Mutated Gene Tied to Diabetes in Some Groups
After years of effort, researchers have identified a genetic mutation that helps explain why the most common form of diabetes is particularly prevalent among Mexican Americans and certain other ethnic groups.
The discovery pinpoints a surprising new biochemical pathway to diabetes and suggests novel approaches to prevention, diagnosis and treatment.
About 4% of the world’s population suffers from Type 2, or adult-onset, diabetes. But nearly one in nine Mexican Americans, or 11%, is a victim, and this gene appears to be one of the major reasons why, according to the researchers.
A second paper suggests that the same gene mutation plays a role in the increased incidence of diabetes in Native Americans, and unpublished data indicates a similar role in African Americans. The mutation appears to be less common among whites.
“Finding this gene finally allows us to go after diabetes treatment strategies that address the underlying molecular defects rather than symptoms,” said geneticist Graeme Bell of the Howard Hughes Medical Institute at the University of Chicago Medical Center, the team leader.
The discovery, reported today in the journal Nature Genetics, represents a major advance in identifying individual genes in genetically complex diseases, such as diabetes and heart disease, where many genes are thought to increase the risk.
“Bell and colleagues’ achievement is a tour de force,” said Dr. Allen Spiegel, director of the National Institute of Diabetes and Digestive and Kidney Diseases. “Actually identifying susceptibility genes for diseases such as diabetes . . . has proved exceedingly difficult.”
Type 2 diabetes afflicts about 15 million Americans and as many as 2 million in California. It is characterized by a decreased output of insulin and a reduced ability of cells throughout the body to respond to insulin’s effects.
Although Type 2 diabetes was once largely restricted to people over the age of 40, the growing incidence of obesity in young people has led to its occurrence in children as young as 12. Obesity is the most important risk factor in the disorder.
Left untreated, diabetes results in the accumulation of glucose in the blood, slowly damaging the cardiovascular system, kidneys, eyes and nerves. Although Type 2 diabetes is sometimes treated with insulin, the most common treatment is the use of drugs to increase insulin production or to make cells more sensitive to its effects. Dietary restrictions and exercise are crucial in controlling the disease.
Researchers believe that 10 or more genes may be responsible for producing Type 2 diabetes, and several researchers have identified approximate locations of diabetes-related genes on at least four separate chromosomes. But identifying the actual genes has proved extremely difficult.
Bell and his group have now found one of those genes.
“This is progress because we have been clueless [about genetics] for so long,” said Dr. Robert Sherwin of Yale University, president of the American Diabetes Assn.
Bell’s group has been studying the genetics of diabetes for more than two decades. In 1996, working with Craig Hanis and his colleagues at the University of Texas at Houston, they reported that a crucial gene appeared to lie on a small section of chromosome 2, one of the 23 pairs of chromosomes that make up the human genetic blueprint. They called the gene NIDDM-1, for non-insulin-dependent diabetes mellitus, the older name for Type 2.
But the existence of NIDDM-1 has been controversial. Some groups who replicated Bell’s work found evidence to support its role, while others did not. That discrepancy is explained by the new results, which show that the gene mutation plays a large role in some ethnic groups and is absent in others.
Bell’s group “did a spectacular amount of work to home in on the gene,” said Dr. Alan Shuldiner of the University of Maryland at Baltimore. Studying DNA from 330 pairs of Mexican American brothers and sisters from Starr County, Texas, they eventually pinpointed the NIDDM gene and identified it as one that serves as the blueprint for a protein called calpain10.
To their great surprise, calpain10 is a protease--a protein that breaks down other proteins, snipping them into smaller segments. Calpain10 is found in tissues throughout the body, but nobody knows its precise function yet.
Until now, proteases were not thought to be involved in any pathways of insulin secretion or use. “No one was thinking about proteases,” Bell said.
The team found that people with the newly discovered mutation produce less calpain10 than do healthy individuals.
The gene for calpain10 is only one of several that increase the risk of diabetes, but Bell’s group estimates that it accounts for about 14% of diabetes cases among Mexican Americans. In contrast, when they looked at samples from white people in Finland and Germany, they found that the mutation was responsible for only about 4% of cases. The researchers hope their new finding will lead to the discovery of some of the other genes involved in diabetes.
Bell’s team also worked with geneticist Leslie Baier of the National Institute of Diabetes and Digestive and Kidney Diseases to look at the gene in Pima Indians, who have the world’s highest prevalence of Type 2 diabetes.
They report in the October issue of the Journal of Clinical Investigation that the calpain10 gene plays a major role in that population as well.
And Shuldiner has studied the mutation in African Americans and found, in as-yet-unpublished work, that the gene is responsible for as much as 25% of Type 2 diabetes in that group.
The findings are strikingly consistent with a 30-year-old theory that certain ethnic groups have evolved “thrifty” genes that have protected them during times of famine, but that are a danger in the current environment of nutritional overabundance.
Pimas with the mutated calpain10 gene thus demonstrate many characteristics associated with a more frugal energy balance, such as a decreased metabolic rate while sleeping and a tendency to “hoard” rather than “burn” glucose.
But the discovery doesn’t mean that a cure is just around the corner, said Sherwin. It “can’t be immediately translated into therapies, because we don’t really know what this gene does.”
