cell Metab. 34, 1719–1731.e1715 (2022).
Google Scholar
Egbuche, O. et al. Fatty acid binding protein-4 and risk of cardiovascular disease: the cardiovascular health study. J. Am. Heart Assoc. 9, e014070 (2020).
Google Scholar
Kim, M. et al. The impact of endotrophin on the progression of chronic liver disease. Exp. Mol. Med. 52, 1766–1776 (2020).
Google Scholar
An, Y. A. et al. Endotrophin neutralization through targeted antibody treatment protects from renal fibrosis in a podocyte ablation model. Mol. Metab. 69, 101680 (2023).
Google Scholar
Tougaard, N. H. et al. Endotrophin as a marker of complications in a type 2 diabetes cohort. Diabetes Care 45, 2746–2748 (2022).
Google Scholar
Priest, C. & Tontonoz, P. Inter-organ cross-talk in metabolic syndrome. Nat. Metab. 1, 1177–1188 (2019).
Google Scholar
Cetin, E., Pedersen, B., Porter, L. M., Adler, G. K. & Burak, M. F. Protocol for a randomized placebo-controlled clinical trial using pure palmitoleic acid to ameliorate insulin resistance and lipogenesis in overweight and obese subjects with prediabetes. Front. Endocrinol.14, 1306528 (2023).
Google Scholar
Balakrishnan, R. & Thurmond, D. C. Mechanisms by which skeletal muscle myokines ameliorate insulin resistance. Int. J. Mol. Sci. 23, 4636 (2022).
Google Scholar
Riopel, M. et al. Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function. J. Clin. Investig.128, 1458–1470 (2018).
Google Scholar
Eckel, J. Myokines in metabolic homeostasis and diabetes. Diabetologia 62, 1523–1528 (2019).
Google Scholar
Lai, W. et al. Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes. FASEB J. 37, e23175 (2023).
Google Scholar
Ibrahim, A., Neinast, M. & Arany, Z. P. Myobolites: muscle-derived metabolites with paracrine and systemic effects. Curr. Opin. Pharm. 34, 15–20 (2017).
Google Scholar
Mansoori, S., Ho, M. Y., Ng, K. K. & Cheng, K. K. Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases. Obes. Rev. 26, e13856 (2025).
Google Scholar
Barlow, J. P. et al. Beta-aminoisobutyric acid is released by contracting human skeletal muscle and lowers insulin release from INS-1 832/3 cells by mediating mitochondrial energy metabolism. Metab. Open 7, 100053 (2020).
Google Scholar
Duan, Y. et al. Interleukin-15 in obesity and metabolic dysfunction: current understanding and future perspectives. Obes. Rev. 18, 1147–1158 (2017).
Google Scholar
Kahn, D. et al. Exploring visceral and subcutaneous adipose tissue secretomes in human obesity: implications for metabolic disease. Endocrinology 163, bqac140 (2022).
Google Scholar
Pafili, K. et al. Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease. J. Hepatol. 77, 1504–1514 (2022).
Google Scholar
Flippo, K. H. & Potthoff, M. J. Metabolic messengers: FGF21. Nat. Metab. 3, 309–317 (2021).
Google Scholar
Jin, L. et al. FGF21-Sirtuin 3 axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity. Circulation 146, 1537–1557 (2022).
Google Scholar
Lin, S. et al. Fibroblast Growth Factor 21 Attenuates diabetes-induced renal fibrosis by negatively regulating Tgf-beta-p53-smad2/3-mediated epithelial-to-mesenchymal transition via activation of AKT. Diabetes Metab. J. 44, 158–172 (2020).
Google Scholar
Salgado, J. V., Goes, M. A. & Salgado Filho, N. FGF21 and chronic kidney disease. Metabolism 118, 154738 (2021).
Google Scholar
Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).
Google Scholar
Wang, D. et al. GDF15 promotes weight loss by enhancing energy expenditure in muscle. Nature 619, 143–150 (2023).
Google Scholar
Aghanoori, M. R. et al. CEBPbeta regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth. Cell Mol. Life Sci. 79, 193 (2022).
Google Scholar
Li, X., Wu, T. T., Chen, J. & Qiu, W. Elevated expression levels of serum insulin-like growth factor-1, tumor necrosis factor-alpha and vascular endothelial growth factor 165 might exacerbate type 2 diabetic nephropathy. J. Diabetes Investig. 8, 108–114 (2017).
Google Scholar
Zhang, Y. et al. Insulin-like growth factor 1 knockdown attenuates high glucose-induced podocyte injury by promoting the JAK2/STAT signalling-mediated autophagy. Nephrology29, 394–404 (2024).
Google Scholar
Opazo-Rios, L. et al. Lipotoxicity and diabetic nephropathy: novel mechanistic insights and therapeutic opportunities. Int. J. Mol. Sci. 21, 2632 (2020).
Google Scholar
Schulze, P. C. Myocardial lipid accumulation and lipotoxicity in heart failure. J. Lipid Res. 50, 2137–2138 (2009).
Google Scholar
Herman-Edelstein, M., Scherzer, P., Tobar, A., Levi, M. & Gafter, U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J. Lipid Res. 55, 561–572 (2014).
Google Scholar
Wu, M. et al. Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation. Redox Biol. 73, 103184 (2024).
Google Scholar
Nawrot, M., Peschard, S., Lestavel, S. & Staels, B. Intestine-liver crosstalk in Type 2 diabetes and non-alcoholic fatty liver disease. Metabolism 123, 154844 (2021).
Google Scholar
Nauck, M. A., Quast, D. R., Wefers, J. & Pfeiffer, A. F. H. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes. Metab. 23, 5–29 (2021).
Google Scholar
Hammoud, R. & Drucker, D. J. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat. Rev. Endocrinol. 19, 201–216 (2023).
Google Scholar
Rosendo-Silva, D. & Matafome, P. Gut-adipose tissue crosstalk: a bridge to novel therapeutic targets in metabolic syndrome?. Obes. Rev. 22, e13130 (2021).
Google Scholar
Letchumanan, G. et al. Gut microbiota composition in prediabetes and newly diagnosed type 2 diabetes: a systematic review of observational studies. Front. Cell Infect. Microbiol 12, 943427 (2022).
Google Scholar
Iatcu, C. O., Steen, A. & Covasa, M. Gut microbiota and complications of type-2 diabetes. Nutrients 14, 166 (2021).
Google Scholar
Di Vincenzo, F., Del Gaudio, A., Petito, V., Lopetuso, L. R. & Scaldaferri, F. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern. Emerg. Med. 19, 275–293 (2024).
Google Scholar
Liu, W. et al. Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy. Acta Diabetol. 58, 221–229 (2021).
Google Scholar
Winther, S. A. et al. Utility of plasma concentration of trimethylamine N-oxide in predicting cardiovascular and renal complications in individuals with type 1 diabetes. Diabetes Care 42, 1512–1520 (2019).
Google Scholar
Croyal, M. et al. Plasma trimethylamine N-oxide and risk of cardiovascular events in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 105, dgaa188 (2020).
Google Scholar
de Vos, W. M., Tilg, H., Van Hul, M. & Cani, P. D. Gut microbiome and health: mechanistic insights. Gut 71, 1020–1032 (2022).
Google Scholar
May, K. S. & den Hartigh, L. J. Gut Microbial-derived short chain fatty acids: impact on adipose tissue physiology. Nutrients 15, 272 (2023).
Google Scholar
Li, W. et al. Cardiac corin and atrial natriuretic peptide regulate liver glycogen metabolism and glucose homeostasis. Cardiovasc. Diabetol. 23, 383 (2024).
Google Scholar
Perry, R. J. et al. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).
Google Scholar
Prokopidis, K., Chambers, E., Ni Lochlainn, M. & Witard, O. C. Mechanisms linking the gut-muscle axis with muscle protein metabolism and anabolic resistance: implications for older adults at risk of sarcopenia. Front. Physiol. 12, 770455 (2021).
Google Scholar
Byndloss, M. et al. The gut microbiota and diabetes: research, translation, and clinical applications-2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum. Diabetes 73, 1391–1410 (2024).
Google Scholar
Li, X. et al. RAAS in diabetic retinopathy: mechanisms and therapies. Arch. Endocrinol. Metab. 68, e230292 (2024).
Google Scholar
Gu, J. et al. Piperlongumine attenuates angiotensin-II-induced cardiac hypertrophy and fibrosis by inhibiting Akt-FoxO1 signalling. Phytomedicine 82, 153461 (2021).
Google Scholar
Yu, L. X. et al. Potential application of Klotho as a prognostic biomarker for patients with diabetic kidney disease: a meta-analysis of clinical studies. Ther. Adv. Chronic Dis. 14, 20406223231213246 (2023).
Google Scholar
Kanbay, M. et al. Klotho: a potential therapeutic target in aging and neurodegeneration beyond chronic kidney disease-a comprehensive review from the ERA CKD-MBD working group. Clin. Kidney J. 17, sfad276 (2024).
Google Scholar
Edmonston, D., Grabner, A. & Wolf, M. FGF23 and klotho at the intersection of kidney and cardiovascular disease. Nat. Rev. Cardiol. 21, 11–24 (2024).
Google Scholar
Chen, X. et al. Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/beta-catenin signaling. Kidney Int. 102, 506–520 (2022).
Google Scholar
Hajare, A. D., Dagar, N. & Gaikwad, A. B. Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases. Mol. Biomed. 6, 19 (2025).
Google Scholar
Rao, Z. et al. Administration of alpha klotho reduces liver and adipose lipid accumulation in obese mice. Heliyon 5, e01494 (2019).
Google Scholar
Tang, S. et al. Cardiac-to-adipose axis in metabolic homeostasis and diseases: special instructions from the heart. Cell Biosci. 13, 161 (2023).
Google Scholar
Hernandez-Anzaldo, S. et al. Identification of a novel heart-liver axis: matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate lipid metabolism and inflammation in the liver. J. Am. Heart Assoc. 4, e002553 (2015).
Google Scholar
Lu, Y. Y. et al. C-atrial natriuretic peptide (ANP)(4-23) attenuates renal fibrosis in deoxycorticosterone-acetate-salt hypertensive mice. Exp. Cell Res. 431, 113738 (2023).
Google Scholar
Wang, W. et al. Cellular crosstalk in organotypic vasculature: mechanisms of diabetic cardiorenal complications and SGLT2i responses. Cardiovasc. Diabetol. 24, 90 (2025).
Google Scholar
Lee, C. H. et al. Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria. J. Clin. Endocrinol. Metab. 100, 1368–1375 (2015).
Google Scholar
Dushay, J. et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139, 456–463 (2010).
Google Scholar
Liu, D. et al. Fibroblast growth factor 23 predicts incident diabetic kidney disease: a 4.6-year prospective study. Diabetes Obes. Metab. 27, 2232–2241 (2025).
Google Scholar
Silva, A. P. et al. Plasmatic Klotho and FGF23 levels as biomarkers of CKD-associated cardiac disease in type 2 diabetic patients. Int. J. Mol. Sci. 20, 1536 (2019).
Google Scholar
American Diabetes Association Professional Practice, Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2024. Diabetes Care 47, S158–S178 (2024).
Google Scholar
Milenkovic, T. et al. Mediterranean diet and type 2 diabetes mellitus: a perpetual inspiration for the scientific world. Rev. Nutr. 13, 1307 (2021).
Google Scholar
Dai, W. & Albrecht, S. S. Sitting time and its interaction with physical activity in relation to all-cause and heart disease mortality in U.S. Adults with diabetes. Diabetes Care 47, 1764–1768 (2024).
Google Scholar
Garcia-Hermoso, A., Lopez-Gil, J. F., Izquierdo, M., Ramirez-Velez, R. & Ezzatvar, Y. Exercise and insulin resistance markers in children and adolescents with excess weight: a systematic review and network meta-analysis. JAMA Pediatr. 177, 1276–1284 (2023).
Google Scholar
El Assar, M., Alvarez-Bustos, A., Sosa, P., Angulo, J. & Rodriguez-Manas, L. Effect of physical activity/exercise on oxidative stress and inflammation in muscle and vascular aging. Int. J. Mol. Sci. 23, 8713 (2022).
Google Scholar
Nian, T. et al. Non-pharmacological interventions for smoking cessation: analysis of systematic reviews and meta-analyses. BMC Med. 21, 378 (2023).
Google Scholar
Rutters, F. & Nefs, G. Sleep and circadian rhythm disturbances in diabetes: a narrative review. Diabetes Metab. Syndr. Obes. 15, 3627–3637 (2022).
Google Scholar
Stenvers, D. J., Scheer, F., Schrauwen, P., la Fleur, S. E. & Kalsbeek, A. Circadian clocks and insulin resistance. Nat. Rev. Endocrinol. 15, 75–89 (2019).
Google Scholar
Shan, Z. et al. Sleep duration and risk of type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 38, 529–537 (2015).
Google Scholar
Han, H. et al. Sleep duration and risks of incident cardiovascular disease and mortality among people with type 2 diabetes. Diabetes Care 46, 101–110 (2023).
Google Scholar
Jee, D., Keum, N., Kang, S. & Arroyo, J. G. Sleep and diabetic retinopathy. Acta Ophthalmol. 95, 41–47 (2017).
Google Scholar
Liu, C. et al. Effects of sleep duration and changes in body mass index on diabetic kidney disease: a prospective cohort study. Front. Endocrinol.14, 1278665 (2023).
Google Scholar
Schipper, S. B. J. et al. Sleep disorders in people with type 2 diabetes and associated health outcomes: a review of the literature. Diabetologia 64, 2367–2377 (2021).
Google Scholar
Sultana, R. et al. Relationship between diabetes-related complications and sleep complaints in older Mexican Americans. J. Prim. Care Community Health 13, 21501319221123471 (2022).
Google Scholar
Tan, X., van Egmond, L., Chapman, C. D., Cedernaes, J. & Benedict, C. Aiding sleep in type 2 diabetes: therapeutic considerations. Lancet Diabetes Endocrinol. 6, 60–68 (2018).
Google Scholar
Meyer, N., Harvey, A. G., Lockley, S. W. & Dijk, D. J. Circadian rhythms and disorders of the timing of sleep. Lancet 400, 1061–1078 (2022).
Google Scholar
Lee, D. Y. et al. Attention to innate circadian rhythm and the impact of its disruption on diabetes. Diabetes Metab. J. 48, 37–52 (2024).
Google Scholar
Wang, Q. et al. Effects of light therapy on sleep and circadian rhythm in older type 2 diabetics living in long-term care facilities: a randomized controlled trial. Front. Endocrinol. 15, 1307537 (2024).
Google Scholar
Sacks, D. B. Smart insulin switches itself off in response to low blood sugar. Nature 634, 785–787 (2024).
Google Scholar
Natale, P., Palmer, S. C., Navaneethan, S. D., Craig, J. C. & Strippoli, G. F. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst. Rev. 4, CD006257 (2024).
Google Scholar
Pei, J., Wang, X., Pei, Z. & Hu, X. Glycemic control, HbA1c variability, and major cardiovascular adverse outcomes in type 2 diabetes patients with elevated cardiovascular risk: insights from the ACCORD study. Cardiovasc. Diabetol. 22, 287 (2023).
Google Scholar
Han, K. et al. Fasting plasma glucose level and in-hospital cardiac arrest in patients with acute coronary syndrome: findings from the CCC-ACS project. Ann. Med. 56, 2419546 (2024).
Google Scholar
Carew, A. S. et al. The relationship between repeated measurements of HbA(1c) and risk of coronary events among the common haptoglobin phenotype groups: the Action for Health in Diabetes (Look AHEAD) study. Cardiovasc. Diabetol. 23, 356 (2024).
Google Scholar
Joseph, J. J. et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement From the American Heart Association. Circulation 145, e722–e759 (2022).
Google Scholar
Luo, F. et al. ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases. Trends Cardiovasc. Med. 34, 215–222 (2024).
Google Scholar
Arnaud, C., Veillard, N. R. & Mach, F. Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis. Curr. Drug Targets Cardiovasc. Haematol. Disord. 5, 127–134 (2005).
Google Scholar
Zhou, S. et al. Statin initiation and risk of incident kidney disease in patients with diabetes. CMAJ 195, E729–E738 (2023).
Google Scholar
Luo, X. et al. Influence of SGLT2i and RAASi and their combination on risk of hyperkalemia in DKD: a network meta-analysis. Clin. J. Am. Soc. Nephrol. 18, 1019–1030 (2023).
Google Scholar
Tan, Y. et al. Efficacy and safety of Abelmoschus manihot capsule combined with ACEI/ARB on diabetic kidney disease: a systematic review and meta analysis. Front. Pharm. 14, 1288159 (2023).
Google Scholar
Mazzieri, A., Porcellati, F., Timio, F. & Reboldi, G. Molecular targets of novel therapeutics for diabetic kidney disease: a new era of nephroprotection. Int. J. Mol. Sci. 25, 3969 (2024).
Google Scholar
Alwashmi, M. F., Mugford, G., Abu-Ashour, W. & Nuccio, M. A digital diabetes prevention program (transform) for adults with prediabetes: secondary analysis. JMIR Diabetes 4, e13904 (2019).
Google Scholar
Batten, R. et al. A 12-month follow-up of the effects of a digital diabetes prevention program (vp transform for prediabetes) on weight and physical activity among adults with prediabetes: secondary analysis. JMIR Diabetes 7, e23243 (2022).
Google Scholar
Sebastian, S. A., Padda, I. & Johal, G. Cardiovascular-kidney-metabolic (CKM) syndrome: a state-of-the-art review. Curr. Probl. Cardiol. 49, 102344 (2024).
Google Scholar
Griffin, S. J., Leaver, J. K. & Irving, G. J. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 60, 1620–1629 (2017).
Google Scholar
Xu, Z., Zhang, H., Wu, C., Zheng, Y. & Jiang, J. Effect of metformin on adverse outcomes in T2DM patients: Systemic review and meta-analysis of observational studies. Front. Cardiovasc. Med. 9, 944902 (2022).
Google Scholar
Orloff, J., Min, J. Y., Mushlin, A. & Flory, J. Safety and effectiveness of metformin in patients with reduced renal function: a systematic review. Diabetes Obes. Metab. 23, 2035–2047 (2021).
Google Scholar
Pinyopornpanish, K., Leerapun, A., Pinyopornpanish, K. & Chattipakorn, N. Effects of metformin on hepatic steatosis in adults with nonalcoholic fatty liver disease and diabetes: insights from the cellular to patient levels. Gut Liver 15, 827–840 (2021).
Google Scholar
Salari, N. et al. Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease: a systematic review and meta-analysis. BMC Endocr. Disord. 21, 125 (2021).
Google Scholar
Yasmin, T. et al. Metformin treatment reverses high fat diet- induced non-alcoholic fatty liver diseases and dyslipidemia by stimulating multiple antioxidant and anti-inflammatory pathways. Biochem. Biophys. Rep. 28, 101168 (2021).
Google Scholar
Wicik, Z. et al. Characterization of the SGLT2 interaction network and its regulation by SGLT2 inhibitors: a bioinformatic analysis. Front. Pharm. 13, 901340 (2022).
Google Scholar
Yamato, M., Kato, N., Yamada, K. I. & Inoguchi, T. The early pathogenesis of diabetic retinopathy and its attenuation by sodium-glucose transporter 2 inhibitors. Diabetes 73, 1153–1166 (2024).
Google Scholar
Patel, S. M. et al. Sodium-glucose cotransporter-2 inhibitors and major adverse cardiovascular outcomes: a SMART-C collaborative meta-analysis. Circulation 149, 1789–1801 (2024).
Google Scholar
Wheeler, D. C. et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 9, 22–31 (2021).
Google Scholar
Lee, K. A., Jin, H. Y., Lee, N. Y., Kim, Y. J. & Park, T. S. Effect of empagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on kidney and peripheral nerves in streptozotocin-induced diabetic rats. Diabetes Metab. J. 42, 338–342 (2018).
Google Scholar
Rizzo, M. R. et al. Cognitive impairment and type 2 diabetes mellitus: focus of SGLT2 inhibitors treatment. Pharm. Res. 176, 106062 (2022).
Google Scholar
Mancinetti, F. et al. Diabetes-Alzheimer’s connection in older age: SGLT2 inhibitors as promising modulators of disease pathways. Ageing Res. Rev. 90, 102018 (2023).
Google Scholar
Kandeel, M. The outcomes of sodium-glucose co-transporter 2 inhibitors (SGLT2I) on diabetes-associated neuropathy: a systematic review and meta-analysis. Front Pharm. 13, 926717 (2022).
Google Scholar
Mone, P. et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care 45, 1247–1251 (2022).
Google Scholar
Kim, H. K. et al. SGLT2 inhibitor use and risk of dementia and parkinson disease among patients with type 2 diabetes. Neurology 103, e209805 (2024).
Google Scholar
Yen, F. S. et al. Sodium-glucose cotransporter 2 inhibitors and risk of retinopathy in patients with type 2 diabetes. JAMA Netw. Open 6, e2348431 (2023).
Google Scholar
Ishibashi, R. et al. Sodium-glucose co-transporter 2 inhibitor therapy reduces the administration frequency of anti-vascular endothelial growth factor agents in patients with diabetic macular oedema with a history of anti-vascular endothelial growth factor agent use: a cohort study using the Japanese health insurance claims database. Diabetes Obes. Metab. 26, 1510–1518 (2024).
Google Scholar
Hanaguri, J. et al. The effect of sodium-dependent glucose cotransporter 2 inhibitor tofogliflozin on neurovascular coupling in the retina in type 2 diabetic mice. Int. J. Mol. Sci. 23, 1362 (2022).
Google Scholar
Androutsakos, T. et al. SGLT-2 Inhibitors in NAFLD: expanding their role beyond diabetes and cardioprotection. Int. J. Mol. Sci. 23, 3107 (2022).
Jang, H. et al. Outcomes of various classes of oral antidiabetic drugs on nonalcoholic fatty liver disease. JAMA Intern. Med. 184, 375–383 (2024).
Google Scholar
Cheung, K. S. et al. Effects of empagliflozin on liver fat in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Hepatology 80, 916–927 (2024).
Google Scholar
Afsar, B. & Afsar, R. E. Sodium-glucose co-transporter 2 inhibitors and Sarcopenia: a controversy that must be solved. Clin. Nutr. 42, 2338–2352 (2023).
Google Scholar
Yabe, D. et al. Efficacy and safety of the sodium-glucose co-transporter-2 inhibitor empagliflozin in elderly Japanese adults (>/=65 years) with type 2 diabetes: a randomized, double-blind, placebo-controlled, 52-week clinical trial (EMPA-ELDERLY). Diabetes Obes. Metab. 25, 3538–3548 (2023).
Google Scholar
Zhang, S., Qi, Z., Wang, Y., Song, D. & Zhu, D. Effect of sodium-glucose transporter 2 inhibitors on sarcopenia in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Front. Endocrinol.14, 1203666 (2023).
Google Scholar
Lin, D. S. et al. Major adverse cardiovascular and limb events in people with diabetes treated with GLP-1 receptor agonists vs SGLT2 inhibitors. Diabetologia 65, 2032–2043 (2022).
Google Scholar
Fralick, M. et al. Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study. BMJ 370, m2812 (2020).
Google Scholar
Butt, J. H. et al. Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER. Eur. Heart J. 44, 2170–2183 (2023).
Google Scholar
Gudemann, L. M. et al. Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach. Diabetologia 67, 1817–1827 (2024).
Google Scholar
Zhao, X. et al. GLP-1 Receptor agonists: beyond their pancreatic effects. Front Endocrinol.12, 721135 (2021).
Google Scholar
American Diabetes Association Professional Practice, C. 8 Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of care in diabetes-2025. Diabetes Care 48, S167–S180 (2025).
Google Scholar
Stefanou, M. I. et al. Risk of major adverse cardiovascular events and all-cause mortality under treatment with GLP-1 RAs or the dual GIP/GLP-1 receptor agonist tirzepatide in overweight or obese adults without diabetes: a systematic review and meta-analysis. Ther. Adv. Neurol. Disord. 17, 17562864241281903 (2024).
Google Scholar
Kosiborod, M. N. et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N. Engl. J. Med. 390, 1394–1407 (2024).
Google Scholar
Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N. Engl. J. Med. 391, 109–121 (2024).
Google Scholar
Apperloo, E. M. et al. Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial. Nat. Med. 31, 278–285 (2025).
Google Scholar
Heerspink, H. J. L. et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 10, 774–785 (2022).
Google Scholar
Wilson, J. M. et al. The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes. Diabetes Obes. Metab. 22, 2451–2459 (2020).
Google Scholar
Frias, J. P. et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet 402, 720–730 (2023).
Google Scholar
Yao, H. et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ 384, e076410 (2024).
Google Scholar
Chen, J. et al. GLP-1 receptor agonist as a modulator of innate immunity. Front. Immunol. 13, 997578 (2022).
Google Scholar
Yassine, H. N. et al. Brain energy failure in dementia syndromes: opportunities and challenges for glucagon-like peptide-1 receptor agonists. Alzheimers Dement. 18, 478–497 (2022).
Google Scholar
Hong, C. T., Chen, J. H. & Hu, C. J. Role of glucagon-like peptide-1 receptor agonists in Alzheimer’s disease and Parkinson’s disease. J. Biomed. Sci. 31, 102 (2024).
Google Scholar
Ghosh, P. et al. Targeting redox imbalance in neurodegeneration: characterizing the role of GLP-1 receptor agonists. Theranostics 13, 4872–4884 (2023).
Google Scholar
Cheng, H. et al. Enhancement of impaired olfactory neural activation and cognitive capacity by liraglutide, but not dapagliflozin or acarbose, in patients with type 2 diabetes: a 16-week randomized parallel comparative study. Diabetes Care 45, 1201–1210 (2022).
Google Scholar
Dhanapalaratnam, R. et al. Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy. Diabetologia 67, 561–566 (2024).
Google Scholar
Kuate Defo, A. et al. Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis. Diabetes Obes. Metab. 26, 441–462 (2024).
Google Scholar
Garcia-Casares, N. et al. Effects of GLP-1 receptor agonists on neurological complications of diabetes. Rev. Endocr. Metab. Disord. 24, 655–672 (2023).
Google Scholar
Halloum, W., Dughem, Y. A., Beier, D. & Pellesi, L. Glucagon-like peptide-1 (GLP-1) receptor agonists for headache and pain disorders: a systematic review. J. Headache Pain. 25, 112 (2024).
Google Scholar
Yabut, J. M. & Drucker, D. J. Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease. Endocr. Rev. 44, 14–32 (2023).
Google Scholar
Majzoub, A. M. et al. Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. Aliment Pharm. Ther. 54, 880–889 (2021).
Google Scholar
Qi, X., Li, J., Caussy, C., Teng, G. J. & Loomba, R. Epidemiology, screening, and co-management of type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease. Hepatology, (2024). Online ahead of print. https://doi.org/10.1097/HEP.0000000000000913.
Newsome, P. N. et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2021).
Google Scholar
Rinella, M. E. et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 77, 1797–1835 (2023).
Google Scholar
Romero-Gomez, M. et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J. Hepatol. 79, 888–897 (2023).
Google Scholar
Harrison, S. A. et al. Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: A randomized, double-blind, placebo-controlled study. J. Hepatol. 82, 7–17 (2025).
Google Scholar
Nahra, R. et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 44, 1433–1442 (2021).
Google Scholar
Shankar, S. S. et al. Safety and efficacy of novel incretin co-agonist cotadutide in biopsy-proven noncirrhotic MASH with fibrosis. Clin. Gastroenterol. Hepatol. 22, 1847–1857 e1811 (2024).
Google Scholar
Loomba, R. et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N. Engl. J. Med 391, 299–310 (2024).
Google Scholar
Locatelli, J. C. et al. Incretin-based weight loss pharmacotherapy: can resistance exercise optimize changes in body composition?. Diabetes Care 47, 1718–1730 (2024).
Google Scholar
Linge, J., Birkenfeld, A. L. & Neeland, I. J. Muscle mass and glucagon-like peptide-1 receptor agonists: adaptive or maladaptive response to weight loss?. Circulation 150, 1288–1298 (2024).
Google Scholar
Agarwal, R. et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur. Heart J. 43, 474–484 (2022).
Google Scholar
Heerspink, H. J. L. et al. Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease: the FINE-ONE trial. Diabetes Res. Clin. Pract. 204, 110908 (2023).
Google Scholar
Rossing, P. et al. Effect of finerenone on the occurrence of vision-threatening complications in patients with non-proliferative diabetic retinopathy: Pooled analysis of two studies using routine ophthalmological examinations from clinical trial participants (ReFineDR/DeFineDR). Diabetes Obes. Metab. 25, 894–898 (2023).
Google Scholar
Zhao, M. et al. Mineralocorticoid receptor pathway and its antagonism in a model of diabetic retinopathy. Diabetes 70, 2668–2682 (2021).
Google Scholar
Jerome, J. R., Deliyanti, D., Suphapimol, V., Kolkhof, P. & Wilkinson-Berka, J. L. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduces vascular injury and increases regulatory T-cells: studies in rodents with diabetic and neovascular retinopathy. Int. J. Mol. Sci. 24, 2334 (2023).
Google Scholar
Koide, M. et al. Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease. J. Clin. Investig. 131, e149029 (2021).
Google Scholar
Chambers, L. C., Diaz-Otero, J. M., Fisher, C. L., Jackson, W. F. & Dorrance, A. M. Mineralocorticoid receptor antagonism improves transient receptor potential vanilloid 4-dependent dilation of cerebral parenchymal arterioles and cognition in a genetic model of hypertension. J. Hypertens. 40, 1722–1734 (2022).
Google Scholar
Howard, Z. M., Gomatam, C. K., Piepho, A. B. & Rafael-Fortney, J. A. Mineralocorticoid receptor signaling in the inflammatory skeletal muscle microenvironments of muscular dystrophy and acute injury. Front. Pharm. 13, 942660 (2022).
Google Scholar
Heerspink, H. J. L. et al. Canagliflozin and kidney-related adverse events in type 2 diabetes and CKD: findings from the randomized CREDENCE trial. Am. J. Kidney Dis. 79, 244–256.e241 (2022).
Google Scholar
Perkovic, V. et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 380, 2295–2306 (2019).
Google Scholar
The EMPA-KIDNEY Collaborative Group Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 388, 117–127 (2023).
Google Scholar
Tuttle, K. R. The landscape of diabetic kidney disease transformed. Nat. Rev. Nephrol. 16, 67–68 (2020).
Google Scholar
Bakris, G. L. et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N. Engl. J. Med. 383, 2219–2229 (2020).
Google Scholar
Pitt, B. et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N. Engl. J. Med. 385, 2252–2263 (2021).
Google Scholar
Neuen, B. L. et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 7, 845–854 (2019).
Google Scholar
Kang, A. & Jardine, M. J. SGLT2 inhibitors may offer benefit beyond diabetes. Nat. Rev. Nephrol. 17, 83–84 (2021).
Google Scholar
Agarwal, R. et al. Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes. N. Engl. J. Med. 393, 533–543 (2025).
Google Scholar
Neuen, B. L. et al. Estimated lifetime cardiovascular, kidney, and mortality benefits of combination treatment with SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal mra compared with conventional care in patients with type 2 diabetes and albuminuria. Circulation 149, 450–462 (2024).
Google Scholar
Cherney, D. Z. I. et al. Management of type 2 diabetic kidney disease in 2022: a narrative review for specialists and primary care. Can. J. Kidney Health Dis. 10, 20543581221150556 (2023).
Google Scholar
Patoulias, D., Popovic, D. S., Fragakis, N. & Rizzo, M. Has the time come to step up to “triple therapy” for the treatment of diabetic kidney disease?. Diabetes Res. Clin. Pract. 201, 110726 (2023).
Google Scholar
Zhang, C. et al. A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation. Diabetes Metab. Syndr. Obes. 12, 1297–1309 (2019).
Google Scholar
Peng, W. et al. BMP-7 ameliorates partial epithelial-mesenchymal transition by restoring SnoN protein level via Smad1/5 pathway in diabetic kidney disease. Cell Death Dis. 13, 254 (2022).
Google Scholar
Liang, Y. et al. Critical role of FGF21 in diabetic kidney disease: from energy metabolism to innate immunity. Front. Immunol. 15, 1333429 (2024).
Google Scholar
Wang, J. et al. Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway. Diabetes Obes. Metab. 26, 32–45 (2024).
Google Scholar
Yu, S. et al. Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats. Stem Cell Res. Ther. 10, 333 (2019).
Google Scholar
Xiang, E. et al. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis. Stem Cell Res. Ther. 11, 336 (2020).
Google Scholar
Cheng, J. & Zhang, C. Mesenchymal stem cell therapy: therapeutic opportunities and challenges for diabetic kidney disease. Int. J. Mol. Sci. 25, 10540 (2024).
Perico, N. et al. Safety and preliminary efficacy of mesenchymal stromal cell (ORBCEL-M) therapy in diabetic kidney disease: a randomized clinical trial (NEPHSTROM). J. Am. Soc. Nephrol. 34, 1733–1751 (2023).
Google Scholar
Habib, H. A., Heeba, G. H. & Khalifa, M. M. A. Effect of combined therapy of mesenchymal stem cells with GLP-1 receptor agonist, exenatide, on early-onset nephropathy induced in diabetic rats. Eur. J. Pharm. 892, 173721 (2021).
Google Scholar
Yang, C. C. et al. Repeated administration of adipose-derived mesenchymal stem cells added on beneficial effects of empagliflozin on protecting renal function in diabetic kidney disease rat. Biomed. J. 47, 100613 (2024).
Google Scholar
Meng, J. et al. Effects of xenogeneic transplantation of umbilical cord-derived mesenchymal stem cells combined with irbesartan on renal podocyte damage in diabetic rats. Stem Cell Res Ther. 15, 239 (2024).
Google Scholar
Liu, Q. et al. Mesenchymal stem cells modified with angiotensin-converting enzyme 2 are superior for amelioration of glomerular fibrosis in diabetic nephropathy. Diabetes Res. Clin. Pract. 162, 108093 (2020).
Google Scholar
Kim, H. et al. Mesenchymal stem cell 3D encapsulation technologies for biomimetic microenvironment in tissue regeneration. Stem Cell Res. Ther. 10, 51 (2019).
Google Scholar
Wechsler, M. E., Rao, V. V., Borelli, A. N. & Anseth, K. S. Engineering the MSC secretome: a hydrogel focused approach. Adv. Health Mater. 10, e2001948 (2021).
Google Scholar
Raghav, P. K., Mann, Z., Ahlawat, S. & Mohanty, S. Mesenchymal stem cell-based nanoparticles and scaffolds in regenerative medicine. Eur. J. Pharm. 918, 174657 (2022).
Google Scholar
Mou, L., Wang, T. B., Wang, X. & Pu, Z. Advancing diabetes treatment: the role of mesenchymal stem cells in islet transplantation. Front. Immunol. 15, 1389134 (2024).
Google Scholar
Song, Y. et al. Optimizing therapeutic outcomes: preconditioning strategies for MSC-derived extracellular vesicles. Front. Pharm. 16, 1509418 (2025).
Google Scholar
Nikfarjam, S., Rezaie, J., Zolbanin, N. M. & Jafari, R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J. Transl. Med. 18, 449 (2020).
Google Scholar
Jin, J. et al. Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte. Stem Cell Res. Ther. 10, 95 (2019).
Google Scholar
Liu, L. et al. Bone Marrow mesenchymal stem cell-derived exosomes alleviate diabetic kidney disease in rats by inhibiting apoptosis and inflammation. Front Biosci. (Landmark Ed.) 28, 203 (2023).
Google Scholar
Zhang, Y. et al. MicroRNA-146a-5p-modified human umbilical cord mesenchymal stem cells enhance protection against diabetic nephropathy in rats through facilitating M2 macrophage polarization. Stem Cell Res. Ther. 13, 171 (2022).
Google Scholar
Jiang, Z. Z. et al. Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats. Stem Cell Res. Ther. 7, 24 (2016).
Google Scholar
Banerjee, A. & Singla, D. K. MSC exosomes attenuate sterile inflammation and necroptosis associated with TAK1-pJNK-NFKB mediated cardiomyopathy in diabetic ApoE KO mice. Front. Immunol. 15, 1348043 (2024).
Google Scholar
Taherian, M., Bayati, P. & Mojtabavi, N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res. Ther. 15, 170 (2024).
Google Scholar
Zhang, W., Wang, Y. & Kong, Y. Exosomes derived from mesenchymal stem cells modulate miR-126 to ameliorate hyperglycemia-induced retinal inflammation via targeting HMGB1. Investig. Ophthalmol. Vis. Sci. 60, 294–303 (2019).
Google Scholar
Luo, Y. & Li, C. Advances in research related to MicroRNA for diabetic retinopathy. J. Diabetes Res. 2024, 8520489 (2024).
Google Scholar
Pradhan Nabzdyk, L. et al. Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. J. Vasc. Surg. 58, 766–775.e712 (2013).
Google Scholar
Dalirfardouei, R., Jamialahmadi, K., Jafarian, A. H. & Mahdipour, E. Promising effects of exosomes isolated from menstrual blood-derived mesenchymal stem cell on wound-healing process in diabetic mouse model. J. Tissue Eng. Regen. Med. 13, 555–568 (2019).
Google Scholar
Mohanty, A. R., Ravikumar, A. & Peppas, N. A. Recent advances in glucose-responsive insulin delivery systems: novel hydrogels and future applications. Regen. Biomater. 9, rbac056 (2022).
Google Scholar
Moon, J. E. et al. Enhancing differentiation and functionality of insulin-producing cells derived from iPSCs using esterified collagen hydrogel for cell therapy in diabetes mellitus. Stem Cell Res Ther. 15, 374 (2024).
Google Scholar
Chen, S. et al. A 3D-printed microdevice encapsulates vascularized islets composed of iPSC-derived beta-like cells and microvascular fragments for type 1 diabetes treatment. Biomaterials 315, 122947 (2025).
Google Scholar
Campo, F. et al. Bioengineering of a human iPSC-derived vascularized endocrine pancreas for type 1 diabetes. Cell Rep. Med. 6, 101938 (2025).
Google Scholar
Marques, J. M. et al. GLP-1 Analogue-loaded glucose-responsive nanoparticles as allies of stem cell therapies for the treatment of type I diabetes. ACS Pharm. Transl. Sci. 7, 1650–1663 (2024).
Google Scholar
Ho, J., Yue, D., Cheema, U., Hsia, H. C. & Dardik, A. Innovations in stem cell therapy for diabetic wound healing. Adv. Wound Care12, 626–643 (2023).
Google Scholar
Wang, K. et al. Combined placental mesenchymal stem cells with guided nanoparticles effective against diabetic nephropathy in mouse model. Int. J. Nanomed. 19, 901–915 (2024).
Google Scholar
Chen, C. et al. New perspectives on the treatment of diabetic nephropathy: challenges and prospects of mesenchymal stem cell therapy. Eur. J. Pharm. 998, 177543 (2025).
Google Scholar
Wu, Y. et al. Innovative nanotechnology in drug delivery systems for advanced treatment of posterior segment ocular diseases. Adv. Sci.11, e2403399 (2024).
Google Scholar
Gui, S. et al. Ultrasmall coordination polymer nanodots fe-quer nanozymes for preventing and delaying the development and progression of diabetic retinopathy. Adv. Funct. Mater. 33, 2300261 (2023).
Google Scholar
Lee, W. et al. Dopamine-functionalized gellan gum hydrogel as a candidate biomaterial for a retinal pigment epithelium cell delivery system. ACS Appl. Bio Mater. 4, 1771–1782 (2021).
Google Scholar
Kong, W. et al. Collaborative Enhancement of Diabetic Wound Healing and Skin Regeneration by Recombinant Human Collagen Hydrogel and hADSCs. Adv. Health. Mater. 13, e2401012 (2024).
Google Scholar
Zhang, H. M., Yang, M. L., Xi, J. Z., Yang, G. Y. & Wu, Q. N. Mesenchymal stem cells-based drug delivery systems for diabetic foot ulcer: a review. World J. Diabetes 14, 1585–1602 (2023).
Google Scholar
Huang, Y. et al. Sodium butyrate ameliorates diabetic retinopathy in mice via the regulation of gut microbiota and related short-chain fatty acids. J. Transl. Med. 21, 451 (2023).
Google Scholar
Zhang, Y. et al. The diversity of gut microbiota in type 2 diabetes with or without cognitive impairment. Aging Clin. Exp. Res. 33, 589–601 (2021).
Google Scholar
Miranda Alatriste, P. V., Urbina Arronte, R., Gomez Espinosa, C. O. & Espinosa Cuevas Mde, L. Effect of probiotics on human blood urea levels in patients with chronic renal failure. Nutr. Hosp. 29, 582–590 (2014).
Google Scholar
Arteaga-Muller, G. Y. et al. Changes in the progression of chronic kidney disease in patients undergoing fecal microbiota transplantation. Nutrients 16, 1109 (2024).
Google Scholar
Si, H. et al. A graminan type fructan from Achyranthes bidentata prevents the kidney injury in diabetic mice by regulating gut microbiota. Carbohydr. Polym. 339, 122275 (2024).
Google Scholar
Companys, J. et al. Effects of enriched seafood sticks (heat-inactivated B. animalis subsp. lactis CECT 8145, inulin, omega-3) on cardiometabolic risk factors and gut microbiota in abdominally obese subjects: randomized controlled trial. Eur. J. Nutr. 61, 3597–3611 (2022).
Google Scholar
Verma, A. et al. Angiotensin-(1-7) expressed from lactobacillus bacteria protect diabetic retina in mice. Transl. Vis. Sci. Technol. 9, 20 (2020).
Google Scholar
Liu, Z. et al. Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat. Commun. 11, 855 (2020).
Google Scholar
Chen, Y. et al. Adjunctive probio-X treatment enhances the therapeutic effect of a conventional drug in managing type 2 diabetes mellitus by promoting short-chain fatty acid-producing bacteria and bile acid pathways. mSystems 8, e0130022 (2023).
Google Scholar
Gradisteanu Pircalabioru, G. et al. Dysbiosis in the development of type I diabetes and associated complications: from mechanisms to targeted gut microbes manipulation therapies. Int J. Mol. Sci. 22, 2763 (2021).
Google Scholar
Hanif, N. et al. Proteomic changes to the updated discovery of engineered insulin and its analogs: pros and cons. Curr. Issues Mol. Biol. 44, 867–888 (2022).
Google Scholar
Sebastian, S. A., Co, E. L., Mehendale, M. & Hameed, M. Insulin analogs in the treatment of type II diabetes and future perspectives. Dis. Mon. 69, 101417 (2023).
Google Scholar
Yu, X., Jia, Y. & Ren, F. Multidimensional biological activities of resveratrol and its prospects and challenges in the health field. Front. Nutr. 11, 1408651 (2024).
Google Scholar
Ahmad, I. & Hoda, M. Molecular mechanisms of action of resveratrol in modulation of diabetic and non-diabetic cardiomyopathy. Pharm. Res. 161, 105112 (2020).
Google Scholar
Chen, S., Li, B., Chen, L. & Jiang, H. Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation. J. Transl. Med. 21, 380 (2023).
Google Scholar
Gomez-Jimenez, V., Burggraaf-Sanchez de Las Matas, R. & Ortega, A. L. Modulation of Oxidative Stress in Diabetic Retinopathy: Therapeutic Role of Natural Polyphenols. Antioxidants 14, 875 (2025).
Google Scholar
Hartwig, S. et al. Exosomal proteins constitute an essential part of the human adipose tissue secretome. Biochim. Biophys. Acta Proteins Proteom. 1867, 140172 (2019).
Google Scholar
Samadi, P. et al. Berberine: a novel therapeutic strategy for cancer. IUBMB Life 72, 2065–2079 (2020).
Google Scholar
Bansod, S., Saifi, M. A. & Godugu, C. Molecular updates on berberine in liver diseases: bench to bedside. Phytother. Res. 35, 5459–5476 (2021).
Google Scholar
Harrison, S. A. et al. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nat. Commun. 12, 5503 (2021).
Google Scholar
Qin, X. et al. Berberine protects glomerular podocytes via inhibiting Drp1-mediated mitochondrial fission and dysfunction. Theranostics 9, 1698–1713 (2019).
Google Scholar
Wang, N. et al. Berberine improves insulin-induced diabetic retinopathy through exclusively suppressing Akt/mTOR-mediated HIF-1alpha/VEGF activation in retina endothelial cells. Int. J. Biol. Sci. 17, 4316–4326 (2021).
Google Scholar
Ahmedy, O. A., Salem, H. H., Mohamed, Y. S. & Zaky, D. A. Unleashing the cardioprotective potential of berberine against doxorubicin cardiotoxicity: Innovative exploitation of the peculiar antipyroptotic/antioxidant/anti-inflammatory capacity via modulation of inflammasome/caspase-1/interleukin pathway in rats. Int. Immunopharmacol. 159, 114964 (2025).
Google Scholar
Chan, K. W. et al. Add-on Rehmannia-6-based chinese medicine in type 2 diabetes and CKD: a multicenter randomized controlled trial. Clin. J. Am. Soc. Nephrol. 18, 1163–1174 (2023).
Google Scholar
Chan, K. W. et al. Add-on astragalus in type 2 diabetes and chronic kidney disease: a multi-center, assessor-blind, randomized controlled trial. Phytomedicine 130, 155457 (2024).
Google Scholar
Li, W. et al. The signaling pathways of traditional Chinese medicine in treating diabetic retinopathy. Front. Pharm. 14, 1165649 (2023).
Google Scholar
Snyder, M. J., Gibbs, L. M. & Lindsay, T. J. Treating painful diabetic peripheral neuropathy: an update. Am. Fam. Physician 94, 227–234 (2016).
Google Scholar
Deng, L. et al. The mechanisms underlying Chinese medicines to treat inflammation in diabetic kidney disease. J. Ethnopharmacol. 333, 118424 (2024).
Google Scholar
Song, W. & Zhu, Y. W. Chinese medicines in diabetic retinopathy therapies. Chin. J. Integr. Med. 25, 316–320 (2019).
Google Scholar
Hermanns, N. et al. Coordination of glucose monitoring, self-care behaviour and mental health: achieving precision monitoring in diabetes. Diabetologia 65, 1883–1894 (2022).
Google Scholar
ElSayed, N. A. et al. Facilitating positive health behaviors and well-being to improve health outcomes: standards of care in diabetes-2023. Diabetes Care 46, S68–S96 (2023).
Google Scholar
Ashrafzadeh, S. & Hamdy, O. Patient-driven diabetes care of the future in the technology era. Cell Metab. 29, 564–575 (2019).
Google Scholar
Ljubic, B. et al. Predicting complications of diabetes mellitus using advanced machine learning algorithms. J. Am. Med. Inf. Assoc. 27, 1343–1351 (2020).
Google Scholar
Dai, L. et al. A deep learning system for detecting diabetic retinopathy across the disease spectrum. Nat. Commun. 12, 3242 (2021).
Google Scholar
Bhaskaranand, M. et al. The value of automated diabetic retinopathy screening with the EyeArt system: a study of more than 100,000 consecutive encounters from people with diabetes. Diabetes Technol. Ther. 21, 635–643 (2019).
Google Scholar
Bhaskaranand, M. et al. Automated diabetic retinopathy screening and monitoring using retinal fundus image analysis. J. Diabetes Sci. Technol. 10, 254–261 (2016).
Google Scholar
Tufail, A. et al. Automated diabetic retinopathy image assessment software: diagnostic accuracy and cost-effectiveness compared with human graders. Ophthalmology 124, 343–351 (2017).
Google Scholar
Topol, E. J. High-performance medicine: the convergence of human and artificial intelligence. Nat. Med. 25, 44–56 (2019).
Google Scholar
Aljuraid, R. & Justinia, T. Classification of challenges and threats in healthcare cybersecurity: a systematic review. Stud. Health Technol. Inf. 295, 362–365 (2022).
Zhang, W. et al. New diagnostic model for the differentiation of diabetic nephropathy from non-diabetic nephropathy in Chinese patients. Front. Endocrinol.13, 913021 (2022).
Google Scholar
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 352, 837–853 (1998).
Khandakar, A. et al. A Novel Machine Learning Approach for Severity Classification of Diabetic Foot Complications Using Thermogram Images. Sensors 22, 4249 (2022).
Google Scholar
Kim, R. B. et al. Utilization of smartphone and tablet camera photographs to predict healing of diabetes-related foot ulcers. Comput Biol. Med. 126, 104042 (2020).
Google Scholar
Williams, B. M. et al. An artificial intelligence-based deep learning algorithm for the diagnosis of diabetic neuropathy using corneal confocal microscopy: a development and validation study. Diabetologia 63, 419–430 (2020).
Google Scholar
Salahouddin, T. et al. Artificial intelligence-based classification of diabetic peripheral neuropathy from corneal confocal microscopy images. Diabetes Care 44, e151–e153 (2021).
Google Scholar
Preston, F. G. et al. Artificial intelligence utilising corneal confocal microscopy for the diagnosis of peripheral neuropathy in diabetes mellitus and prediabetes. Diabetologia 65, 457–466 (2022).
Google Scholar
Eberle, C. & Stichling, S. Clinical improvements by telemedicine interventions managing type 1 and type 2 diabetes: systematic meta-review. J. Med. Internet Res. 23, e23244 (2021).
Google Scholar
Zhang, K. et al. Telemedicine in improving glycemic control among children and adolescents with type 1 diabetes mellitus: systematic review and meta-analysis. J. Med Internet Res. 26, e51538 (2024).
Google Scholar
Lee, E. Y. et al. Efficacy of personalized diabetes self-care using an electronic medical record-integrated mobile app in patients with type 2 diabetes: 6-month randomized controlled trial. J. Med. Internet Res. 24, e37430 (2022).
Google Scholar
Gong, E. et al. My diabetes coach, a mobile app-based interactive conversational agent to support type 2 diabetes self-management: randomized effectiveness-implementation trial. J. Med. Internet Res. 22, e20322 (2020).
Google Scholar
Lotfy, A., AboQuella, N. M. & Wang, H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem Cell Res Ther. 14, 66 (2023).
Google Scholar
Belge Bilgin, G. et al. Theranostics and artificial intelligence: new frontiers in personalized medicine. Theranostics 14, 2367–2378 (2024).
Google Scholar
American Diabetes Association Professional Practice, C. 11 Chronic kidney disease and risk management: standards of care in diabetes-2024. Diabetes Care 47, S219–S230 (2024).
Google Scholar
Marup, F. H., Thomsen, M. B. & Birn, H. Additive effects of dapagliflozin and finerenone on albuminuria in non-diabetic CKD: an open-label randomized clinical trial. Clin. Kidney J. 17, sfad249 (2024).
Google Scholar
Sbrignadello, S., Gobl, C. & Tura, A. Bioelectrical impedance analysis for the assessment of body composition in sarcopenia and type 2 diabetes. Nutrients 14, 1864 (2022).
Google Scholar
Johri, N. et al. A comprehensive review on the risks assessment and treatment options for Sarcopenia in people with diabetes. J. Diabetes Metab. Disord. 22, 995–1010 (2023).
Google Scholar
Chen, L. K. et al. Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J. Am. Med. Dir. Assoc. 21, 300–307 e302 (2020).
Google Scholar
Feldman, E. L. et al. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17, 1281–1289 (1994).
Google Scholar
Bril, V. & Perkins, B. A. Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care 25, 2048–2052 (2002).
Google Scholar
Bril, V., Tomioka, S., Buchanan, R. A., Perkins, B. A. & mTCNS Study Group Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy. Diabet. Med. 26, 240–246 (2009).
Google Scholar
Young, M. J., Boulton, A. J., MacLeod, A. F., Williams, D. R. & Sonksen, P. H. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36, 150–154 (1993).
Google Scholar
Meijer, J. W. et al. Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score. Diabet. Med. 19, 962–965 (2002).
Google Scholar
Dyck, P. J. et al. Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann. Neurol. 8, 590–596 (2004).
Google Scholar
