August 15, 2005
Type 2 Diabetes: Problems in the Furnace
A detectable decline in energy production by mitochondria — the
organelles that are the cell's furnace for energy production — seems
to be a key problem leading to insulin resistance, and thus to type 2
diabetes, according to studies by Howard Hughes Medical Institute
researchers.
The research team said that insulin resistance — an impaired
response to the presence of insulin — is detectable as early as 20
years before the symptoms of diabetes become evident. In fact, insulin
resistance is now seen as the best predictor that type 2 diabetes will
eventually develop, said the study's senior author, Gerald I. Shulman,
a Howard Hughes Medical Institute investigator at the Yale University
School of Medicine.
“This is further evidence that people who are prone to develop diabetes have signs of mitochondrial dysfunction.”
Gerald I. Shulman
In the new study examining how insulin interacts with the
energy-producing mitochondria inside living cells, Shulman and his
colleagues found that the rate of insulin-stimulated energy production
by mitochondria is significantly reduced in the muscles of lean,
healthy young adults who have already developed insulin resistance and
who are at increased risk of developing diabetes later in life.
“This is further evidence that people who are prone to develop
diabetes have signs of mitochondrial dysfunction,” Shulman said
in an interview. This is important because mitochondria are the
“energy factories” inside cells and produce most of the
chemical power needed to sustain life.
The new research, which is published in the September 2005 issue of
the open-access journal PLoS Medicine, indicates that a
decreased ability to burn sugars and fats efficiently is an early and
central part of the diabetes problem. Their new data also suggest the
basic defect lies within the mitochondria, which exist in almost every
cell.
The young adults studied by the research team are the offspring of
parents who have type 2 diabetes, adding support to the idea that the
risk can be inherited, and that the problem begins well before diabetes
symptoms become evident. In an earlier research study published in the
journal Science, Shulman and his colleagues had also found that
healthy, lean older individuals have a major reduction in mitochondrial
energy production that leads to accumulation of fat inside muscle cells
resulting in insulin resistance. “These data may explain the
increased prevalence of type 2 diabetes that occurs with aging”
Shulman said.
In the new studies, Shulman and his Yale colleagues — Kitt Falk
Petersen and Sylvie Dufour — discovered that the mitochondria in
muscle cells respond poorly to insulin stimulation. Normal mitochondria
react to insulin by boosting production of an energy-carrying molecule,
ATP, by 90 percent. But the mitochondria from the insulin-resistant
people they tested only boosted ATP production by 5 percent.
“These data demonstrate that insulin-stimulated rates of ATP
synthesis are reduced in the insulin-resistant offspring of parents
with Type 2 diabetes,” the researchers wrote in their report.
Their work offers new insight into the early steps in the development
of insulin resistance, and offers important clues to where the problem
lies.
Among their findings was also evidence for a severe reduction in the
amount of insulin stimulated phosphorus transport into the muscle cells
of the insulin-resistant participants. This also points to a dramatic
defect in insulin signaling and may explain the observed abnormalities
in insulin-stimulated power production in the insulin-resistant study
subjects, since phosphorus is a key element in the mitochondrion's
complex energy-production process, the oxidative-phosphorylation
pathway.
“Type 2 diabetes affects about 171 million people worldwide,
and the number of people likely to be affected by diabetes is expected
to double by 2030,” Shulman and his colleagues added. “Type
2 Diabetes develops when resistance to insulin action is combined with
impaired insulin secretion,” resulting in a severe oversupply of
sugars and fats in the blood. “Studies have demonstrated the
presence of insulin resistance in virtually all patients with type 2
diabetes,” Shulman added. Diabetes is the leading cause of
blindness, end stage kidney disease and non-traumatic loss of limb, and
has associated health care costs that exceed $130 billion a year in the
United States.
Such fundamental research is important because the problem of
diabetes is growing rapidly worldwide, and effective drugs are needed
to halt or even reverse the disease process. Understanding how the
cell's internal energy system is controlled by the hormone, insulin,
and how the mitochondria behave, may eventually lead to improved ways
to overcome or prevent diabetes.
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Jennifer Michalowski
