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 to 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. Impaired insulin secretion, which
has long been associated with T2D, is briefly presented. Insulin secretion is biphasic: an initial 'triggering'
first phase, dependent on ATP-sensitive potassium channels, (KATP) is
followed by an 'amplifying' second phase, largely independent of KATP
channels. In T2D patients, the first phase is almost completely lost while the
second is severely diminished. Mutations in both the pore-forming and the
regulatory subunits of the KATP channel have been reported. Their association
with diabetes has been primarily with the neonatal type but rare polymorphisms
have been linked to adult T2D. The transcript of one of the two genes believed
to be involved in the calcium-dependent exocytosis of insulin- containing granules
(Syt9) is severely decreased in post-mortem islets of type 2 diabetic patients
(~75%); mutations in the gene have not been reported[To access the interactive diagram page for the normal insulin
secretion pathway, click here]. Impaired insulin secretion can negatively
affect insulin action: the insulin signaling and the events downstream of
it. Alterations in insulin signaling and in insulin-responsive glucose uptake
mediated in part by the Akt2 member of PI3K-Akt signaling - one of the two
intracellular pathways triggered by insulin - have been associated with insulin
resistance, a hallmark of T2D. 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. miRNAs 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)
polymorphisms in the human gene are linked to altered insulin secretion; E23K polymorphism appears to confer susceptibility to diabetes type-2 in Caucasian population DNA:missense mutation::p.E23K (human)
