How Does Obesity Cause Diabetes?

By Julia Michelle, eHow Contributor

Understanding Diabetes

1. When we eat, the pancreas releases insulin, which sits on receptors in the cells,
allowing blood sugar to enter the cells for use in energy production. Diabetes
mellitus is a condition where the cells are unable to use insulin to convert sugar into
energy, so the sugar remains in the blood stream. There are three types of diabetes:
type 1, type 2 and gestational. Type 1 diabetes is not linked to obesity and occurs
when the islet cells in the pancreas stop producing insulin. Type 2 and gestational
diabetes are both conditions where the body produces insulin, but the cell receptors
do not respond properly. Gestational diabetes is linked to hormonal changes during
pregnancy and type 2 diabetes is linked to obesity. Medical science is not exactly
clear how obesity causes type 2 diabetes, but there are several theories.

ER Stress and Overnutrition

2. The endoplasmic reticulum (ER) is a specialized membrane, inside the cell, that
synthesizes proteins and processes blood fats. Overnutrition is a state where the
body has more calories and fat that it can process at one time. When the body
enters a state of overnutrition, this puts stress on the ER, causing it to signal the
insulin receptors to stop responding to insulin. Temporarily reducing insulin
receptivity allows the ER to catch up with its workload. If the body repeatedly enters
a state of overnutrition, the ER continually signals the cells to dampen their insulin
receptors. Over time, the body is no longer able to respond to insulin properly.

IRS Suppression

3. Insulin receptor substrates (IRS) are proteins, inside the cell, that rest against the
insulin receptors. When insulin activates the receptors, the receptors release
chemicals onto the IRS, causing them to activate the glucose transporter machinery
within the cell. In studies with mice, scientists disabled IRS function, resulting in type
2 diabetes. While studies in human subjects with inherited type 2 diabetes showed
no abnormality in IRS genes, scientists believe the link between obesity and
impaired IRS function lies with a hormone called resistin.
 Resistin

4. Resistin is produced by fat cells and causes the body to resist insulin. It is
believed that resistin production evolved as a response to famine, allowing the body
to survive by conserving energy stores. In laboratory studies, mice that were given
resistin lost the ability to transport glucose. High levels of resistin were also found in
mice that were obese from overeating. In the mice that were given resistin, resistin-
lowering drugs reversed the effect, and they were able to transport glucose.

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Study Suggests How

Obesity Causes Diabetes

Scientists know that obesity is a key player in the development of type 2 diabetes,
but exactly how excess weight causes the disease isn't clear.

While trying to answer that question, Harvard University researchers have

discovered a new pathway that sets in motion a series of reactions that leads to the
development of insulin resistance, a precursor of type 2 diabetes, a new study
reports.

The researchers found that obesity causes stress in a system of cellular membranes
called endoplasmic reticulum (ER), which in turn causes the endoplasmic reticulum
to suppress the signals of insulin receptors, which then leads to insulin resistance.

Endoplasmic reticulum is a network of membranes found inside cells. Study author

Dr. Gokhan Hotamisligil, a professor of genetics and metabolism at Harvard School
of Public Health, said endoplasmic reticulum is "really the synthetic machine of the
cell." It is responsible for processing proteins and fats.

Results of the study appear in the Oct. 15 issue of the journal Science.

Christopher Newgard is director of the Sarah W. Stedman Nutrition and Metabolism

Center at Duke University Medical Center and author of an editorial in the journal
accompanying the study. He suggested thinking of endoplasmic reticulum "as a
factory for producing protein and the site at which excess lipids -- blood fats -- are
processed."
"As you enter a state of overnutrition, as we often do living in our supersized
society, all of those nutrients that come in need to be processed, stored, and
utilized and the ER factory is overworked and starts sending out SOS signals,"
Newgard explained.

These SOS signals, he said, tell cells to dampen their insulin receptors. Insulin is the
hormone that converts blood sugar to energy for the body's cells.

"In the case of obesity, what is designed as a short-term adaptive response triggers
long-term chronic illness," said Hotamisligil.

"It's the ER's way of saying, 'Enough, already; you're bombing us with nutrients,'"
Newgard said. "When there's too much going on, the cell knows that insulin is out
there, but doesn't want insulin receptors signaling for more insulin because there's
already enough on board. This has a downside, because insulin soon loses its ability
to help clear sugar from the body."

Besides suppressing normal responses to insulin, ER stress also triggers

inflammation in cells. Hotamisligil said he wouldn't be surprised to learn that this
pathway had a role in cardiovascular disease because inflammation is increasingly
being implicated in heart disease.

In the current study, Hotamisligil and his colleagues looked at cell cultures and
mouse models. In addition to finding the effects of ER stress, they also discovered
that mice who were deficient in a protein called XBP-1 developed insulin resistance.
Newgard said it appeared that when more XBP-1 was present in a cell, it had a
protective effect against ER stress. He added that this could be a potential target for
new therapies for type 2 diabetes.

"In the future, if one can develop ways to reduce ER stress or generate less ER
stress or to find a way to boost the system's ability to handle stress, all of these
maneuvers could help cope with [type 2 diabetes]."

Both Hotamisligil and Newgard caution, however, that these findings were in mice,
and therefore aren't necessarily applicable in humans.

Newgard added, "This is a significant, novel finding. It's an important piece in our
understanding of how signaling goes wrong, but more work needs to be done."

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