that link these alterations to the onset and progress of the condition and the few mutations found are either rare or their importance in the condition controversial. The pathways altered and the known mutations are briefly presented. Mutations have been reported for the pore-forming Kcnj11 and the regulatory Abcc8 subunits of the ATP-sensitive potassium channel (KATP) whose function underlies the first phase of insulin secretion. In T2D patients, the first phase is almost completely lost while the second is severely diminished. Alterations in insulin signaling and the pathways downstream of it have been associated with insulin resistance, a hallmark of T2D. Mutations in the insulin gene alter the binding efficiency of the hormone to its receptor while mutations in the insulin receptor gene fall into two categories ¿ those that diminish the affinity of the receptor for insulin and those that reduce its tyrosine kinase activity. The activity of the receptor is heavily regulated: kinases, phosphatases, and various adapters acting primarily as inhibitors control its autophosphorylation and substrate kinase activities. Activated protein kinase C ¿ one of the inhibitors of insulin receptor ¿ is thought to play a role in insulin resistance and is target for drug development. PI3K-Akt signaling ¿ one of the two pathways triggered by insulin, via Akt2 member contributes to the insulin responsive translocation of Glut4 glucose transporter to the plasma membrane. Mutations in Akt2 gene have been identified in a diabetic human family with severe insulin resistance. Knock-down and gene silencing experiments confirm that loss of Akt2 diminishes insulin mediated transporter activity and thus the ability of insulin to lower blood glucose levels. It is possible that accumulated effects, stemming from alterations within several pathways, their regulators, upstream and downstream events including those underlying beta-cell functioning and gene expression, contribute to the onset and development of the disease and each could be heightened by environmental factors. In addition to the handful of mutations in pathways altered in T2D, linkage analyses and GWAS studies have identified a number of candidate genes as potential susceptibility loci. Interestingly, some of the SNPs are found in non-coding regions. miRNA have also been identified with a potential role in the regulation of insulin secretion, beta-cell development, insulin gene expression and action, as well as in diabetic complications such as cardiac and myocardial dysfunction and diabetic nephropathy. To see the ontology report for annotations, GViewer and download, click here
To see the Disease Ontology report for genes that in some fashion have been associated with T2D or suspected to confer susceptibility, click here
To link to the Diabetes Disease Portal click here
[click to see associated KEGG map ¿ map04930 and related entry at Reactome]...(less)