Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy

  • American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes-2024. Diabetes Care 47 (2024).

  • Lonardo, A., Nascimbeni, F., Mantovani, A. & Targher, G. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence. J. Hepatol. 68, 335–352 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • GBD 2021 Diabetes Collaborators. 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).

    Article 

    Google Scholar
     

  • GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1204–1222 (2020).

    Article 

    Google Scholar
     

  • Sun, H. et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pr. 183, 109119 (2022).

    Article 

    Google Scholar
     

  • Kautzky-Willer, A., Harreiter, J. & Pacini, G. Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus. Endocr. Rev. 37, 278–316 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bonnefond, A. & Froguel, P. Rare and common genetic events in type 2 diabetes: what should biologists know? Cell Metab. 21, 357–368 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Harding, J. L., Pavkov, M. E., Magliano, D. J., Shaw, J. E. & Gregg, E. W. Global trends in diabetes complications: a review of current evidence. Diabetologia 62, 3–16 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Liu, W. et al. Global trends in the burden of chronic kidney disease attributable to type 2 diabetes: an age-period-cohort analysis. Diabetes Obes. Metab. 26, 602–610 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Armstrong, D. G., Tan, T.-W., Boulton, A. J. M. & Bus, S. A. Diabetic foot ulcers: a review. JAMA 330, 62–75 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hicks, C. W. & Selvin, E. Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. Curr. Diab Rep. 19, 86 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Teo, Z. L. et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology 128, 1580–1591 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Mulder, H. Transcribing β-cell mitochondria in health and disease. Mol. Metab. 6, 1040–1051 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Festa, A. et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102, 42–47 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gado, M., Tsaousidou, E., Bornstein, S. R. & Perakakis, N. Sex-based differences in insulin resistance. J. Endocrinol. 261, e230245 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Petersen, K. F. et al. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc. Natl Acad. Sci. USA 103, 18273–18277 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lear, S. A., Kohli, S., Bondy, G. P., Tchernof, A. & Sniderman, A. D. Ethnic variation in fat and lean body mass and the association with insulin resistance. J. Clin. Endocrinol. Metab. 94, 4696–4702 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sylow, L., Tokarz, V. L., Richter, E. A. & Klip, A. The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia. Cell Metab. 33, 758–780 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Smith, U. & Kahn, B. B. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J. Intern Med. 280, 465–475 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xie, Z., Xie, T., Liu, J., Zhang, Q. & Xiao, X. Emerging role of protein O-GlcNAcylation in liver metabolism: implications for diabetes and NAFLD. Int. J. Mol. Sci. 24, 2142 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hart, G. W., Slawson, C., Ramirez-Correa, G. & Lagerlof, O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem. 80, 825–858 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, B. et al. Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency. Nature 605, 761–766 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Epstein, F. H., Moller, D. E. & Flier, J. S. Insulin resistance—mechanisms, syndromes, and implications. N. Engl. J. Med. 325, 938–948 (1991).

    Article 

    Google Scholar
     

  • Jaldin-Fincati, J. R., Pavarotti, M., Frendo-Cumbo, S., Bilan, P. J. & Klip, A. Update on GLUT4 vesicle traffic: a cornerstone of insulin action. Trends Endocrinol. Metab. 28, 597–611 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • He, L. Alterations of gut microbiota by overnutrition impact gluconeogenic gene expression and insulin signaling. Int J. Mol. Sci. 22, 2121 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Poitout, V. & Robertson, R. P. Glucolipotoxicity: fuel excess and β-cell dysfunction. Endocr. Rev. 29, 351–366 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Weir, G. C. & Bonner-Weir, S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 53, S16–S21 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shaikh, S. R., Beck, M. A., Alwarawrah, Y. & MacIver, N. J. Emerging mechanisms of obesity-associated immune dysfunction. Nat. Rev. Endocrinol. 20, 136–148 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bays, H., Mandarino, L. & DeFronzo, R. A. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J. Clin. Endocrinol. Metab. 89, 463–478 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Glass, C. K. & Olefsky, J. M. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 15, 635–645 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, P. et al. Role of macrophages in peripheral nerve injury and repair. Neural Regen. Res 14, 1335–1342 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • El, F., Ka, N., Ts, J. & Dlh, B. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron 93, 1296–1313 (2017).

    Article 

    Google Scholar
     

  • Oeckinghaus, A., Hayden, M. S. & Ghosh, S. Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12, 695–708 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kracht, M., Müller-Ladner, U. & Schmitz, M. L. Mutual regulation of metabolic processes and proinflammatory NF-κB signaling. J. Allergy Clin. Immunol. 146, 694–705 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Villalobos-Labra, R., Subiabre, M., Toledo, F., Pardo, F. & Sobrevia, L. Endoplasmic reticulum stress and development of insulin resistance in adipose, skeletal, liver, and foetoplacental tissue in diabesity. Mol. Asp. Med. 66, 49–61 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Prasad, M. K., Mohandas, S. & Ramkumar, K. M. Dysfunctions, molecular mechanisms, and therapeutic strategies of pancreatic β-cells in diabetes. Apoptosis 28, 958–976 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Qin, W. & Weng, J. Hepatocyte NLRP3 interacts with PKCε to drive hepatic insulin resistance and steatosis. Sci. Bull. (Beijing) 68, 1413–1429 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Petersen, K. F. et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc. Natl Acad. Sci. USA 104, 12587–12594 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bhat, O. M. et al. Interleukin-18-induced cell adhesion molecule expression is associated with feedback regulation by PPAR-γ and NF-κB in Apo E-/- mice. Mol. Cell Biochem. 428, 119–128 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fu, Y., Wu, N. & Zhao, D. Function of NLRP3 in the Pathogenesis and Development of Diabetic Nephropathy. Med Sci. Monit. 23, 3878–3884 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Matoba, K. et al. Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease. Int J. Mol. Sci. 20, 3393 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sheu, M. L. et al. High glucose induces human endothelial cell apoptosis through a phosphoinositide 3-kinase-regulated cyclooxygenase-2 pathway. Arterioscler. Thromb. Vasc. Biol. 25, 539–545 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Romeo, G., Liu, W.-H., Asnaghi, V., Kern, T. S. & Lorenzi, M. Activation of nuclear factor-kappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. Diabetes 51, 2241–2248 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kowluru, R. A., Koppolu, P., Chakrabarti, S. & Chen, S. Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants. Free Radic. Res. 37, 1169–1180 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu, M.-Y., Yiang, G.-T., Lai, T.-T. & Li, C.-J. The oxidative stress and mitochondrial dysfunction during the pathogenesis of diabetic retinopathy. Oxid. Med. Cell Longev. 2018, 3420187 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chaurasia, S. S. et al. The NLRP3 inflammasome may contribute to pathologic neovascularization in the advanced stages of diabetic retinopathy. Sci. Rep. 8, 2847 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dodington, D. W., Desai, H. R. & Woo, M. JAK/STAT—emerging players in metabolism. Trends Endocrinol. Metab. 29, 55–65 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tian, S., Zhao, H. & Song, H. Shared signaling pathways and targeted therapy by natural bioactive compounds for obesity and type 2 diabetes. Crit. Rev. Food Sci. Nutr. 64, 5039–5056 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Bako, H. Y., Ibrahim, M. A., Isah, M. S. & Ibrahim, S. Inhibition of JAK-STAT and NF-κB signalling systems could be a novel therapeutic target against insulin resistance and type 2 diabetes. Life Sci. 239, 117045 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, H. et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int. 92, 909–921 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, Z. et al. Nobiletin suppresses high-glucose-induced inflammation and ECM accumulation in human mesangial cells through STAT3/NF-κB pathway. J. Cell Biochem. 120, 3467–3473 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Eg, L. et al. Interleukin 6 function in the skin and isolated keratinocytes is modulated by hyperglycemia. J. Immunol. Res. 2019, 5087847 (2019).


    Google Scholar
     

  • Ap, S. et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat. Commun. 11, 4678 (2020).

    Article 

    Google Scholar
     

  • Yung, J. H. M. & Giacca, A. Role of c-Jun N-terminal kinase (JNK) in obesity and type 2 diabetes. Cells 9, 706 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kitamura, T. The role of FOXO1 in β-cell failure and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 9, 615–623 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Back, S. H. & Kaufman, R. J. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev. Biochem. 81, 767–793 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gorman, A. M., Healy, S. J. M., Jäger, R. & Samali, A. Stress management at the ER: Regulators of ER stress-induced apoptosis. Pharm. Thers 134, 306–316 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Wang, Y., He, Z., Yang, Q. & Zhou, G. XBP1 inhibits mesangial cell apoptosis in response to oxidative stress via the PTEN/AKT pathway in diabetic nephropathy. FEBS Open Bio 9, 1249–1258 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yao, W. et al. IRE1α siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro. Sci. Rep. 8, 2579 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, L. et al. Role of endoplasmic reticulum stress in the loss of retinal ganglion cells in diabetic retinopathy. Neural Regen. Res. 8, 3148–3158 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gupta, D., Kono, T. & Evans-Molina, C. The role of peroxisome proliferator-activated receptor γ in pancreatic β cell function and survival: therapeutic implications for the treatment of type 2 diabetes mellitus. Diabetes Obes. Metab. 12, 1036–1047 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Powers, S. K. & Schrager, M. Redox signaling regulates skeletal muscle remodeling in response to exercise and prolonged inactivity. Redox Biol. 54, 102374 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Petersen, K. F. et al. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proc. Natl Acad. Sci. USA 109, 8236–8240 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lu, Q. et al. The mTOR promotes oxidative stress-induced apoptosis of mesangial cells in diabetic nephropathy. Mol. Cell Endocrinol. 473, 31–43 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Samadi, M., Aziz, S. G.-G. & Naderi, R. The effect of tropisetron on oxidative stress, SIRT1, FOXO3a, and claudin-1 in the renal tissue of STZ-induced diabetic rats. Cell Stress Chaperones 26, 217–227 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Domingueti, C. P. et al. Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J. Diabetes Complications 30, 738–745 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Kang, Q. & Yang, C. Oxidative stress and diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 37, 101799 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eid, S. A. et al. New perspectives in diabetic neuropathy. Neuron 111, 2623–2641 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eid, S. A. et al. Targeting the NADPH oxidase-4 and liver X receptor pathway preserves Schwann cell integrity in diabetic mice. Diabetes 69, 448–464 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu, J. et al. Oxidative stress induced by NOX2 contributes to neuropathic pain via plasma membrane translocation of PKCε in rat dorsal root ganglion neurons. J. Neuroinflammation 18, 106 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiao, Y. et al. MicroRNA-7a-5p ameliorates diabetic peripheral neuropathy by regulating VDAC1/JNK/c-JUN pathway. Diabet. Med. 40, e14890 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Taylor, R. Type 2 diabetes. Diabetes Care 36, 1047–1055 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Samuel, V. T., Petersen, K. F. & Shulman, G. I. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375, 2267–2277 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yao, Z. et al. Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice. Nat. Metab. 5, 1706–1725 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Geisler, C. E. et al. Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release. Cell Rep. 35, 109298 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Das, A. & Reis, F. mTOR signaling: new insights into cancer, cardiovascular diseases, diabetes and aging. Int J. Mol. Sci. 24, 13628 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leibowitz, G., Cerasi, E. & Ketzinel-Gilad, M. The role of mTOR in the adaptation and failure of β-cells in type 2 diabetes. Diabetes Obes. Metab. 10, 157–169 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Qiao, S. et al. Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/β-TrcP/Nrf2 pathway. Free Radic. Biol. Med. 145, 118–135 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bouçanova, F. et al. Disrupted function of lactate transporter MCT1, but not MCT4, in Schwann cells affects the maintenance of motor end-plate innervation. Glia 69, 124–136 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Yang, H.-L., Tsai, Y.-C., Korivi, M., Chang, C.-T. & Hseu, Y.-C. Lucidone promotes the cutaneous wound healing process via activation of the PI3K/AKT, Wnt/β-catenin and NF-κB signaling pathways. Biochim. Biophys. Acta Mol. Cell Res. 1864, 151–168 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wei, F. et al. Plasma endothelial cells-derived extracellular vesicles promote wound healing in diabetes through YAP and the PI3K/Akt/mTOR pathway. Aging (Albany NY) 12, 12002–12018 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jere, S. W., Houreld, N. N. & Abrahamse, H. Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev. 50, 52–59 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, E., Gao, B., Yang, L., Wu, X. & Wang, Z. Notoginsenoside Ft1 promotes fibroblast proliferation via PI3K/Akt/mTOR signaling pathway and benefits wound healing in genetically diabetic mice. J. Pharm. Exp. Ther. 356, 324–332 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Kim, W., Shin, Y.-K., Kim, B.-J. & Egan, J. M. Notch signaling in pancreatic endocrine cell and diabetes. Biochem. Biophys. Res. Commun. 392, 247–251 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pajvani, U. B. et al. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat. Med. 19, 1054–1060 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pajvani, U. B. et al. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat. Med. 17, 961–967 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hasan, S. S. et al. Endothelial Notch signaling controls insulin transport in muscle. EMBO Mol. Med. 12, e09271 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Siebel, C. & Lendahl, U. Notch signaling in development, tissue homeostasis, and disease. Physiol. Rev. 97, 1235–1294 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stumvoll, M., Goldstein, B. J. & Van Haeften, T. W. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Townsend, L. K. & Steinberg, G. R. AMPK and the endocrine control of metabolism. Endocr. Rev. 44, 910–933 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Steinberg, G. R. & Hardie, D. G. New insights into activation and function of the AMPK. Nat. Rev. Mol. Cell Biol. 24, 255–272 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stromsdorfer, K. L. et al. NAMPT-mediated NAD(+) biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep. 16, 1851–1860 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tabák, A. G. et al. Adiponectin trajectories before type 2 diabetes diagnosis: Whitehall II study. Diabetes Care 35, 2540–2547 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yc, H. et al. AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice. Cell Death Dis. 12, 925 (2021).

    Article 

    Google Scholar
     

  • Xu, J., Liu, L.-Q., Xu, L.-L., Xing, Y. & Ye, S. Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis. Clin. Exp. Pharm. Physiol. 47, 599–608 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Ren, H. et al. Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway. Mol. Cell Endocrinol. 500, 110628 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gurung, M. et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine 51, 102590 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cox, A. J., West, N. P. & Cripps, A. W. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol. 3, 207–215 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, H. et al. The Wnt signaling pathway in diabetic nephropathy. Front. Cell Dev. Biol. 9, 701547 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zuriaga, M. A. et al. Activation of non-canonical WNT signaling in human visceral adipose tissue contributes to local and systemic inflammation. Sci. Rep. 7, 17326 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nie, X., Wei, X., Ma, H., Fan, L. & Chen, W.-D. The complex role of Wnt ligands in type 2 diabetes mellitus and related complications. J. Cell Mol. Med. 25, 6479–6495 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, H. et al. Regulatory mechanisms of the Wnt/β-catenin pathway in diabetic cutaneous ulcers. Front. Pharmacol. 9, 1114 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yamaguchi, Y. et al. Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/beta-catenin signaling in keratinocytes. FASEB J. 22, 1009–1020 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Catrina, S.-B. & Zheng, X. Hypoxia and hypoxia-inducible factors in diabetes and its complications. Diabetologia 64, 709–716 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Koyasu, S., Kobayashi, M., Goto, Y., Hiraoka, M. & Harada, H. Regulatory mechanisms of hypoxia‐inducible factor 1 activity: Two decades of knowledge. Cancer Sci. 109, 560–571 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pitale, P. M. & Gorbatyuk, M. S. Diabetic retinopathy: from animal models to cellular signaling. Int J. Mol. Sci. 23, 1487 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, D., Lv, F.-L. & Wang, G.-H. Effects of HIF-1α on diabetic retinopathy angiogenesis and VEGF expression. Eur. Rev. Med. Pharm. Sci. 22, 5071–5076 (2018).

    CAS 

    Google Scholar
     

  • Ibar, C. & Irvine, K. D. Integration of Hippo-YAP signaling with metabolism. Dev. Cell 54, 256–267 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Taylor, R., Al-Mrabeh, A. & Sattar, N. Understanding the mechanisms of reversal of type 2 diabetes. Lancet Diabetes Endocrinol. 7, 726–736 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sun, T. & Han, X. Death versus dedifferentiation: the molecular bases of beta cell mass reduction in type 2 diabetes. Semin Cell Dev. Biol. 103, 76–82 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cinti, F. et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 1044–1054 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Spijker, H. S. et al. Conversion of mature human β-cells into glucagon-producing α-cells. Diabetes 62, 2471–2480 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150, 1223–1234 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aguayo-Mazzucato, C. et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30, 129–142.e4 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Son, J. et al. Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure. Nat. Commun. 14, 558 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liang, J., Chirikjian, M., Pajvani, U. B. & Bartolomé, A. MafA regulation in β-cells: from transcriptional to post-translational mechanisms. Biomolecules 12, 535 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ebrahim, N., Shakirova, K. & Dashinimaev, E. PDX1 is the cornerstone of pancreatic β-cell functions and identity. Front. Mol. Biosci. 9, 1091757 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ataie-Ashtiani, S. & Forbes, B. A review of the biosynthesis and structural implications of insulin gene mutations linked to human disease. Cells 12, 1008 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Uchizono, Y., Alarcón, C., Wicksteed, B. L., Marsh, B. J. & Rhodes, C. J. The balance between proinsulin biosynthesis and insulin secretion: where can imbalance lead. Diabetes Obes. Metab. 9, 56–66 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cui, D. et al. Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes. Chin. Med. J. (Engl.) 137, 791 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pascal, S. M. A., Guiot, Y., Pelengaris, S., Khan, M. & Jonas, J.-C. Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets. Am. J. Physiol. Endocrinol. Metab. 295, E92–E102 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bensellam, M., Laybutt, D. R. & Jonas, J.-C. The molecular mechanisms of pancreatic β-cell glucotoxicity: recent findings and future research directions. Mol. Cell Endocrinol. 364, 1–27 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Robertson, R. P., Harmon, J., Tran, P. O., Tanaka, Y. & Takahashi, H. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52, 581–587 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, Y. et al. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc. Natl Acad. Sci. USA 91, 10878–10882 (1994).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maedler, K., Oberholzer, J., Bucher, P., Spinas, G. A. & Donath, M. Y. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes 52, 726–733 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brunham, L. R., Kruit, J. K., Verchere, C. B. & Hayden, M. R. Cholesterol in islet dysfunction and type 2 diabetes. J. Clin. Invest. 118, 403–408 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brunham, L. R. et al. β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat. Med. 13, 340–347 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sturek, J. M. et al. An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells. J. Clin. Invest. 120, 2575 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maedler, K. et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, E.-K. et al. Activation of peroxisome proliferator-activated receptor-gamma protects pancreatic beta-cells from cytokine-induced cytotoxicity via NF kappaB pathway. Int J. Biochem Cell Biol. 39, 1260–1275 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kaneto, H. et al. Apoptotic cell death triggered by nitric oxide in pancreatic beta-cells. Diabetes 44, 733–738 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, X., Xiao, G.-Y., Guo, T., Song, Y.-J. & Li, Q.-M. Potential therapeutic role of pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications. Front. Endocrinol. (Lausanne) 13, 986565 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Weng, Q. et al. STAT3 dictates β-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia. Cell Death Differ. 27, 130–145 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, B. et al. Macrophages and neutrophils are necessary for ER stress-induced β cell loss. Cell Rep. 40, 111255 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, B. et al. RIPK3-mediated inflammation is a conserved β cell response to ER stress. Sci. Adv. 6, eabd7272 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chung, S. S. et al. Mechanism for antioxidative effects of thiazolidinediones in pancreatic β-cells. Am. J. Physiol. Endocrinol. Metab. 301, E912–E921 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tang, C. et al. Glucose-induced beta cell dysfunction in vivo in rats: link between oxidative stress and endoplasmic reticulum stress. Diabetologia 55, 1366–1379 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421–438 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sharma, R. B., Landa-Galván, H. V. & Alonso, L. C. Living dangerously: protective and harmful ER stress responses in pancreatic β-cells. Diabetes 70, 2431–2443 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Y. et al. THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass. Nat. Commun. 14, 1020 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ardestani, A. et al. MST1 is a novel regulator of apoptosis in pancreatic beta-cells. Nat. Med. 20, 385–397 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, T. et al. Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells. JCI Insight 1, e86326 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Filippatos, T. D., Alexakis, K., Mavrikaki, V. & Mikhailidis, D. P. Nonalcoholic fatty pancreas disease: role in metabolic syndrome, ‘prediabetes,’ diabetes and atherosclerosis. Dig. Dis. Sci. 67, 26–41 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tt, C. et al. Fatty pancreas is independently associated with subsequent diabetes mellitus development: a 10-year prospective cohort study. Clin. Gastroenterol. Hepatol. 20, 2013–2022 (2022).


    Google Scholar
     

  • Pinnick, K. E. et al. Pancreatic ectopic fat is characterized by adipocyte infiltration and altered lipid composition. Obes. (Silver Spring) 16, 522–530 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Gerst, F. et al. What role do fat cells play in pancreatic tissue? Mol. Metab. 25, 1–10 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, T.-Y. & Wang, C.-Y. Impact of non-alcoholic fatty pancreas disease on glucose metabolism. J. Diabetes Investig. 8, 735–747 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Haataja, L., Gurlo, T., Huang, C. J. & Butler, P. C. Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr. Rev. 29, 303–316 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, C. et al. High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes 56, 2016–2027 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Montane, J., Klimek-Abercrombie, A., Potter, K. J., Westwell-Roper, C. & Bruce Verchere, C. Metabolic stress, IAPP and islet amyloid. Diabetes Obes. Metab. 14, 68–77 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Montemurro, C. et al. IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function. Nat. Commun. 10, 2679 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gunton, J. E. Hypoxia-inducible factors and diabetes. J. Clin. Invest. 130, 5063–5073 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gonzalez, F. J., Xie, C. & Jiang, C. The role of hypoxia-inducible factors in metabolic diseases. Nat. Rev. Endocrinol. 15, 21–32 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, T. et al. Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes. Diabetologia 60, 668–678 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ardestani, A., Lupse, B., Kido, Y., Leibowitz, G. & Maedler, K. mTORC1 signaling: a double-edged sword in diabetic β cells. Cell Metab. 27, 314–331 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, J. et al. Role of Wnt signaling pathways in type 2 diabetes mellitus. Mol. Cell Biochem. 476, 2219–2232 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bowen, A., Kos, K., Whatmore, J., Richardson, S. & Welters, H. J. Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1. Biochem. Biophys. Res. Commun. 479, 793–799 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Florez, J. C. et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N. Engl. J. Med. 355, 241–250 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bartolome, A., Zhu, C., Sussel, L. & Pajvani, U. B. Notch signaling dynamically regulates adult β cell proliferation and maturity. J. Clin. Invest. 129, 268–280 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Bartolomé, A. et al. Notch-mediated Ephrin signaling disrupts islet architecture and β cell function. JCI Insight 7, e157694 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, M. et al. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct. Target Ther. 7, 216 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bergman, M. & Tuomilehto, J. International Diabetes Federation Position Statement on the 1-hour post-load plasma glucose for the diagnosis of intermediate hyperglycaemia and type 2 diabetes. Diabetes Res. Clin. Pr. 210, 111636 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Liu, Y. et al. Evidence from a systematic review and meta-analysis: classical impaired glucose tolerance should be divided into subgroups of isolated impaired glucose tolerance and impaired glucose tolerance combined with impaired fasting glucose, according to the risk of progression to diabetes. Front. Endocrinol. (Lausanne) 13, 835460 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Twig, G. et al. Adolescent obesity and early-onset type 2 diabetes. Diabetes Care 43, 1487–1495 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, X. et al. A1C level and future risk of diabetes: a systematic review. Diabetes Care 33, 1665–1673 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tabák, A. G. et al. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 373, 2215–2221 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Garvey, W. T. et al. Association of baseline factors with glycemic outcomes in GRADE: a comparative effectiveness randomized clinical trial. Diabetes Care 47, 562–570 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ogurtsova, K. et al. IDF diabetes Atlas: Global estimates of undiagnosed diabetes in adults for 2021. Diabetes Res. Clin. Pr. 183, 109118 (2022).

    Article 

    Google Scholar
     

  • WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363, 157–163 (2004).

    Article 

    Google Scholar
     

  • Prillaman, M. Why BMI is flawed—and how to redefine obesity. Nature 622, 232–233 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jayedi, A., Soltani, S., Zargar, M. S., Khan, T. A. & Shab-Bidar, S. Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies. BMJ 370, m3324 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • National Institute for Health and Care Excellence (NICE). Obesity: Identification, Assessment and Management (NICE, 2023).

  • Charchar, F. J. et al. Lifestyle management of hypertension: International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension. J. Hypertens. 42, 23–49 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu, S. et al. Evaluation of the value of diabetes risk scores in screening for undiagnosed diabetes and prediabetes: a community-based study in southwestern China. Postgrad. Med. 132, 737–745 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ortiz-Martínez, M. et al. Recent developments in biomarkers for diagnosis and screening of type 2 diabetes mellitus. Curr. Diabetes Rep. 22, 95–115 (2022).

    Article 

    Google Scholar
     

  • Laakso, M. Biomarkers for type 2 diabetes. Mol. Metab. 27S, S139–S146 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Sacks, D. B. et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin. Chem. 69, 808–868 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Caixeta, D. C. et al. Salivary molecular spectroscopy: a sustainable, rapid and non-invasive monitoring tool for diabetes mellitus during insulin treatment. PLoS ONE 15, e0223461 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ascaso, F. J. & Huerva, V. Noninvasive continuous monitoring of tear glucose using glucose-sensing contact lenses. Optom. Vis. Sci. 93, 426–434 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Lee, H. et al. Wearable/disposable sweat-based glucose monitoring device with multistage transdermal drug delivery module. Sci. Adv. 3, e1601314 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shilo, S. et al. Continuous glucose monitoring and intrapersonal variability in fasting glucose. Nat. Med. 30, 1424–1431 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Durnwald, C. et al. Continuous Glucose Monitoring Profiles in Pregnancies With and Without Gestational Diabetes Mellitus. Diabetes Care https://doi.org/10.2337/dc23-2149

  • Ferrannini, E. et al. beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J. Clin. Endocrinol. Metab. 90, 493–500 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ziegler, D. et al. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care 31, 464–469 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet. Med. 24, 137–144 (2007).

    Article 
    PubMed Central 

    Google Scholar
     

  • Pan, X. R. et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 20, 537–544 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tuomilehto, J. et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344, 1343–1350 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ramachandran, A. et al. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 49, 289–297 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hamman, R. F. et al. Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes Care 29, 2102–2107 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Gong, Q. et al. Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study. Lancet Diabetes Endocrinol. 7, 452–461 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, G. et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2, 474–480 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Lindström, J. et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 368, 1673–1679 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 3, 866–875 (2015).

    Article 
    PubMed Central 

    Google Scholar
     

  • Lee, C. G. et al. Effect of metformin and lifestyle interventions on mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Diabetes Care 44, 2775–2782 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chiasson, J.-L. et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359, 2072–2077 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368, 1096–1105 (2006).

    Article 

    Google Scholar
     

  • DeFronzo, R. A. et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med. 364, 1104–1115 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kernan, W. N. et al. Pioglitazone after ischemic stroke or transient ischemic attack. N. Engl. J. Med. 374, 1321–1331 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yaghi, S. et al. Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke: a planned secondary analysis of the IRIS Trial (Insulin Resistance Intervention After Stroke). Circulation 137, 455–463 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • le Roux, C. W. et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 389, 1399–1409 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lincoff, A. M. et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N. Engl. J. Med. 389, 2221–2232 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rossing, P. et al. Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials. Lancet Diabetes Endocrinol. 10, 24–34 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • James, S. et al. Dapagliflozin in myocardial infarction without diabetes or heart failure. NEJM Evid. 3, EVIDoa2300286 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Speight, J. et al. Bringing an end to diabetes stigma and discrimination: an international consensus statement on evidence and recommendations. Lancet Diabetes Endocrinol. 12, 61–82 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, F. et al. Expert consensus on personalized initiation of glucose-lowering therapy in adults with newly diagnosed type 2 diabetes without clinical cardiovascular disease or chronic kidney disease. J. Evid. Based Med. 15, 168–179 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Marx, N. et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur. Heart J. 39, 4043–4140 (2023).

    Article 

    Google Scholar
     

  • ADVANCE Collaborative Group. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

    Article 

    Google Scholar
     

  • Lachin, J. M. & Nathan, D. M. Understanding metabolic memory: the prolonged influence of glycemia during the Diabetes Control and Complications Trial (DCCT) on future risks of complications during the study of the Epidemiology of Diabetes Interventions and Complications (EDIC). Diabetes Care 44, 2216–2224 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Skyler, J. S. et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials. Circulation 119, 351–357 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Ismail-Beigi, F. et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 376, 419–430 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goldenberg, J. Z. et al. Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data. BMJ 372, m4743 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Riddle, M. C. et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care 44, 2438–2444 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bonekamp, N. E. et al. Leisure-time and occupational physical activity and health outcomes in cardiovascular disease. Heart 109, 686–694 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Uusitupa, M. et al. Prevention of type 2 diabetes by lifestyle changes: a systematic review and meta-analysis. Nutrients 11, 2611 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kirkpatrick, C. F., Liday, C. & Maki, K. C. The effects of carbohydrate-restricted dietary patterns and physical activity on body weight and glycemic control. Curr. Atheroscler. Rep. 22, 20 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhu, X. et al. The effect of physical activity on glycemic variability in patients with diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Endocrinol. (Lausanne) 12, 767152 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Liu, M. et al. Association of accelerometer-measured physical activity and its change with progression to chronic kidney disease in adults with type 2 diabetes and overweight/obesity. Br. J. Sports Med. 58, 313–319 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Sabag, A. et al. Timing of moderate to vigorous physical activity, mortality, cardiovascular disease, and microvascular disease in adults with obesity. Diabetes Care 47, 890–897 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Clavero-Jimeno, A. et al. Impact of lifestyle moderate-to-vigorous physical activity timing on glycemic control in sedentary adults with overweight/obesity and metabolic impairments. Obesity (Silver Spring) 32,1465–1473.

  • Hamaya, R. et al. Time- vs step-based physical activity metrics for health. JAMA Intern. Med. 184, 718–725 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Pavlou, V. et al. Effect of time-restricted eating on weight loss in adults with type 2 diabetes: a randomized clinical trial. JAMA Netw. Open 6, e2339337 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Delgado-Lista, J. et al. Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial. Lancet 399, 1876–1885 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cienfuegos, S. et al. Effects of 4- and 6-h Time-Restricted Feeding on Weight and Cardiometabolic Health: A Randomized Controlled Trial in Adults with Obesity. Cell Metab. 32, 366–378.e3 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horne, B. D., Grajower, M. M. & Anderson, J. L. Limited evidence for the health effects and safety of intermittent fasting among patients with type 2 diabetes. JAMA 324, 341–342 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Wilkinson, M. J. et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab. 31, 92–104.e5 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Carter, S., Clifton, P. M. & Keogh, J. B. Effect of intermittent compared with continuous energy restricted diet on glycemic control in patients with type 2 diabetes: a randomized noninferiority trial. JAMA Netw. Open 1, e180756 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guo, L. et al. A 5:2 intermittent fasting meal replacement diet and glycemic control for adults with diabetes: the early randomized clinical trial. JAMA Netw. Open 7, e2416786 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, L. et al. High-fiber diet ameliorates gut microbiota, serum metabolism and emotional mood in type 2 diabetes patients. Front. Cell Infect. Microbiol. 13, 1069954 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Y. et al. Effectiveness of mobile health interventions on diabetes and obesity treatment and management: systematic review of systematic reviews. JMIR Mhealth Uhealth 8, e15400 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • DeMarsilis, A. et al. Pharmacotherapy of type 2 diabetes: an update and future directions. Metabolism 137, 155332 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wing, R. R. et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 34, 1481–1486 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Elmaleh-Sachs, A. et al. Obesity management in adults: a review. JAMA 330, 2000–2015 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lingvay, I., Sumithran, P., Cohen, R. V. & le Roux, C. W. Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet 399, 394–405 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Davies, M. J. et al. Management of hyperglycemia in type 2 diabetes, 2022. a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 45, 2753–2786 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Davies, M. et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 397, 971–984 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Davies, M. J. et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA 314, 687–699 (2015).

    Article 
    CAS 
    PubMed 

    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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Garvey, W. T. et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 402, 613–626 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Drucker, D. J. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 27, 740–756 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, K. S. et al. GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans. Science https://doi.org/10.1126/science.adj2537 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Drucker, D. J. GLP-1 physiology informs the pharmacotherapy of obesity. Mol. Metab. 57, 101351 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Silveira, S. Q. et al. Relationship between perioperative semaglutide use and residual gastric content: a retrospective analysis of patients undergoing elective upper endoscopy. J. Clin. Anesth. 87, 111091 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Garza, K. et al. Glucagon-like peptide-1 receptor agonists increase solid gastric residue rates on upper endoscopy especially in patients with complicated diabetes: a case-control study. Am. J. Gastroenterol. 119, 1081–1088 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Welk, B. et al. No association between semaglutide and postoperative pneumonia in people with diabetes undergoing elective surgery. Diabetes Obes. Metab. https://doi.org/10.1111/dom.15711 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Hiramoto, B. et al. Quantified metrics of gastric emptying delay by glucagon-like peptide-1 agonists: a systematic review and meta-analysis with insights for periprocedural management. Am. J. Gastroenterol. 119, 1126–1140 (2024).

    CAS 
    PubMed 

    Google Scholar
     

  • Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Rinella, M. E. et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 29, 101133 (2024).


    Google Scholar
     

  • Lee, B.-W. et al. Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: a position statement of the Fatty Liver Research Group of the Korean Diabetes Association. Diabetes Metab. J. 44, 382–401 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Younossi, Z. M. et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J. Hepatol. 71, 793–801 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Ballestri, S. et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J. Gastroenterol. Hepatol. 31, 936–944 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut 70, 962–969 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sinn, D. H. et al. Regression of nonalcoholic fatty liver disease is associated with reduced risk of incident diabetes: a longitudinal cohort study. PLoS One 18, e0288820 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297–2307 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Aithal, G. P. et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135, 1176–1184 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Ratziu, V. et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135, 100–110 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cusi, K. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern Med. 165, 305–315 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Bril, F. et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 42, 1481–1488 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Musso, G., Cassader, M., Paschetta, E. & Gambino, R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 177, 633–640 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ekstedt, M. et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61, 1547–1554 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397.e10 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Xie, Q. et al. Histological analysis of hypoglycemic agents on liver fibrosis in patients with non-alcoholic fatty liver disease: a systematic review. Chin. Med. J. (Engl.) 136, 2014–2016 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Della Pepa, G. et al. Pioglitazone even at low dosage improves NAFLD in type 2 diabetes: clinical and pathophysiological insights from a subgroup of the TOSCA.IT randomised trial. Diabetes Res. Clin. Pr. 178, 108984 (2021).

    Article 

    Google Scholar
     

  • Lutchman, G. et al. Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic steatohepatitis: relationship to histological improvement. Clin. Gastroenterol. Hepatol. 4, 1048–1052 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alatas, F. S., Matsuura, T., Pudjiadi, A. H., Wijaya, S. & Taguchi, T. Peroxisome proliferator-activated receptor gamma agonist attenuates liver fibrosis by several fibrogenic pathways in an animal model of cholestatic fibrosis. Pediatr. Gastroenterol. Hepatol. Nutr. 23, 346–355 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, S. et al. PPARγ regulates macrophage polarization by inhibiting the JAK/STAT pathway and attenuates myocardial ischemia/reperfusion injury in vivo. Cell Biochem. Biophys. 81, 349–358 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, X., Zhang, P., Song, X., Cui, H. & Shen, W. PPARγ mediates protective effect against hepatic ischemia/reperfusion injury via NF-κB pathway. J. Invest. Surg. 35, 1648–1659 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Newsome, P. N. et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Loomba, R. et al. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol. Hepatol. 8, 511–522 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Loomba, R. et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2401943 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Sanyal, A. J. et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2401755 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Tacke, F., Puengel, T., Loomba, R. & Friedman, S. L. An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH. J. Hepatol. 79, 552–566 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nesti, L., Tricò, D., Mengozzi, A. & Natali, A. Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug. Cardiovasc. Diabetol. 20, 109 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Smith, S. R. et al. Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial. Metabolism 54, 24–32 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Miyazaki, Y. et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J. Clin. Endocrinol. Metab. 87, 2784–2791 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cusi, K. et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr. Pr. 28, 528–562 (2022).

    Article 

    Google Scholar
     

  • Duell, P. B. et al. Nonalcoholic fatty liver disease and cardiovascular risk: a scientific statement from the American Heart Association. Arterioscler Thromb. Vasc. Biol. 42, e168–e185 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chinese Society of Endocrinology & Chinese Diabetes Society. Management of Chinese adults with type 2 diabetes and non-alcoholic fatty liver disease: an expert consensus (in Chinese). Chin. J. Endocrinol. Metab. 37, 589–598 (2021).

  • Husain, M. et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 381, 841–851 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gerstein, H. C. et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 394, 121–130 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hernandez, A. F. et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 392, 1519–1529 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Holman, R. R. et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 377, 1228–1239 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pfeffer, M. A. et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247–2257 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kristensen, S. L. et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 7, 776–785 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366, 1279–1289 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vaccaro, O. et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 5, 887–897 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Ahmadi, A., Panahi, Y., Johnston, T. P. & Sahebkar, A. Antidiabetic drugs and oxidized low-density lipoprotein: a review of anti-atherosclerotic mechanisms. Pharm. Res. 172, 105819 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Neal, B., Perkovic, V. & Matthews, D. R. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 2099 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Wiviott, S. D. et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 380, 347–357 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cannon, C. P. et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N. Engl. J. Med. 383, 1425–1435 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N. Engl. J. Med. 384, 129–139 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kenny, H. C. & Abel, E. D. Heart failure in type 2 diabetes mellitus: impact of glucose lowering agents, heart failure therapies and novel therapeutic strategies. Circ. Res. 124, 121–141 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Solomon, S. D. et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N. Engl. J. Med. 387, 1089–1098 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995–2008 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Anker, S. D. et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl. J. Med. 385, 1451–1461 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N. Engl. J. Med. 384, 117–128 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427–2443 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373, 2125–2135 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Erdmann, E. et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care 30, 2773–2778 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lago, R. M., Singh, P. P. & Nesto, R. W. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370, 1129–1136 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lincoff, A. M., Wolski, K., Nicholls, S. J. & Nissen, S. E. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298, 1180–1188 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van der Meer, R. W. et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 119, 2069–2077 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Dorkhan, M., Dencker, M., Stagmo, M. & Groop, L. Effect of pioglitazone versus insulin glargine on cardiac size, function, and measures of fluid retention in patients with type 2 diabetes. Cardiovasc Diabetol. 8, 15 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ferrannini, G. et al. Similar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin. Eur. Heart J. 42, 2565–2573 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Masson, W., Lavalle-Cobo, A., Lobo, M., Masson, G. & Molinero, G. Novel antidiabetic drugs and risk of cardiovascular events in patients without baseline metformin use: a meta-analysis. Eur. J. Prev. Cardiol. 28, 69–75 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Riley, D. R. et al. All-cause mortality and cardiovascular outcomes with sodium-glucose Co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and with combination therapy in people with type 2 diabetes. Diabetes Obes. Metab. 25, 2897–2909 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ussher, J. R. & Drucker, D. J. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat. Rev. Cardiol. 20, 463–474 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, R., Xie, Q., Lu, X., Fan, R. & Tong, N. Research advances in the anti-inflammatory effects of SGLT inhibitors in type 2 diabetes mellitus. Diabetol. Metab. Syndr. 16, 99 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wood, N. et al. Sodium–glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction. Eur. J. Heart Fail 26, 925–935 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kasperova, B. J. et al. Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure. Cardiovasc. Diabetol. 23, 223 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, C. et al. Dapagliflozin ameliorated retinal vascular permeability in diabetic retinopathy rats by suppressing inflammatory factors. J. Diabetes Complications 38, 108631 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Billing, A. M. et al. Metabolic communication by SGLT2 inhibition. Circulation 149, 860–884 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jiang, Y. et al. Gut microbiota-tryptophan metabolism-GLP-1 axis participates in β-cell regeneration induced by dapagliflozin. Diabetes 73, 926–940 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anders, H.-J., Huber, T. B., Isermann, B. & Schiffer, M. CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat. Rev. Nephrol. 14, 361–377 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shao, M. et al. Canagliflozin regulates metabolic reprogramming in diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns. Diabetologia 67, 738–754 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Qiuxiao-Zhu et al. Protective effects and mechanisms of dapagliflozin on renal ischemia/reperfusion injury. Transpl. Immunol. 84, 102010 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lu, Q. et al. Empagliflozin attenuates the renal tubular ferroptosis in diabetic kidney disease through AMPK/NRF2 pathway. Free Radic. Biol. Med. 195, 89–102 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380, 2295–2306 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heerspink, H. J. L. et al. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383, 1436–1446 (2020).

    Article 
    CAS 
    PubMed 

    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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mann, J. F. E. et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat. Med. https://doi.org/10.1038/s41591-024-03133-0 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Muskiet, M. H. A. et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat. Rev. Nephrol. 13, 605–628 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, A. K. et al. Risk factors for severe hypoglycemia in black and white adults with diabetes: The Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care 40, 1661–1667 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 102, S1–S127 (2022).

    Article 

    Google Scholar
     

  • Roddick, A. J. et al. UK Kidney Association Clinical Practice Guideline: sodium-glucose co-transporter-2 (SGLT-2) inhibition in adults with kidney disease 2023 UPDATE. BMC Nephrol. 24, 310 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cersosimo, E., Johnson, E. L., Chovanes, C. & Skolnik, N. Initiating therapy in patients newly diagnosed with type 2 diabetes: combination therapy vs a stepwise approach. Diabetes Obes. Metab. 20, 497–507 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Lim, S. et al. Efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes: A double-blind randomized controlled trial (INICOM study). Diabetes Obes. Metab. 19, 87–97 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pratley, R. E., Fleck, P. & Wilson, C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naïve patients with type 2 diabetes: a randomized, double-blind, 6-month study. Diabetes Obes. Metab. 16, 613–621 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jabbour, S. A. et al. Safety and efficacy of exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy: 52-week results of the DURATION-8 randomized controlled trial. Diabetes Care 41, 2136–2146 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Matthews, D. R. et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 394, 1519–1529 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tuttle, K. R. et al. Molecular mechanisms and therapeutic targets for diabetic kidney disease. Kidney Int. 102, 248–260 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Johnson, R. J. et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a Scientific Workshop Organized by the National Kidney Foundation. Am. J. Kidney Dis. 71, 851–865 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Afkarian, M. et al. Kidney disease and increased mortality risk in type 2 diabetes. J. Am. Soc. Nephrol. 24, 302–308 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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).

    Article 
    CAS 
    PubMed 

    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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ferro, C. J. et al. Lipid management in patients with chronic kidney disease. Nat. Rev. Nephrol. 14, 727–749 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Afshinnia, F. et al. Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes. Ann. Clin. Transl. Neurol. 9, 1392–1404 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pop-Busui, R. et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 40, 136–154 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, Y. et al. An update on potential biomarkers for diagnosing diabetic foot ulcer at early stage. Biomed. Pharmacother. 133, 110991 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Goodall, R. J. et al. A systematic review of the impact of foot care education on self efficacy and self care in patients with diabetes. Eur. J. Vasc. Endovasc. Surg. 60, 282–292 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Antonetti, D. A., Silva, P. S. & Stitt, A. W. Current understanding of the molecular and cellular pathology of diabetic retinopathy. Nat. Rev. Endocrinol. 17, 195–206 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • World Health Organization. Classification of Diabetes Mellitus (World Health Organization, 2019).

  • Related posts

    Physical activity and type 2 diabetes: optimal exercise and planning

    What causes type 2 diabetes? Tips to reduce your risk

    Groundbreaking T1D Illinois Gala Fundraiser to Benefit Type 1 Diabetes Research Held at McCormick Place in Chicago