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Regulation of Beta Cell Phenotype by Glibenclamide

Monday, 5 October, 2009 - 17:00
Campus: Brussels Health Campus
Faculty: Medicine and Pharmacy
auditorium P. Brouwer
Qidi Wang
phd defence

Earlier studies from our department have shown
that the phenotype of beta cells can be altered by
environmental conditions leading to differences in
the viability and function of the cells. Treatment
with the hypoglycemic drug glibenclamide was
found to increase the basal protein and insulin
synthetic activity of the cells. The present work
has identified the site and the mechanisms
through which this effect is achieved. Both in vivo
and in vitro exposure of beta cells to this
therapeutic agent results in an activation of
translation factors through a calcium-dependent
pathway that involves mTOR-, PKA- and MEKdependent
signaling. This activation causes an
up-regulation of genes that encode for enzymes
in protein synthesis and in metabolic pathways
that facilitate nutrient catabolism through
mitochondrial metabolism and fatty acid
oxidation. These effects occur in the
subpopulation of beta cells that has been
degranulated under influence of the insulinreleasing
action of the drug. On basis of these
observations, it is concluded that the sustained
presence of the insulin secretagogue
glibenclamide induces a functional adaptation in
those beta cells that have been degranulated by
administration of this drug. This adaptation
consists in increasing hormone synthesis under
basal conditions, and in decreasing the cellular
susceptibility to toxic effects of fatty acid
overload.