Diabetes mellitus as a multisystem disease: understanding subtypes, complications, and the link with steatotic liver diseases in humans

American Diabetes Association Professional Practice Committee, ElSayed NA, McCoy RG, Aleppo G, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Ebekozien O, Echouffo-Tcheugui JB, Ekhlaspour L, Gaglia JL, Garg R, Khunti K, Lal R, Lingvay I, Matfin G, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Selvin E, Stanton RC, Bannuru RR (2025) 2. Diagnosis and classification of diabetes: standards of care in diabetes—2025. Diabetes Care 48:S27–S49. https://doi.org/10.2337/dc25-S002

Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S, Boyko EJ, Magliano DJ (2022) IDF diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 183:109119. https://doi.org/10.1016/j.diabres.2021.109119

Article  PubMed  Google Scholar 

Ahlqvist E, Storm P, Käräjämäki A, Martinell M, Dorkhan M, Carlsson A, Vikman P, Prasad RB, Aly DM, Almgren P, Wessman Y, Shaat N, Spégel P, Mulder H, Lindholm E, Melander O, Hansson O, Malmqvist U, Lernmark Å, Lahti K, Forsén T, Tuomi T, Rosengren AH, Groop L (2018) Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 6:361–369. https://doi.org/10.1016/S2213-8587(18)30051-2

Article  PubMed  Google Scholar 

Schön M, Prystupa K, Mori T, Zaharia OP, Bódis K, Bombrich M, Möser C, Yurchenko I, Kupriyanova Y, Strassburger K, Bobrov P, Nair ATN, Bönhof GJ, Strom A, Delgado GE, Kaya S, Guthoff R, Stefan N, Birkenfeld AL, Hauner H, Seissler J, Pfeiffer A, Blüher M, Bornstein S, Szendroedi J, Meyhöfer S, Trenkamp S, Burkart V, Schrauwen-Hinderling VB, Kleber ME, Niessner A, Herder C, Kuss O, März W, Pearson ER, Roden M, Wagner R, Al-Hasani H, Belgardt B-F, Bönhof GJ, Geerling G, Herder C, Icks A, Jandeleit-Dahm K, Kotzka J, Kuss O, Lammert E, Rathmann W, Roden M, Schlesinger S, Schrauwen-Hinderling V, Szendroedi J, Trenkamp S, Wagner R (2024) Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective german diabetes study and the LURIC cohort. Lancet Diabetes Endocrinol 12:119–131. https://doi.org/10.1016/S2213-8587(23)00329-7

Article  PubMed  Google Scholar 

Ahlqvist E, Prasad RB, Groop L (2020) Subtypes of type 2 diabetes determined from clinical parameters. Diabetes 69:2086–2093. https://doi.org/10.2337/dbi20-0001

Article  CAS  PubMed  Google Scholar 

Zaharia OP, Strassburger K, Strom A, Bönhof GJ, Karusheva Y, Antoniou S, Bódis K, Markgraf DF, Burkart V, Müssig K, Hwang J-H, Asplund O, Groop L, Ahlqvist E, Seissler J, Nawroth P, Kopf S, Schmid SM, Stumvoll M, Pfeiffer AFH, Kabisch S, Tselmin S, Häring HU, Ziegler D, Kuss O, Szendroedi J, Roden M, Belgardt B-F, Buyken A, Eckel J, Geerling G, Al-Hasani H, Herder C, Hwang J-H, Icks A, Kotzka J, Kuss O, Lammert E, Markgraf D, Müssig K, Rathmann W, Roden M, Szendroedi J, Ziegler D (2019) Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol 7:684–694. https://doi.org/10.1016/S2213-8587(19)30187-1

Article  PubMed  Google Scholar 

Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14:88–98. https://doi.org/10.1038/nrendo.2017.151

Article  PubMed  Google Scholar 

Xourafa G, Korbmacher M, Roden M (2023) Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat Rev Endocrinol. https://doi.org/10.1038/s41574-023-00898-1

Article  PubMed  Google Scholar 

Herder C, Roden M (2022) A novel diabetes typology: towards precision diabetology from pathogenesis to treatment. Diabetologia 65:1770–1781. https://doi.org/10.1007/s00125-021-05625-x

Article  PubMed  PubMed Central  Google Scholar 

Deutsch AJ, Ahlqvist E, Udler MS (2022) Phenotypic and genetic classification of diabetes. Diabetologia 65:1758–1769. https://doi.org/10.1007/s00125-022-05769-4

Article  PubMed  PubMed Central  Google Scholar 

Jiang Q, Hu Y, Ma J-H (2025) Various classification methods for diabetes mellitus in the management of blood glucose control. World J Diabetes 16:103316. https://doi.org/10.4239/wjd.v16.i5.103316

Article  PubMed  PubMed Central  Google Scholar 

Wesolowska-Andersen A, Brorsson CA, Bizzotto R, Mari A, Tura A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, Haid M, Prehn C, Artati A, Hong M-G, Musholt PB, Kurbasic A, De Masi F, Tsirigos K, Pedersen HK, Gudmundsdottir V, Thomas CE, Banasik K, Jennison C, Jones A, Kennedy G, Bell J, Thomas L, Frost G, Thomsen H, Allin K, Hansen TH, Vestergaard H, Hansen T, Rutters F, Elders P, t’Hart L, Bonnefond A, Canouil M, Brage S, Kokkola T, Heggie A, McEvoy D, Hattersley A, McDonald T, Teare H, Ridderstrale M, Walker M, Forgie I, Giordano GN, Froguel P, Pavo I, Ruetten H, Pedersen O, Dermitzakis E, Franks PW, Schwenk JM, Adamski J, Pearson E, McCarthy MI, Brunak S (2022) Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study. Cell Rep Med 3:100477. https://doi.org/10.1016/j.xcrm.2021.100477

Article  PubMed  PubMed Central  Google Scholar 

Kaya S, Khamees A, Geerling G, Strzalkowski P, Gontscharuk V, Szendroedi J, Müssig K, Ziegler D, Roden M, Guthoff R, for the GDS Cohort (2025) Macular perfusion alterations in people with recent-onset diabetes and novel diabetes subtypes. Diabetologia 68:1140–1156. https://doi.org/10.1007/s00125-025-06407-5

Xiong X, Yang Y, Wei L, Xiao Y, Li L, Sun L (2021) Identification of two novel subgroups in patients with diabetes mellitus and their association with clinical outcomes: a two-step cluster analysis. J Diabetes Investig 12:1346–1358. https://doi.org/10.1111/jdi.13494

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kahkoska AR, Geybels MS, Klein KR, Kreiner FF, Marx N, Nauck MA, Pratley RE, Wolthers BO, Buse JB (2020) Validation of distinct type 2 diabetes clusters and their association with diabetes complications in the DEVOTE, LEADER and SUSTAIN -6 cardiovascular outcomes trials. Diabetes Obes Metab 22:1537–1547. https://doi.org/10.1111/dom.14063

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zaharia OP, Strassburger K, Knebel B, Binsch C, Kupriyanova Y, Möser C, Bódis K, Prystupa K, Yurchenko I, Mendez Cardenas DM, Schön M, Herder C, Al-Hasani H, Schrauwen-Hinderling V, Jandeleit-Dahm K, Wagner R, Roden M (2024) Role of patatin-like phospholipase domain-containing 3 gene for decreasing kidney function in recently diagnosed diabetes mellitus. Diabetes Metab Syndr Clin Res Rev 18:103137. https://doi.org/10.1016/j.dsx.2024.103137

Article  CAS  Google Scholar 

Christensen DH, Nicolaisen SK, Ahlqvist E, Stidsen JV, Nielsen JS, Hojlund K, Olsen MH, García-Calzón S, Ling C, Rungby J, Brandslund I, Vestergaard P, Jessen N, Hansen T, Brøns C, Beck-Nielsen H, Sørensen HT, Thomsen RW, Vaag A (2022) Type 2 diabetes classification: a data-driven cluster study of the danish centre for strategic research in type 2 diabetes (DD2) cohort. BMJ Open Diabetes Res Care 10:e002731. https://doi.org/10.1136/bmjdrc-2021-002731

Article  PubMed  PubMed Central  Google Scholar 

Spoto B, Pisano A, Zoccali C (2016) Insulin resistance in chronic kidney disease: a systematic review. Am J Physiol-Ren Physiol 311:F1087–F1108. https://doi.org/10.1152/ajprenal.00340.2016

Article  CAS  Google Scholar 

Smeijer JD, Gomez MF, Rossing P, Heerspink HJL (2025) The effect of the endothelin receptor antagonist atrasentan on insulin resistance in phenotypic clusters of patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 27:511–518. https://doi.org/10.1111/dom.16041

Article  CAS  PubMed  Google Scholar 

Mazzieri A, Porcellati F, Timio F, Reboldi G (2024) Molecular targets of novel therapeutics for diabetic kidney disease: a new era of nephroprotection. Int J Mol Sci 25:3969. https://doi.org/10.3390/ijms25073969

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zaharia OP, Strassburger K, Knebel B, Kupriyanova Y, Karusheva Y, Wolkersdorfer M, Bódis K, Markgraf DF, Burkart V, Hwang J-H, Kotzka J, Al-Hasani H, Szendroedi J, Roden M, GDS Group, Roden M, Al-Hasani H, Burkart V, Buyken AE, Eckel J, Geerling G, Hwang JH, Herder C, Icks A, Jandeleit-Dahm K, Kahl S, Kotzka J, Kuss O, Lammert E, Trenkamp S, Rathmann W, Szendroedi J, Ziegler D (2020) Role of patatin-like phospholipase domain–containing 3 gene for hepatic lipid content and insulin resistance in diabetes. Diabetes Care 43:2161–2168. https://doi.org/10.2337/dc20-0329

Anjana RM, Baskar V, Nair ATN, Jebarani S, Siddiqui MK, Pradeepa R, Unnikrishnan R, Palmer C, Pearson E, Mohan V (2020) Novel subgroups of type 2 diabetes and their association with microvascular outcomes in an Asian Indian population: a data-driven cluster analysis: the INSPIRED study. BMJ Open Diabetes Res Care 8:e001506. https://doi.org/10.1136/bmjdrc-2020-001506

Article  PubMed  PubMed Central  Google Scholar 

Scott RA, Lu VI, Grove N, Patnaik JL, Manoharan N (2024) Rates of diabetic retinopathy among cluster analysis—identified type 2 diabetic mellitus subgroups. Graefes Arch Clin Exp Ophthalmol 262:411–419. https://doi.org/10.1007/s00417-023-06260-5

Article  CAS  PubMed  Google Scholar 

Tang H, Luo N, Zhang X, Huang J, Yang Q, Lin H, Zhang X (2024) Association between biological aging and diabetic retinopathy. Sci Rep 14:10123. https://doi.org/10.1038/s41598-024-60913-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fu S, Zhang L, Xu J, Liu X, Zhu X (2023) Association between abdominal obesity and diabetic retinopathy in patients with diabetes mellitus: a systematic review and meta-analysis. PLoS ONE 18:e0279734. https://doi.org/10.1371/journal.pone.0279734

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moura J, Rodrigues J, Gonçalves M, Amaral C, Lima M, Carvalho E (2017) Impaired T-cell differentiation in diabetic foot ulceration. Cell Mol Immunol 14:758–769. https://doi.org/10.1038/cmi.2015.116

Article  CAS  PubMed  Google Scholar 

Holt RIG, DeVries JH, Hess-Fischl A, Hirsch IB, Kirkman MS, Klupa T, Ludwig B, Nørgaard K, Pettus J, Renard E, Skyler JS, Snoek FJ, Weinstock RS, Peters AL (2021) The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 64:2609–2652.

Comments (0)

No login
gif