title: Dimethylglycine Deficiency and the Development of Diabetes.
abstract: 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 HOMA insulin resistance (P = 0.019), and an 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 encourage future studies examining if inhibition of DMGDH, or alternatively, supplementation of DMG, might prove useful for the treatment/prevention of diabetes.
authors: Department of Heart Failure and Valvular Disease, Skåne University Hospital, Malmö, Sweden Department of Clinical Sciences, Lund University, Malmö, Sweden martin.magnusson@med.lu.se.
authors: Martin
authors: M
authors: Magnusson
authors: Division of Cardiovascular Medicine, Vanderbilt Heart and Vascular Institute, Nashville, TN.
authors: Thomas J
authors: TJ
authors: Wang
authors: The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.
authors: Clary
authors: C
authors: Clish
authors: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors: Gunnar
authors: G
authors: Engström
authors: Department of Clinical Sciences, Lund University, Malmö, Sweden Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors: Peter
authors: P
authors: Nilsson
authors: The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA Cardiology Division and Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: Robert E
authors: RE
authors: Gerszten
authors: Department of Clinical Sciences, Lund University, Malmö, Sweden Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors: Olle
authors: O
authors: Melander
mesh_terms: D000368:Aged; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D050893:Dimethylglycine Dehydrogenase / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D007328:Insulin; C025138:dimethylglycine; D050893:Dimethylglycine Dehydrogenase; D012521:Sarcosine