Abdominal fat, the spare tire that many of us carry, has long been
implicated as a primary suspect in causing the metabolic syndrome, a
cluster of conditions that includes the most dangerous heart attack
risk factors: prediabetes, diabetes, high blood pressure, and changes
But with the help of powerful new imaging
technologies, a team of Howard Hughes Medical Institute (HHMI)
researchers at Yale University School of Medicine has found that
insulin resistance in skeletal muscle leads to alterations in energy
storage that set the stage for the metabolic syndrome.
Insulin resistance is a condition in which the body's cells become
resistant to insulin, a hormone secreted by the pancreas that plays an
essential role in regulating the carbohydrates, lipids, and proteins
obtained from food.
The new study, published July 16, 2007, in
the Proceedings of the National Academy of Sciences (PNAS),
demonstrates that insulin resistance in skeletal muscle -- caused by
decreased ability of muscle to make glycogen, the stored form of
carbohydrate from food energy -- can promote an elevated pattern of
lipids or fats in the bloodstream that underpins the metabolic syndrome.
study was led by HHMI investigator Gerald I. Shulman and Kitt Falk
Petersen, both of the Yale University School of Medicine. Coauthors of
the paper were from Yale and Harvard Medical School.
metabolic syndrome is a very common metabolic abnormality and the
prevalence is growing. However, the underlying factors that cause it
are poorly understood." The syndrome afflicts more than 50 million
Americans and roughly half of all Americans are predisposed to it,
making it one of the nation's most serious human health issues.
begin to shed light on the earliest molecular events that lead to the
metabolic syndrome, Shulman and his colleagues used powerful new
magnetic resonance imaging techniques to observe how nutrients are
channeled in the body in both insulin resistant and insulin sensitive
The subjects for the study were all young, lean,
non-smoking, healthy individuals who were sedentary and matched for
physical activity. Aside from insulin resistance in one cohort, these
volunteers had none of the other confounding factors typically
associated with obesity and type 2 diabetes, which have been thought to
play a key role in the pathogenesis of the metabolic syndrome.
hypothesis was that the metabolic syndrome is really a problem with how
we store energy from food," Shulman explained. "The idea is that
insulin resistance in muscle changes the pattern of energy storage."
providing the study's subjects with two meals high in carbohydrates,
Shulman and his colleagues turned to magnetic resonance spectroscopy to
measure the production of liver and muscle triglyceride, the storage
form of fat, and of glycogen, the storage form of carbohydrate. "What
we found is that (insulin) sensitive individuals took the energy from
carbohydrate in the meals and stored it away as glycogen in both liver
and muscle," said Shulman.
In the insulin resistant subjects,
the energy obtained from their carbohydrate rich meals was rerouted to
liver triglyceride production, elevating triglycerides in the blood by
as much as 60 percent and lowering HDL cholesterol (the "good
cholesterol") by 20 percent. "In contrast to the young, lean,
insulin-sensitive subjects, who stored most of their ingested energy as
liver and muscle glycogen, the young, lean, insulin-resistant subjects
had a marked defect in muscle glycogen synthesis and diverted much more
of their ingested carbohydrate into liver fat production," Shulman and
his colleagues reported.
"What we see," he noted, "is
alterations in patterns of energy storage. An additional key point is
that the insulin resistance, in these young, lean, insulin resistant
individuals, was independent of abdominal obesity and circulating
plasma adipocytokines, suggesting that these abnormalities develop
later in the development of the metabolic syndrome."
findings promise to help untangle the early molecular events of a
syndrome at the root of one of the world's most significant health
issues. "Knowing how insulin resistance alters energy storage before it
leads to more serious problems can help those susceptible prevent the
onset of the metabolic syndrome," Shulman said.
observation was that skeletal muscle insulin resistance precedes the
development of insulin resistance in liver cells, and that fat
production in the liver is increased. "These findings also have
important implications for understanding the pathogenesis of
nonalcoholic fatty liver disease, one of the most prevalent liver
diseases in both adults and children" Shulman said.
news, according to Shulman, is that insulin resistance in skeletal
muscle can be countered through a simple intervention: exercise.
Howard Hughes Medical Institute. July 2007.