Type
2 diabetes mellitus (T2D) is reaching epidemic proportions worldwide, yet the
genetic underpinnings of the disease continue to be remarkably elusive. The
importance and impact of environmental factors such as diet and lifestyle on
the susceptibility of the disease only add additional challenges to the
identification of genetic causes. While it is known that several pathways
important for the maintenance of glucose homeostasis are altered in T2D, less
is known about the molecular mech
anisms 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. Alterations in insulin
signaling and subsequent effects on 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 the autophosphorylation and substrate kinase activities of the
receptor. 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. [To access the
interactive diagram page for the normal insulin signaling pathway, click here].
In T2D, insulin secretion pathway is impaired; a reduction in insulin secretion
will negatively impact on insulin signaling and the events downstream of it. As
a note, mutations in Akt2 member of Akt family have been associated with
insulin resistance in a diabetic family. Akt2 is a component of the PI3K-Akt
pathway - one of the two pathways triggered by insulin; Akt2 positively
contributes to the insulin responsive glucose transport pathway by promoting the
translocation of the Glut4 transporter to the plasma membrane. 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, GVewer and download, click here[Information
on candidate genes and miRNAs can be accessed from their respective entries in
the diagram for the type 2 diabetes pathway] ...(less)
