Dec. 30, 2003 LOS ANGELES (December 29, 2003) – For over a decade, scientists have known that insulin resistance – a syndrome where the body does not respond as well as it should to insulin – is linked to the development of heart disease, diabetes, high blood pressure, obesity and polycystic ovary syndrome. In fact, one in four adult Americans has insulin resistance, with Mexican Americans having the highest prevalence. But because people with insulin resistance are so likely to develop diseases such as diabetes and heart disease, scientists have turned their attention on investigating whether a common gene abnormality may be involved.
Now, researchers at Cedars-Sinai Medical Center, in collaboration with investigators at UCLA, have found that lipoprotein lipase (LPL), a gene that controls the delivery of fatty acids to muscle and tissues in the body, is linked to insulin resistance in Mexican-Americans. Their findings, reported in the January issue of Diabetes, may enable scientists to design therapies that target LPL to prevent insulin resistance, a condition estimated to affect over 80 percent of the 16 million Americans with Type 2 diabetes, and additional millions at risk for heart disease.
"This is the first study to definitively show that LPL is a gene for common insulin resistance," said Jerome I. Rotter, M.D., Director of the Division of Medical Genetics and Director of the Common Disease Genetics Program at Cedars-Sinai Medical Center.
In recent years, LPL has emerged as a likely "gene candidate" to study for insulin resistance because some studies had linked it to high blood pressure, obesity, and atherosclerosis (fatty deposits in the arteries) – all of which are associated with the insulin resistance syndrome. But the studies were small, used limited diagnostic tests, and looked at only small portions of the LPL gene.
To determine whether LPL was directly linked to insulin resistance, researchers under Dr. Rotter's direction, conducted the first study to examine a large, high-risk population of Mexican-Americans using the most precise diagnostic and genetic tests: the glucose clamp, the most precise diagnostic test, coupled with an analysis of the patients' DNA for a group of six of the most common LPL gene markers in this population called haplotypes. As markers of LPL, these haplotypes function similar to a "bar code" and identify all the major variations or differences of LPL in a population that could be associated with disease. In this study of Mexican-Americans, eight different haplotypes were observed.
In the study, 291 adult-offspring of parents with documented heart disease (112 men and 179 women) were tested for six specific LPL markers and underwent the glucose clamp test receiving an infusion of insulin in one arm over a two-hour period. The patients then also had blood samples drawn from the other arm to determine how much glucose was present in the blood. The patient was found to be less insulin resistant when the samples showed low blood sugar levels even when glucose was added, indicating that the cells were taking up glucose. However, if little or no glucose needed to be added, then the patient was insulin resistant because blood sugar levels were too high, indicating that cells were not using it as they should.
"The glucose clamp technique is considered the 'gold standard' for testing insulin resistance because it provides the most direct assessment of insulin's action as opposed to simpler tests that measure glucose or insulin levels while the patient is fasting," commented Dr. Rotter.
To determine whether insulin resistance, as measured by the glucose clamp, was linked to certain variations or haplotypes on the LPL gene, the investigators then examined the level of insulin resistance for each of the eight LPL haplotypes observed in this population. They found that one particular haplotype (designated as Haplotype 4) was associated with a high level of insulin resistance, while another haplotype (Haplotype 1) was linked with low levels of insulin resistance.
"Our study showed that two separate haplotypes of LPL were linked to low or high levels of insulin resistance, confirming that the LPL gene plays a role in determining insulin resistance in this population of Mexican Americans," said Dr. Rotter.
The investigators analyzed larger portions (haplotypes) of the LPL gene, instead of looking at only one or two variations (polymorphisms) in the gene because haplotypes represent the majority of common variation passed down in families, encompassing sections of the gene that have remained unbroken by evolution over time. Consequently, haplotypes are more likely to identify disease associations than single gene variations. Among the 291 patients typed for LPL haplotype markers, 40 patients were found to carry Haplotype 4, the gene marker linked to insulin resistance, while 239 carried Haplotype 1, which is associated with a low level of insulin resistance.
"This finding is significant because it provides direct evidence that LPL is an insulin resistance gene by showing that LPL haplotypes are linked with a direct quantitative measurement of insulin resistance in Mexican Americans," said Dr. Rotter. "The strength of this investigation is that we examined a population at high risk for the insulin resistance syndrome, that we directly measured insulin sensitivity by the glucose clamp study, and that we combined this with the power of a haplotype-based analysis."
Future studies will investigate the actual variation in the LPL gene and how it influences insulin resistance.
Cedars-Sinai Medical Center is one of the largest non-profit academic medical centers in the Western United States. For the fifth straight two-year period, Cedars-Sinai has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 "Most Wired" hospitals in health care in 2001, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.
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