Experimental studies have suggested possible protective effects of dimethylglycine (DMG) on glucose metabolism. DMG is degraded to glycine through a DMG-dehydrogenase (DMGDH)-catalyzed reaction and this is the only known pathway for the breakdown of DMG in mammals. In this study we aimed to identify the strongest genetic determinant of circulating DMG concentration and to investigate its associations with metabolic traits and incident diabetes. In the cohort with full metabolomics data (n=709), low plasma levels of DMG were significantly associated with higher blood glucose levels (p=3.9E-4). In the genome-wide association study (GWAS) of the discovery cohort (n=5,205) the strongest genetic signal of plasma DMG was conferred by rs2431332 at the DMGDH-locus where the major allele was associated with lower DMG levels (p=2.5E-15). The same genetic variant (major allele of rs2431332), was also significantly associated with higher plasma insulin (p=0.019), increased insulin resistance (HOMA-IR) (p=0.019), as well as increased risk of incident diabetes (p=0.001) in the pooled analysis of the discovery cohort together with the two replication cohorts ((n=20,698) and (N=7,995). These data are consistent with a possible causal role of DMG deficiency in diabetes development and encourages for future studies examining if inhibition of DMG-dehydrogenase, or alternatively supplementation of DMG, might prove useful for the treatment/prevention of diabetes.
|Publication status||Published - 2015|