How obesity increases the risk of diabetes
8 July 2009
Obesity is probably the most important factor in the development of
insulin resistance, but science’s understanding of the chain of events
is still spotty. Now, researchers at the Salk Institute for Biological
Studies have filled in the gap and identified the missing link between
the two. Their findings, published in the June 21, 2009 online edition
of the journal Nature, explain how obesity sets the stage for
diabetes and why thin people can become insulin-resistant.
The Salk team, led by Marc Montminy, Ph.D., a professor in the
Clayton Foundation Laboratories for Peptide Biology, discovered how a
condition known as ER (endoplasmic reticulum) stress, which is induced
by a high fat diet and is overly activated in obese people, triggers
aberrant glucose production in the liver, an important step on the path
to insulin resistance.
In healthy people, a "fasting switch" only flips on glucose
production when blood glucose levels run low during fasting. “The
existence of a second cellular signaling cascade — like an alternate
route from A to B — that can modulate glucose production, presents the
potential to identify new classes of drugs that might help to lower
blood sugar by disrupting this alternative pathway,” says Montminy.
It had been well established that obesity promotes insulin resistance
through the inappropriate inactivation of a process called
gluconeogenesis, where the liver creates glucose for fuel and which
ordinarily occurs only in times of fasting. Yet, not all obese people
become insulin resistant, and insulin resistance occurs in non-obese
individuals, leading Montminy and his colleagues to suspect that
fasting-induced glucose production was only half the story.
“When a cell starts to sense stress a red light goes on, which slows
down the production of proteins,” explains Montminy. “This process,
which is known as ER stress response, is abnormally active in livers of
obese individuals, where it contributes to the development of
hyperglycemia, or high blood glucose levels. We asked whether chronic ER
stress in obesity leads to abnormal activation of the fasting switch
that normally controls glucose production in the liver.” The ER, short
for endoplasmic reticulum, is a protein factory within the cell.
To test this hypothesis the Salk team asked whether ER stress can
induce gluconeogenesis in lean mice. Glucose production is turned on by
a transcriptional switch called CRTC2, which normally sits outside the
nucleus waiting for the signal that allows it to slip inside and do its
Once in the nucleus, it teams up with a protein called CREB and
together they switch on the genes necessary to increase glucose output.
In insulin-resistant mice, however, the CRTC2 switch seems to get stuck
in the “on” position and the cells start churning out glucose like sugar
factories in overdrive.
Surprisingly, when postdoctoral researcher and first author Yiguo
Wang, PhD, mimicked the conditions of ER stress in mice, CRTC2 moved to
the nucleus but failed to activate gluconeogenesis. Instead, it switched
on genes important for combating stress and returning cells to health.
On closer inspection, Wang found that in this scenario CRTC2 did not
bind to CREB but instead joined forces with another factor, called
What’s more, like jealous lovers CREB and ATF6a competing for CRTC2’s
affection — the more ATF6a is bound to CRTC2, the less there is for CREB
to bind to. “This clever mechanism ensures that a cell in survival mode
automatically shuts down glucose production, thus saving energy,” says
This observation led the researcher to ask what happens to ATF6a
following the kind of persistent stress presented by obesity? They found
that the levels of ATF6a go down when ER stress is chronically
activated, compromising the cells’ survival pathway and favouring the
glucose production pathway; hyperglycemia wins in conditions of
Explains Wang, “Our study helps to explain why obese people have a
stronger tendency to become diabetic. When ER stress signaling is
abnormal glucose output is actually increased.”
“It is possible that mutations in the highly conserved CRTC2 lead to
a predisposition to inappropriate gluconeogenesis,” says Montminy, who
is now trying to identify natural mutations in CRTC2 that may lead to
insulin resistance in carriers.
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