Editors' ChoiceDiabetes

Mastering Metabolic Pathways in Diabetes

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Science Translational Medicine  22 Jun 2011:
Vol. 3, Issue 88, pp. 88ec93
DOI: 10.1126/scitranslmed.3002781

Type 2 diabetes—the most common metabolic disorder in the developed world—is also the leading cause of coronary artery disease, kidney disease, and blindness in United States. Accordingly, new ways to identify, prevent, and treat this condition are desperately needed.

Recently, genome-wide association studies (GWASs) of tens of thousands of people have linked over 30 single-nucleotide polymorphisms (SNPs) that span numerous genes to the development of diabetes. Nevertheless, the downstream molecular and metabolic alterations caused by these susceptibility loci have remained elusive.

Now, Small et al. demonstrate that a single, previously identified SNP (rs4731702) near the Kruppel-like factor (KLF) 14 transcription factor gene may be a master regulator of genes commonly expressed in adipose tissue. First, they tested expression of 16,663 genes in subcutaneous adipose tissue obtained from 776 healthy female twins. Strikingly, they found a strong association of rs4731702 with expression levels of 10 genes at genome-wide statistical significance (P < 5 × 10–8). These data were then validated in a separate cohort showing that the maternal, not paternal, allele correlated with the expression of seven of the 10 genes discovered in the initial stage. Moreover, several of the genes were found to influence metabolic phenotypes, including body mass index, fasting insulin, HDL cholesterol, and serum triglyceride levels—all of which have been linked to type 2 diabetes. The investigators also noted that five of the 10 genes have been previously implicated in GWAS as susceptibility loci for many of these important metabolic phenotypes.

These data provide strong evidence that complex networks of gene-gene interactions are responsible for diabetes susceptibility and show the utility of GWAS data for leading to targeted approaches to diabetes prevention and treatment. Going forward, because it is a key regulator of multiple genes, KLF14 should be an effective therapeutic target for treating diabetes and its associated metabolic disturbances.

K. S. Small et al., Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat. Genet. 43, 561–564 (2011). [Abstract]

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