February 12, 2004
Researchers Identify New Cause of Insulin Resistance
Howard Hughes Medical Institute researchers have tracked the cause
of insulin resistance in the offspring of patients with type 2 diabetes
to abnormalities in their mitochondria, the cell's “power
plants.”
Mitochondria are responsible for the breakdown of fatty acids.
Impairment of mitochondrial function causes buildup of fats and fatty
acids inside muscle that can produce insulin resistance, which, in
turn, can contribute to the development of diabetes later in life.
“These new findings identify potential new targets for drugs that could either treat or prevent type 2 diabetes.”
Gerald I. Shulman
The researchers, led by Howard Hughes Medical Institute investigator
Gerald
I. Shulman, who is also professor of medicine and physiology at
Yale, published their findings in the February 12, 2004, issue of the
New England Journal of Medicine.
“Prior to this work, it was pretty clear that insulin
resistance was the best predictor for the development of type 2
diabetes; and that accumulation of lipid in muscle correlated very
strongly with insulin resistance,” said Shulman. This correlation
has been observed in cross-sectional studies, as well as in young
people with a family history of type 2 diabetes, he said.
The hormone insulin promotes the transport of blood glucose into
cells for energy production and storage. Mitochondria within the cells
convert glucose and fatty acids into energy via oxidation. Type 2
diabetes develops when cells do not respond to insulin, causing
accumulations of glucose in the blood.
To explore the metabolic origin of insulin resistance, Shulman and
his colleagues recruited young healthy volunteers who tested positive
for insulin resistance and who were the offspring of patients with type
2 diabetes. They also recruited a second, control group of volunteers
who exhibited insulin sensitivity who were matched for age, height,
weight and physical activity.
“These subjects are ideal candidates for studies examining the
earliest defects leading to insulin resistance, since in contrast to
patients with diabetes, they are young, lean, healthy, and unlikely to
have other confounding factors that might cause insulin
resistance,” the authors wrote in the New England Journal of
Medicine.
Further analysis using a technique called proton magnetic resonance
(MR) spectroscopy confirmed that the muscle cells of the
insulin-resistant subjects did, indeed, harbor higher levels of fat.
Previous studies by Shulman and his colleagues had shown that
intramuscular fat interferes with molecular pathways within the cell
that enable insulin action. In MR spectroscopy, harmless magnetic
fields and radio frequency pulses are used to detect and quantify
signals characteristic of specific molecules.
According to Shulman, the researchers had to distinguish between two
possible causes of the fat accumulation in the muscle that could
trigger insulin resistance. “Either there were defects in the fat
cells, called adipocytes, in which there was increased release of fatty
acids to muscle cells,” said Shulman. “And/or, there was a
defect in mitochondrial function in the muscle cells which would lead
to decreased metabolism of these fatty acids. So, we designed the study
to look at both of these possibilities.”
The researchers then performed metabolic and tracer studies which
could reveal in detail whether the insulin-resistant offspring of
patients with diabetes had defects in lipid metabolism, or lipolysis,
that could explain their insulin resistance.
“We found that these lean insulin-resistant offspring — who
have a high probability of later developing type 2 diabetes — had
muscle insulin resistance, but no detectable abnormalities in their fat
cells compared to the insulin-sensitive subjects,” said
Shulman.
The researchers then turned their attention to the mitochondria
within the cells of the insulin-resistant offspring, using a technique
called phosphorus magnetic resonance spectroscopy. This technique can
reveal how well the energy-producing machinery of the mitochondria is
functioning to break down fat, to produce the cell's chief energy
carrying molecule, phosphorus-rich ATP.
“Using this method we found that rates of ATP production in
the muscles of the insulin-resistant offspring was decreased by thirty
percent compared to normal subjects,” said Shulman. Further
phosphorous MR spectroscopy studies revealed a reduction in the ratio
of slow-twitch (oxidative) muscle fiber type compared to fast-twitch
(glycolytic) muscle fiber type in the insulin-resistant offspring.
These data suggest that there may be an inherited gene that leads to
fewer mitochondria in the muscle of insulin-resistant offspring,
resulting in slightly lower rates of fatty acid oxidation” he
said.
Shulman and his colleagues are now performing muscle biopsy studies
to determine whether the mitochondrial impairments are due to defects
in the mitochondria themselves, or due to a reduced number of
mitochondria in the subjects' cells.
“The other direction of our research is to discover whether or
not we can reverse these abnormalities with exercise,” said
Shulman. “It is pretty well established that training will
increase mitochondrial content. For example, it is well known that
marathon runners have more mitochondria than sprinters.” Earlier
studies by Shulman's group established that exercise could promote
activation of an enzyme called AMP kinase that can lead to an increase
in mitochondria content.
“These new findings identify potential new targets for drugs
that could either treat or prevent type 2 diabetes. Furthermore, these
data may help guide us to a better understanding of the genetic basis
of type 2 diabetes”, said Shulman.
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