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

Summary

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.