How Obesity Increases The Risk For Diabetes

[Potter]

http://www.sciencedaily.com/releases...0621143236.htm

How Obesity Increases The Risk For Diabetes

ScienceDaily (June 22, 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, to be
published in the June 21, 2009 advance 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
work. 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,
Ph.D., 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 ATF6a.

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
Wang.

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 favoring the glucose
production pathway; hyperglycemia wins in conditions of persistent stress.

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.

In addition to Drs. Wang and Montminy, researchers contributing to this
study include research technician Liliana Vera, and Wolfgang H. Fischer,
Ph.D., director of the Mass Spectrometry Core Facility.

The work was supported by grants from the National Institutes of Health,
the Clayton Foundation for Medical Research, the Kiekhefer Foundation and
the Vincent J. Coates Foundation.

[Andrew B. Chung, MD/PhD]

Potter wrote:
>
> http://www.sciencedaily.com/releases...0621143236.htm
>
> How Obesity Increases The Risk For Diabetes
>
> ScienceDaily (June 22, 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, to be
> published in the June 21, 2009 advance 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.

Actually ER stress is induced simply by eating more than needed.

Therefore, it remains wise to eat less, down to the right amount in
order to lose the VAT thereby curing the insulin resistance (IR/MetS)
and possibly also be cured of the type-2 diabetes:

http://groups.google.com/group/sci.m...2aafa0aad16eb?

Be hungrier, which is truly healthier for mind, body, and soul:

http://groups.google.com/group/sci.m...d4e30704307e7?

Love in the truth,

Andrew <><
--
Author of WDJW:
http://en.wikipedia.org/wiki/What_does_Jesus_want%3F

"... no one can say 'Jesus is LORD' except by the Holy Spirit." (1 Cor
12:3)
http://groups.google.com/group/sci.m...c93540862751c?

What are the keys of the Kingdom of Heaven?
http://groups.google.com/group/sci.m...b41e6999de315?

Only the truth can cure the "hunger is starvation" delusion:
http://groups.google.com/group/sci.m...81ab7d7ce78de?