Personalized Therapy for Type 2 Diabetes: A Novel Pharmacogenetic Approach

Personalized medicine for diabetes promises to improve both cost and efficacy of care. This approach depends both on understanding the pathogenesis of the disorder and deploying the most effective and appropriate treatments. PPARg is both a master regulator of adipocyte differentiation and also a critical mediator of adipose tissue insulin sensitivity. Obesity induced phosphorylation of PPARg via cyclin dependent kinase 5 (Cdk5) promotes insulin resistance. Both this phosphorylation event and insulin resistance can be reversed by administration of thiazolidinediones (TZDs). Cdkal1 is one of the most reproducibly identified human diabetes susceptibility genes, yet its biochemical function is unknown. It is homologous to a protein known to bind p35, the Cdk5 regulatory protein. We have found that disease-associated SNPs in Cdkal1 alter expression of Cdkal1 in human adipose tissue. We have also confirmed that Cdkal1 binds p35 and promotes protein stability and Cdk5 kinase activity. We hypothesize that Cdkal1 will promote PPARg phosphorylation and insulin resistance. Correspondingly, because the TZDs are FDA approved anti-diabetic therapeutics which effectively reverses PPARg phosphorylation, we believe that individuals harboring the disease associated alleles of Cdkal1 may specifically benefit from treatment with this class of drugs.