TY - JOUR
T1 - Metabolic Trajectories Before Diabetes Diagnosis Across Subgroups
T2 - A Pooled Analysis of Prospective European Cohort Studies
AU - Hakaste, Liisa
AU - Andersen, Mette K.
AU - Ängquist, Lars
AU - Maalmi, Haifa
AU - Vangipurapu, Jagadish
AU - Cakmak, Türküler
AU - Möllsten, Anna
AU - Tavelin, Björn
AU - Lehtovirta, Mikko
AU - Begum, Most Champa
AU - Prasad, Rashmi B.
AU - Peters, Annette
AU - Thorand, Barbara
AU - Linneberg, Allan
AU - Laakso, Markku
AU - Rolandsson, Olov
AU - Åsvold, Bjørn Olav
AU - Lyssenko, Valeriya
AU - Nilsson, Peter M.
AU - Herder, Christian
AU - Roden, Michael
AU - Hansen, Torben
AU - Ahlqvist, Emma
AU - Tuomi, Tiinamaija
N1 - Publisher Copyright:
© 2026 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/
PY - 2026/7
Y1 - 2026/7
N2 - Background: Adult-onset diabetes comprises subgroups differing in pathophysiology, clinical presentation, and risk of comorbidities. We investigated early phenotypic differences between individuals who later developed diabetes, stratified by subgroup at diabetes diagnosis. Methods: We conducted a pooled analysis of nine prospective European cohorts with 3309 individuals developing incident diabetes and 13,963 age- and sex-matched controls without diabetes. Cases were assigned to previously defined cluster-based subgroups: severe autoimmune (SAID), insulin-deficient (SIDD), or insulin-resistant diabetes (SIRD), and moderate obesity- (MOD) or age-related diabetes (MARD). Clinical and metabolic characteristics were retroactively assessed for three time periods (>12, 6–12, 1–6 years) before diagnosis. Findings: Despite similarly high body mass index (BMI) in MOD and SIRD at diagnosis, MOD differed from controls already >12 years before diagnosis (31% higher than controls), while BMI increased progressively in SIRD (from 14% to 25% higher than controls). Compared to controls in period 1–6 years, age-, sex-, and BMI-adjusted insulin-glucose ratio was higher in SIRD, MOD and MARD at fasting (88%, 45% and 14%, respectively) and 120 min (110%, 70%, 26%) during an oral glucose tolerance test (p < 0.0001 for all), and the first-phase insulin-glucose ratio was higher in SIRD (23% [6; 43] p = 0.0072) but lower in SIDD (−30% [−37; −22], p < 0.0001) and MARD (−29% [−34; −24], p < 0.0001). The autoimmune subgroup SAID also exhibited features of metabolic syndrome. Despite differences in HOMA2-B and HbA1c at diagnosis, insulin and glucose levels did not differ significantly between the SIDD and MARD subgroups 1–6 years earlier suggesting a rapid deterioration in glycemic control in SIDD around diagnosis. Interpretation: Subgroups of diabetes display different trajectories of insulin resistance, insulin deficiency, and features of the metabolic syndrome before diagnosis. Funding: ERC, local governments, private foundations, University of Helsinki, and Research councils of Finland and Sweden.
AB - Background: Adult-onset diabetes comprises subgroups differing in pathophysiology, clinical presentation, and risk of comorbidities. We investigated early phenotypic differences between individuals who later developed diabetes, stratified by subgroup at diabetes diagnosis. Methods: We conducted a pooled analysis of nine prospective European cohorts with 3309 individuals developing incident diabetes and 13,963 age- and sex-matched controls without diabetes. Cases were assigned to previously defined cluster-based subgroups: severe autoimmune (SAID), insulin-deficient (SIDD), or insulin-resistant diabetes (SIRD), and moderate obesity- (MOD) or age-related diabetes (MARD). Clinical and metabolic characteristics were retroactively assessed for three time periods (>12, 6–12, 1–6 years) before diagnosis. Findings: Despite similarly high body mass index (BMI) in MOD and SIRD at diagnosis, MOD differed from controls already >12 years before diagnosis (31% higher than controls), while BMI increased progressively in SIRD (from 14% to 25% higher than controls). Compared to controls in period 1–6 years, age-, sex-, and BMI-adjusted insulin-glucose ratio was higher in SIRD, MOD and MARD at fasting (88%, 45% and 14%, respectively) and 120 min (110%, 70%, 26%) during an oral glucose tolerance test (p < 0.0001 for all), and the first-phase insulin-glucose ratio was higher in SIRD (23% [6; 43] p = 0.0072) but lower in SIDD (−30% [−37; −22], p < 0.0001) and MARD (−29% [−34; −24], p < 0.0001). The autoimmune subgroup SAID also exhibited features of metabolic syndrome. Despite differences in HOMA2-B and HbA1c at diagnosis, insulin and glucose levels did not differ significantly between the SIDD and MARD subgroups 1–6 years earlier suggesting a rapid deterioration in glycemic control in SIDD around diagnosis. Interpretation: Subgroups of diabetes display different trajectories of insulin resistance, insulin deficiency, and features of the metabolic syndrome before diagnosis. Funding: ERC, local governments, private foundations, University of Helsinki, and Research councils of Finland and Sweden.
KW - Classification
KW - Diabetes
KW - Diabetes stratification
KW - Diabetes subgroup
KW - Diabetes subtype
KW - Precision medicine
UR - https://www.scopus.com/pages/publications/105040614645
U2 - 10.1016/j.lanepe.2026.101715
DO - 10.1016/j.lanepe.2026.101715
M3 - Journal article
C2 - 42254809
AN - SCOPUS:105040614645
SN - 2666-7762
VL - 66
JO - The Lancet Regional Health - Europe
JF - The Lancet Regional Health - Europe
M1 - 101715
ER -