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Context: Recent studies have discovered a role of apolipoprotein M (apoM) in energy metabolism, and observational analyses in humans suggest an association with type 2 diabetes. The causal relationship remains however elusive., Objective: To investigate whether reduced plasma apoM concentrations are causally linked to increased risk of type 2 diabetes., Design: Prospective study design analyzed by Mendelian randomization., Setting and Participants: Two cohorts reflecting the Danish general population: the Copenhagen City Heart Study (CCHS, n = 8589) and the Copenhagen General Population Study (CGPS; n = 93 857). Observational analyses included a subset of participants from the CCHS with available plasma apoM (n = 725). Genetic analyses included the complete cohorts (n = 102 446). During a median follow-up of 16 years (CCHS) and 8 years (CGPS), 563 and 2132 participants developed type 2 diabetes., Main Outcome Measures: Plasma apoM concentration, genetic variants in APOM, and type 2 diabetes., Results: First, we identified an inverse correlation between plasma apoM and risk of type 2 diabetes in a subset of participants from the CCHS (hazard ratio between highest vs lowest quartile (reference) = 0.32; 95% confidence interval = 0.1-1.01; P for trend = .02). Second, genotyping of specific single nucleotide polymorphisms in APOM further revealed a 10.8% (P = 6.2 × 10-5) reduced plasma apoM concentration in participants with variant rs1266078. Third, a meta-analysis including data from 599 451 individuals showed no association between rs1266078 and risk of type 2 diabetes., Conclusions: The present study does not appear to support a causal association between plasma apoM and risk of type 2 diabetes., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)