Researchers Identify New Cause of Insulin Resistance

[Guest guest]

,

This talks about ATP.

Judith,

More sense here than fiber with fatty acid oxidation, imo

Wanita

> Researchers Identify New Cause of Insulin Resistance

>

> " These new findings identify potential new targets for drugs that

could either treat or prevent type 2 diabetes, " said HHMI investigator

Gerald Shulman.

>

>

> February 12, 2004- 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.

>

>

> The researchers, led by 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.

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>

> " 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.

>

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> " 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.

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> 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.

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> " 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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> Photo: Gale Zucker

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> ©2004 Medical Institute

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>