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Scientists Identify Major Molecular Pathway That Leads to Diabetes
Scientists Identify Major Molecular Pathway That Leads to Diabetes -- Posted by Gumbo on 11-19-04 05:18
Scientists Identify Major Molecular Pathway That Leads to Diabetes
BOSTON, Oct. 14 (AScribe Newswire) -- Researchers from the Harvard School of
Public Health have discovered what they believe is the fundamental mechanism
within cells that links two fast-rising public health threats: obesity and
Type 2 diabetes.
In identifying a specific cell-signaling pathway through which excess fat
sets in motion a series of steps culminating in diabetes, the scientists
have gone farther than previous studies that provided shards of evidence but
not a satisfactory whole. An article on the work appears in the October 15
issue of Science.
A series of experiments in isolated cells and in mice revealed that
accumulation of excess fat put unusual demands on crucial synthetic
machinery of cells. In attempting to adapt to this condition, cells activate
a cascade of genes and proteins that ultimately disrupts insulin function.
The result is cellular stress inflammation and diabetes.
Type 2 diabetes - 90 to 95 percent of all diabetes cases - affects an
estimated 18 million people in the United States, and causes some 200,000
deaths a year. Its description as "adult-onset" diabetes has been dropped,
as it is now being diagnosed in younger and younger people including
children and teenagers, most of whom are overweight.
"What we have found is an important step toward understanding the roots of
Type 2 diabetes and metabolic disease," said Gokhan Hotamisligil, chair of
the Department of Genetics and Complex Diseases, who headed the research
team. "It is a missing piece that integrates the mechanisms of the disease
at different sites in the body, including fatty tissue, liver and the
pancreas." he said.
Hotamisligil is the senior author; co-first authors are Harvard School of
Public Health fellows Umut Ozcan and Qiong Cao. Laurie H. Glimcher of the
Department of Immunology and Infectious Diseases is a collaborator and
provided the genetically altered mice.
Until now, scientists have obtained only a sketchy picture of how the
accumulation of excess calories and millions of extra fat cells in an obese
person triggers a chain of events that leads to a chronic state of
inflammation and insulin resistance (when cells can no longer respond to the
hormone insulin, hence are unable to import sugar from the blood). Over
time, these events create a high risk of heart disease and stroke, kidney
disease, amputation of feet and legs, and blindness.
Hotamisligil has done pioneering work on the discovery of inflammation as a
cause of obesity and type 2 diabetes. He and others previously showed that
fat cells are not just inert storage receptacles; instead, they play an
important role in communicating with other organs to maintain proper
metabolic balance. They also secrete chemical messengers that stimulate the
immune system.
With the goal of reaching to the deeper mechanisms, he tested a hypothesis
that the key to the obesity-diabetes connection might be found in the
endoplasmic reticulum, or ER - a system of folded membranes and tubules in
the cytoplasm of cells where proteins and lipids are manufactured,
processed, and shipped around the cell. When unusual demands are put on the
ER's capacity, the life of the cell is threatened and it goes into emergency
mode. This condition is called ER stress. It can be triggered by a viral
infection, gene mutations, exposure to toxins, or a shortage of intra
cellular nutrients. The cell responds with a flurry of activity aimed at
survival but which suppresses the cell's normal responsiveness to insulin
and sets off inflammation.
Hotamisligil showed that turning the adaptive capacity in the ER "on or off"
by regulating the levels of a gene called XBP-1 also changes insulin action.
In mice, when there is less XBP-1 activity - hence susceptibility to ER
stress - the animals develop insulin resistance and diabetes. The XBP-1 gene
was first isolated by Glimcher.
How does obesity cause ER stress to begin with? Although the details aren't
all known, Hotamisligil says that fat cells by their nature are perpetually
on the verge of ER stress. "It's a big, spherical cell that under the best
of conditions uses up all its excess capacity to be able to run," he said.
"Obesity brings a huge amount of stress to a cell that has no reserve
capacity to tolerate it."
With the missing link in hand, Hotamisligil said the discovery will open up
many therapeutic possibilities by focusing on how to enhance the cell's
tolerance of ER stress. He cautions, however, that there no treatment based
on this concept on the immediate horizon, though he is "very excited" about
the work's rich potential for treating diabetes.
The study was funded by the National Institutes of Health
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