Christopher J. Rhodes, Ph.D.
Signaling Transduction Mechanisms in the
for Control of Insulin Production & Secretion; ß-Cell Growth
general theme of Rhodes’ laboratory
examine molecular mechanisms that control key functions of the
ß-cell, and investigating how these go awry in the pathogenesis
The following projects are ongoing:
Control of Proinsulin Biosynthesis –
is the principle means by which insulin secreted from the ß-cell
replenished to keep insulin stores at optimal levels. However, the
mechanism behind glucose-regulated translation control of proinsulin
biosynthesis has yet to be unveiled. We are currently investigating the
metabolic signaling pathway that controls the process. Also, a
in 5’-untranslated region of preproinsulin mRNA has been discovered
required for specific translation control of proinsulin biosynthesis. A
protein associates with this cis-element
in a glucose-dependent fashion is currently undergoing identification.
between the metabolic signaling pathway and post-translational
this mRNA-binding protein will be a major breakthrough for better
the mechanism behind translation control of proinsulin biosynthesis
normal and diabetic conditions.
Regulation of Insulin Exocytosis
is known about how signals, such as [Ca2+]i,
transport of insulin secretory granules (known as ß-granules) to
regions of the ß-cell to dock then fuse with the plasma membrane
to undergo regulated
exocytosis. The molecular mechanism behind microtubule mediated
trafficking to specific ‘active zones of exocytosis’ on the
membrane is being studied. However, there is an excess of ~10,000
a ß-cell and relatively few undergo exocytosis. Those
ß-granules that do not
take the path to exocytosis are eventually degraded by autophagy after
days, depending on the metabolic homeostasis. The molecular mechanism
this retirement of senior ß-granules is also being investigated.
role that autophagic mediated cell death plays during the pathogenesis
type-2 diabetes is also being examined.
Transduction Pathways for Control of ß-Cell Growth
has only been recently acknowledged that the onset of type-2 diabetes
type-1 diabetes) is marked by significant loss of ß-cells. As
increasing ß-cell growth and/or promoting ß-cell survival
could be an effective
therapy to delay (or even prevent) the onset of type-2 diabetes.
little is known about the molecular mechanisms that instigate
ß-cell growth and
death relative to temporal metabolic homeostasis. The Rhodes laboratory
been investigating growth factor and nutrient signal transduction
IRS/PI3K/PKB; IRS/Ras/Raf/Erk; JAK2/STAT etc.)
to see if they play a role in increasing ß-cell growth
(by ß-cell replication, size and neogenesis) and/or promoting
ß-cell survival (i.e.
anti-apoptotic). An important role for IRS-2 has arisen from these
Without IRS-2 expression ß-cells undergo spontaneous apoptosis,
IRS-2 levels promotes ß-cell growth and survival. IRS-2 turnover
rapid in ß-cells and its expression is dynamically regulated at
transcriptional level. As such, control of IRS-2 expression may be an
attractive therapeutic target. Investigations to better define the
of IRS-2 gene expression in ß-cells are underway. Molecular
trigger ß-cell apoptosis relative to the pathogenesis of type-2
also being examined, with a focus on fatty acid induced inhibition of
IRS/PI3K/PKB signaling pathways.
K, Julyan R, Wicksteed B, Hays L, Alarcon C, Sommers S, Poitout V,
Wang Y, Philipson L, Rhodes CJ. (2003). Insulin secretory deficiency
intolerance in Rab3A null mice. J. Biol. Chem. 278:9715-9821.
BL, Alarcón C, Briaud I, Lingohr MK, Rhodes CJ. (2003).
control of proinsulin biosynthesis is proportional to preproinsulin
levels, but not regulated via a positive feedback of secreted insulin on in islet ß-cells. J. Biol. Chem. 278: 42080-42090.
I, Dickson LM, Lingohr MK, McCuaig J, Lawrence JC, Rhodes CJ. (2005).
degradation mediated by mTOR Ser/Thr phosphorylation decreases
ß-cell survival. J. Biol. Chem. 280:2282-93
CJ. (2005). Type-2 diabetes – A matter of ß-cell life and death?
MK, Briaud I, Dickson
LM, McCuaig JF, Alarcón C, Wicksteed BL Rhodes CJ.
Regulation of IRS-2 Expression by Glucose in Rat Primary Pancreatic
ß-cells. J. Biol. Chem. 281:15884-92
Faculty and Research