Bell team discovers biochemical pathway to type 2 diabetesBy John Easton
Medical Center Public Affairs
The discovery, published in the October issue of Nature Genetics, pinpoints a new and unexpected biochemical pathway leading to diabetes and suggests novel approaches to prevention, diagnosis and treatment.
Identifying this new diabetes gene also is a major coup for genetics. This is the first time that a genome-wide approach has successfully led to the identification of a susceptibility gene responsible for a common, genetically complex disorder.
Finding this gene finally allows us to go after diabetes treatment strategies that address the underlying molecular defects rather than the symptoms, said research team leader Graeme Bell, the Louis Block Professor in Biochemistry & Molecular Biology and an investigator in the Howard Hughes Medical Institute at the University.
At the same time, our unexpected success and the techniques we developed along the way should restore faith in the power of genetic approaches and provide the tools to identify the genes for other common genetically complex disorders such as hypertension, obesity, psychiatric diseases or asthma.
Bell and colleagues accomplishment is a tour-de-force, said Allen Spiegel, director of the National Institute of Diabetes and Digestive and Kidney Diseases. Actually identifying susceptibility genes for diseases such as diabetes with complex as opposed to simple Mendelian inheritance has proved exceedingly difficult.
Moreover, identification of this geneone that would not have leaped to mind as an obvious candidateis exciting because it should lead to greater understanding of the pathogenesis of type 2 diabetes, and possibly to new forms of treatment, he continued.
Type 2 diabetes, or NIDDM, affects an estimated 135 million people worldwide, including more than 15 million Americans. Almost 6 percent of the U.S. population is afflicted, and 18.4 percent of those cases are in people over age 65. Diabetes is the seventh leading killer in the United States, where the cost of the disease is estimated to exceed $98 billion each year.
The disease also is common among particular ethnic groups, affecting 10.6 percent of all Mexican Americans, 10.8 percent of African Americans and as many as 50 percent of Pima Indians, an American Indian tribe based in Arizona.
Finding the genes responsible for type 2 diabetes has been unusually difficult because diabetes is not a single disease but a group of related disorders with similar symptoms. In 1996, Bell led a team of researchers, including Craig Hanis from the Human Genetics Center at the University of Texas-Houston, in a study using Mexican-American subjects. During the study, Bell, Hanis and their colleagues were able to demonstrate linkage between an increased risk of diabetes in Mexican Americans and an unknown gene located near one end of chromosome 2, which they called NIDDM1.
However, no one studying a complex disease had ever been able to take the next step, to identify the specific gene that had originally been localized by linkage.
People kept telling us it was impossible, recalled Bell. But working with the Texas samples, Bell and his colleague Nancy Cox, Associate Professor in Human Genetics, developed several new analytic techniques that enabled them to zero in on NIDDM1.
The gene they tagged as NIDDM1 codes for a new protein, calpain 10. The precise functions of most of the calpains are unknown.
Bells team discovered overwhelming evidence that the risk-increasing abnormality in the calpain 10 gene occurs not in a functional part of the gene but in an intron. Introns are pieces of non-coding DNA, sometimes referred to as junk DNA. Introns are edited out when the DNA is transcribed into RNA.
The tiny genetic change that can cause susceptibility to diabetes is located in intron 3, at a location dubbed University of Chicago Single Nucleotide Polymorphism-43. It is an alternative version of a single building block of DNA, shifting an adenine (A) to a guanine (G), changing just one of the three billion base pairs that make up the human genome. This minute alteration of the DNA acts in a recessive manner; individuals who inherit two copies of the G version have increased risk for diabetes.
Finding a significant mutation in an intron is almost, but not entirely, unheard of, noted Bell.
Susceptibility to diabetes, however, turns out to be still more complex. Two other tiny genetic variations within the same gene appear to act together with UCSNP-43 to affect risk. Curiously, patients most at risk had two different versions of the gene at these additional two sites.
The researchers suspect that these genetic variations work together to alter the way the gene is expressed in different tissues. They propose a two-hit model, where one version alters calpain 10 expression in the pancreas, and the other version alters expression in muscle or fat cells, tissues that either use or store glucose.
Because the discovery was so surprising and the techniques so innovative, the referees for Nature Genetics requested a series of supporting studies to help verify the finding, delaying publication of the study by nearly 18 months.
One of the supporting studies is a paper that is published in the October issue of the Journal of Clinical Investigation. This study demonstrates the effect of the gene variation in a different ethnic group at extremely high risk for diabetes, the Pima Indians.