Global collaboration leads to discovery of insulin-resistance mutation

An international team led by Stanford researchers has discovered a gene associated with insulin resistance, a condition in which the body doesn’t use insulin properly.

Thomas Quertermous and his colleagues have pinpointed a gene associated with insulin resistance, a condition that can lead to type 2 diabetes.
Steve Fisch

In the four decades since Stanford’s Gerald Reaven, MD, helped demonstrate that insulin resistance can lead to type 2 diabetes, researchers have been hunting for the genetic triggers of the condition.

Now, an international team spearheaded by researchers at the Stanford University School of Medicine has discovered a gene that, when mutated, increases insulin resistance.

A paper describing the findings was published online March 23 in the Journal of Clinical Investigation.

Insulin resistance affects nearly one-third of the U.S. population and occurs when the body’s tissues become less responsive to insulin’s command to gobble glucose. This disconnect increases the likelihood of diabetes, heart disease, hypertension and a variety of other health problems.

“It’s been a long road, but it’s exciting,” said senior author Thomas Quertermous, MD, the William G. Irwin Professor in Cardiovascular Medicine. “Insulin resistance is probably the No. 1 risk factor for complex human disease.”

The team associated a mutation in a gene called NAT2 with insulin resistance by matching its prevalence in the genomes of 5,624 individuals with their scores on a test of insulin sensitivity. The results were then confirmed using genetic studies in mice. NAT2 is expressed in the liver and intestine and known previously for its involvement in drug processing.

International effort

The finding is one of the first to emerge from the GENEticS of Insulin Sensitivity, or GENESIS, an international consortium launched by Stanford in an effort to pin down the genetic origins of insulin sensitivity.

In 1988, Reaven, now a professor emeritus of medicine and a co-author of the paper, introduced the idea of a link between insulin resistance and a cluster of other metabolic abnormalities, which he called Syndrome X and which is now often referred to as metabolic syndrome. Whatever the name, insulin resistance is now recognized to lead to a number of other diseases, but the inherited basis has remained elusive, said Joshua Knowles, MD, PhD, assistant professor of medicine and lead author of the paper.

Joshua Knowles

“This is another step to reiterate to the community that insulin resistance is a major problem that has a real, distinct genetic basis,” Knowles said.

Insulin resistance is highly variable among humans: Some people are six times more sensitive to insulin than others. Genes control only about half the probability of becoming insulin resistant. The other half is environmental and determined primarily by weight and activity level. Insulin resistance occurs on a spectrum, so there is no measurement that triggers a diagnosis of  “insulin resistant,” yet the most resistant people are more likely to develop complications such as diabetes, hypertension and heart problems.

The NAT2 gene accounts for only a small percentage — about 1 percent — of the genetic variability of insulin resistance.

“It’s still early days,” Knowles said. “We’re just scratching the surface with the handful of variants that are related to insulin resistance that have been found.”

Discovering NAT2

Researchers found NAT2 by compiling data from about 5,600 individuals for whom they had both genetic information and a direct test of insulin sensitivity. Measuring insulin sensitivity takes several hours and is usually done in research settings. No genes met the high standards demanded by genome-wide association studies. Yet NAT2 appeared promising, so researchers followed up with experiments using mice.

When they knocked out the analogous gene in mice, the mice’s cells took up less glucose in response to insulin. These mice also had higher fasting-glucose, insulin and triglyceride levels.

Ultimately, we hope this effort will lead to new drugs, new therapies and new diagnostic tests.

“Our goal was to try to get a better understanding of the foundation of insulin resistance,” Knowles said. “Ultimately, we hope this effort will lead to new drugs, new therapies and new diagnostic tests.”

Other Stanford authors are postdoctoral scholars Indumathi Chennamsetty, PhD, and Ivan Carcamo-Oribe, PhD; Themistocles Assimes, MD, PhD, assistant professor of medicine; Fahim Abbasi, MBBS, senior clinical research scientist; and Philip Tsao, PhD, professor of medicine.

The research at Stanford was supported by a grant from the Stanford Cardiovascular Institute, an American Heart Association Fellow-to-Faculty Transition Award, and Merck & Co. Inc. Additional funding for consortium co-authors came from the European Union, Foundation Leducq, the National Institutes of Health, Taiwan and a variety of other sources.

Information about Stanford’s Department of Medicine, which also supported the work, is available at http://medicine.stanford.edu.


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