Major Clue to Type 2 Diabetes’ Causes Found
The first major clue in the long and frustrating search for the causes of Type 2 diabetes, a complex and devastating genetic disorders that affects 16 million Americans, has been found in an unusual population of Mexican Americans in Starr County, Texas.
Studying 330 pairs of diabetic siblings from the area, a multinational team of researchers reports today in the journal Nature Genetics that they have sharply narrowed the search for one of the most important of the estimated 10 or more genes that cause the disease.
In 30 months of intense work, the team has eliminated 98% of the human genome--the complete genetic blueprint of humans--as the location for this important gene.
The remaining 2%, which is now being analyzed, is a completely uncharted region of Chromosome 2 that is not known to contain any genes controlling the body’s use of sugars. “That means we are onto something new, something unexpected,” said molecular biologist Graeme Bell of the University of Chicago Medical Center, who headed the team.
Scientists expect to identify the gene itself within two years, a discovery that they say could provide powerful insights into the causes of diabetes--and eventually into prevention and cures.
“This is a very important finding,” said Dr. Philip Cryer of the Washington University School of Medicine and president-elect of the American Diabetes Assn. “It’s only a piece of the puzzle, but it will narrow the focus of the search for that gene away from vast amounts of the genome.”
Diabetes is a disorder in the metabolism of insulin, the protein that regulates the body’s storage and use of sugars from the diet. In Type 1, commonly called juvenile-onset diabetes, insulin-producing cells in the pancreas are destroyed by the immune system. Unless the 1 million Americans who suffer from this form receive insulin artificially, they die quickly.
Type 2, called adult-onset or non-insulin-dependent diabetes, is both more complicated and more subtle. In some cases, the pancreas doesn’t produce enough insulin. In others, cells do not respond normally to insulin. This type of the disease can be treated with a broad spectrum of drugs that stimulate insulin production, as well as with diet and exercise.
But as many as 75% of diabetics do not have their blood sugar levels under adequate control--a problem that leads to many disabling consequences, including limb and nerve damage, kidney failure and blindness.
Although gene scientists have had great success in identifying the defects that produce the 3,000 or so hereditary disorders involving a single gene, the more complex and widespread diseases--cancer, heart disease, diabetes--caused by several genes acting together have been exceptionally resistant to their probings.
Geneticists have so far discovered two genes that are important in a rare form of the disease called maturity-onset diabetes of youth, which causes no more than 5% of Type 2 cases. But they have yet to find a gene that plays a role in the vast majority of cases.
Researchers turned to Starr County.
The rural Texas county, nestled along the Rio Grande, has a prevalence of diabetes several times as high as that of the U.S. as a whole and one of the highest death rates from diabetes in the country. About 97% of the residents identify themselves as Mexican Americans, a group that statistically has an above-normal incidence of the disorder.
The team collected blood samples from 408 Type 2 diabetics in 170 families, dividing them into 330 brother/brother, brother/sister and sister/sister pairs.
Using newly developed genetic engineering techniques that identify abnormalities in sibling pairs, researchers from eight institutions looked for unusual genetic markers on each of the 23 pairs of human chromosomes.
They have found several different chromosomal sites that may contain diabetes-related genes, but one unique stretch of DNA on Chromosome 2 stood out. “We now believe that late-onset [diabetes] in Mexican Americans results from the action of at least one relatively major susceptibility gene on Chromosome 2,” said geneticist Craig Hanis of the University of Texas, Houston.
Abnormalities in this gene, called NIDDM1, account for at least 30%, and perhaps as much as 75%, of Type 2 diabetes among Mexican Americans, the researchers believe, and a lesser proportion in non-Latino whites.
“Our next step is to locate that gene,” Hanis said.
That will be a daunting task. The region in question is large enough to contain 100 or more genes. The team may have to individually identify each of the 5 million chemical units that make up the chromosome segment, a tedious, time-consuming process.
