Metabolic Trajectories Before Diabetes Diagnosis Across Subgroups: A Pooled Analysis of Prospective European Cohort Studies

<h2>Summary</h2><h3>Background</h3> 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. <h3>Methods</h3> 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. <h3>Findings</h3> 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. <h3>Interpretation</h3> Subgroups of diabetes display different trajectories of insulin resistance, insulin deficiency, and features of the metabolic syndrome before diagnosis. <h3>Funding</h3> ERC, local governments, private foundations, University of Helsinki, and Research councils of Finland and Sweden.