Joshua W. Knowles

Publication Details

• Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.

  Xie W, Wood AR, Lyssenko V, Weedon MN, Knowles JW, Alkayyali S, Assimes TL, Quertermous T, Abbasi F, Paananen J, Häring H, Hansen T, Pedersen O, Smith U, Laakso M, Dekker JM, Nolan JJ, Groop L, Ferrannini E, Adam KP, Gall WE, Frayling TM, Walker M. Diabetes. 2013

  Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. Using 1,004 non-diabetic individuals from the RISC study we performed a genome wide association study of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n=342). We assessed the association of these variants with diabetes-related traits in genome wide association study meta-analyses (GENESIS (including RISC, EUGENE2 and Stanford), MAGIC, DIAGRAM). We identified four associations with three metabolites; glycine (rs715 at CPS1), serine (rs478093 at PHGDH), betaine (rs499368 at SLC6A12; rs17823642 at BHMT); and one association signal with glycine/serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.

  PubMedID: 23378610