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Barton Wicksteed, Ph.D.
Cell Biology of the Pancreatic Islets of Langerhans
Research Summary
The research interests of the
Wicksteed laboratory a centered around the pancreatic islets of
Langerhans. The
beta-cells of the islets of Langerhans secrete insulin to drive insulin
storage
and lower circulating glucose levels, thereby preventing hyperglycemia
(high
glucose levels). Conversely, the islet alpha cells secrete glucagon
that acts
primarily to promote hepatic glucose production and so prevents
hypoglycemia
(low glucose levels). Between them the secretion of these hormones from
these
cell types is important in maintaining circulating glucose levels
within a
narrow range.
Our interest in the islet beta cell
lies within understanding the role of cyclic AMP (cAMP), which is an
important
second messenger molecule that affects many aspects of the beta
including
insulin secretion, insulin synthesis and beta-cell survival. Due to
these roles
there is considerable pharmaceutical interest in employing cAMP in the
beta-cell to improved beta-cell function in diabetes (insulin synthesis
and
secretion) which maintaining beta-cell mass. To understand the
downstream
signaling of cAMP the laboratory has focused upon the cAMP-dependent
kinase,
protein kinase A (PKA), which is believed to be the major downstream
target of
cAMP. In vitro we are examining the
complexes associated with A-kinase anchoring proteins (AKAP). AKAPs
direct PKA
to specific locations within the cell and draw PKA into complexes with
PKA
substrates, with phosphatases that down-regulate PKA signaling and with
proteins that control local cAMP levels. Therefore, we believe that
understanding AKAP complexes is central to understanding the mechanisms
by
which cAMP signals via PKA. In conjunction with the in vitro studies we
are using and developing new in vivo mouse models to understand the
role of PKA in glucose homeostasis and in regulating beta-cell mass.
Using
mutant PKA molecules, expressed specifically in the beta-cells in a
time
dependent manner we are starting understand the in vivo function of PKA.
Our research in to the islet
alpha-cell has initially focused upon the regulation of the expression
of the
proglucagon gene. Glucagon is synthesized as a precursor, proglucagon,
that is
processed differently in the pancreas compared to the gut and central
nervous
system. We are examining both the nutrient regulation of proglucagon
gene
expression and tissue distribution of expression. To examine the tissue
distribution of proglucagon expression we are identifying candidate
evolutionarily conserved regions (ECRs) that lie distant to the
proglucagon coding
region. To assess the role of these ECRs as tissues specifying enhancer
elements we are using a combination of transgenic mouse models,
zebrafish,
chromatin immunoprecipitation and adenovirus infection of isolated
islets of
Langerhans.
Overall these projects aim to understand the role of
the islets of Langerhans in regulating the production of peptide
hormones to
control circulating glucose levels. Furthermore, our research aims to
understand the potential of cAMP/PKA signaling in treating diabetes and
the
role of aberrant glucagon secretion contributing to the hyperglycemia
seen in
diabetes.
Selected Papers
Wicksteed, B.,
Herbert, T.P, Alarcon, C., Lingohr, M.K., Moss, L.G., Rhodes,
C.J. Co-operativity between the preproinsulin mRNA UTRs is
necessary for glucose-stimulated translation. J. Biol. Chem. (2001).
276:22553-22558.
Skelly, R.H., Wicksteed, B., Antinozzi, P.A., Rhodes, C.J.
Glycerol stimulated proinsulin biosynthesis in isolated rat islets via
recombinant adenovirus induced expression of glycerol kinase is
mediated via increased anaplerosis. Diabetes (2001). 50:1791-8.
Alarcon C, Wicksteed B., Prentki M, Corkey BE, Rhodes CJ.
Succinate is a preferential metabolic stimulus-coupling signal for
glucose-induced proinsulin biosynthesis translation. Diabetes
(2002). 51:2496-2504.
Yaekura, K., Julyan, R., Wicksteed, B., Hays, L.B., Alarcon, C.,
Sommers, S., Poitout, V., Baskin, D.G., Wang, Y., Philipson, L.H.,
Rhodes, C.J. Insulin secretory deficiency and glucose intolerance
in Rab3A Null mice. J. Biol Chem. (2003). 278: 9715-9721.
Wicksteed, B., Alarcon, C., Briaud, I., Lingohr, M.K., Rhodes,
C.J. Glucose-induced translational control of proinsulin
biosynthesis is proportional to preproinsulin mRNA levels in islet
beta-cells, but not regulated via a positive feedback of secreted
insulin. J. Biol. Chem. (2003). 278:42080-90.
Hays, L.B., Wicksteed, B., Wang, Y., McCuaig, J.F., Philipson, L.H.,
Edwardson, J.M., Rhodes, C.J. Intragranular targeting of
syncollin, but not a syncollin-GFP chimera, inhibits regulated insulin
exocytosis in pancreatic -cells. J Endocrinol. (2005). 185:57-67.
Alarcon, C., Wicksteed, B., Rhodes, C.J. Exendin 4 controls
insulin production in rat islet beta cells predominantly by
potentiation of glucose-stimulated proinsulin biosynthesis at the
translational level. Diabetologia (2006). 49:2920-9.
Wicksteed, B., Uchizono, Y., Alarcon, C., McCuaig, J.F., Shalev, A.,
Rhodes, C.J. A cis-Element in the 5' Untranslated Region of the
Preproinsulin mRNA (ppIGE) Is Required for Glucose Regulation of
Proinsulin Translation. Cell Metab. (2007). 5:221-7.
Marsh, B.J., Soden, C., Alarcon, C., Wicksteed, B., Yaekura, K., Cosin,
A., Morgan, G.P., Rhodes, C.J. Regulated autophagy controls
hormone content in secretory-deficient pancreatic endocrine beta-cells.
Mol Endocrinol. (2007) 21:2255-69.
Uchizono, Y., Alarcon, Wicksteed, B.L., Marsh, B.J., Rhodes, C.J.
The balance between proinsulin biosynthesis and insulin secretion:
where can imbalance lead? Diabetes Obes Metab. (2007) 9:56-66.
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