Gene Variant Increases Risk of Type 2 Diabetes
But Healthy Lifestyle Changes Reduce Genetic Risk
Researchers have confirmed that a gene variant confers susceptibility to type
2 diabetes in participants of the Diabetes Prevention Program (DPP), a large
clinical trial in adults at increased risk for developing type 2 diabetes. The
finding, published in the July 20, 2006, issue of the New England Journal of
Medicine, follows the discovery by deCode Genetics that a variant in a gene called
TCF7L2 predisposes people to type 2 diabetes.
“The DPP is an outstanding example of a robust clinical trial that continues
to answer crucial questions about the etiology and prevention of type 2 diabetes,
a complex disease that is steadily rising throughout the nation and the world,” said
National Institutes of Health (NIH) Director Elias A. Zerhouni, M.D. The NIH,
which sponsored the DPP, continues to fund the follow-up study of DPP participants.
The researchers were delighted to observe that even the participants at highest
genetic risk benefited from healthy lifestyle changes as much or perhaps more
than those who did not inherit the variant. “The lifestyle intervention reduced
risk even in those who carried both copies of the risk variant,” said lead author
Jose Florez, M.D., Ph.D., of Massachusetts General Hospital (MGH) in Boston. “This
finding emphasizes that people at risk of diabetes, whether they’re overweight,
have elevated blood glucose levels, or have this particular genetic variant,
can benefit greatly by implementing a healthy lifestyle.”
Launched in 1995, the DPP ended in 2001, a year earlier than planned because
the results were so clear. The researchers published their main findings in 2002
(http://www.nih.gov/news/pr/feb2002/hhs-06.htm).
The 3,234 people who took part in the study were adults with blood glucose readings
that were higher than normal but not yet in the diabetic range. Most were significantly
overweight. Nearly half were minorities, who are at disproportionately high risk
for diabetes. Those who lost 5 to 7 percent of weight by cutting calories in
their diet and increasing physical activity (e.g., walking 5 days a week 30 minutes
a day) reduced the onset of type 2 diabetes by 58 percent. Treatment with metformin
lowered the chances of developing diabetes by 31 percent.
The DPP participants randomly assigned to lifestyle changes received guidance
from a dietitian and lifestyle coach during the study. Most adults at risk for
diabetes don’t have access to such support. “Finding better ways to predict who
is at greatest risk for developing diabetes might focus interventions on those
most likely to benefit,” says Sanford Garfield, Ph.D., of the National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK), which spearheaded the
DPP.
The newly identified gene variant, or allele, is located on chromosome 10q25.3.
It is a single nucleotide polymorphism (SNP), or single base pair change, in
the region of a gene that codes for a transcription factor — a protein that acts
like a “master switch” regulating the expression of other genes. In their DNA
analysis, the researchers found one copy of the risk variant in 40 percent of
DPP participants, and two copies in 10 percent. “For the 10 percent of people
who inherited two copies of the variant, the risk of developing diabetes is about
80 percent higher than it is for non-carriers,” explained Dr. Florez.
The DPP Genetics subgroup conducted the study in a multi-institutional collaborative
effort.* Its findings build on the deCode Genetics report, published online in
Nature Genetics in January 2006, by:
- confirming the finding in an independent population that included the racial
and ethnic diversity typical of the U.S. population with diabetes
- showing that the gene variant increases risk in those with pre-diabetes,
and in a prospective study where patients are followed over time
- examining for the first time the relationship between the genetic risk factor
and interventions that delay diabetes onset, and
- showing that the gene variant affects insulin production, not cells’ response
to insulin.
The hallmarks of type 2 diabetes are insulin resistance — the inability of target
tissues to respond to insulin — and a gradual failure of beta cells to produce
enough insulin. “This variant of TCF7L2 is associated with decreased insulin
production, but not with any increase in insulin resistance,” said DPP study
chair David M. Nathan, M.D., of MGH.
“Our data, combined with previous longitudinal studies and genetic findings,
show that type 2 diabetes can be triggered by decreased insulin production and
not just by insulin resistance. However, researchers need to learn more about
this gene before they can even begin to translate the discovery into a drug treatment
that benefits people with diabetes or those at risk,” added Dr. Florez.
About 20.8 million people in the United States — 7 percent of the population — have
diabetes, the most common cause of blindness, kidney failure, and amputations
in adults and a major cause of heart disease and stroke. Type 2 diabetes accounts
for up to 95 percent of all diabetes cases. The prevalence of this form of diabetes
has skyrocketed in the last 30 years, due mostly to the upsurge in obesity. In
addition, at least 54 million U.S. adults age 20 and older have pre-diabetes,
which independently raises the risk of developing type 2 diabetes and cardiovascular
disease.
While this genetic variant does predict a greater risk of developing type 2
diabetes in addition to the recognized risk factors such as being age 45 and
older, overweight, inactive, and having history of gestational diabetes, the
researchers are not recommending routine genetic testing for it. “We don’t currently
have evidence that such a test would mean better outcomes for patients or that
it would be cost-effective,” said principal investigator of the DPP Genetics
Project, David Altshuler, M.D., Ph.D., of MGH and the Broad Institute of Harvard
and MIT.
As scientists probe deeper into the genetic underpinnings of type 2 diabetes,
they have found a number of genes that raise a person’s risk for developing type
2 diabetes. Testing these variants in the DPP may lead to a better understanding
of their role in the progression from “pre-diabetes” to overt diabetes, and whether
they influence interventions shown to reduce risk of getting the disease.
The “Small Steps. Big Rewards. Prevent Type 2 Diabetes” campaign of the National
Diabetes Education Program (NDEP) is based on the results of the DPP. The Program,
sponsored by the NIH, the Centers for Disease Control and Prevention, and 200
partner organizations, is reaching out to people at risk for type 2 diabetes,
e.g., the elderly, minorities, and women with a history of gestational diabetes,
with the message that they have the power to turn the tide against this disease.
The NDEP (www.ndep.nih.gov/) is providing
those at risk and their health care providers with the tools for lifestyle change
proven effective in the DPP.
The NIDDK funds a great deal of research to improve ways to treat and prevent
diabetes. Recently, NIDDK’s Central Repository (https://www.niddkrepository.org),
which houses data collected in large clinical trials funded by the Institute,
made data from the DPP available to researchers free of charge.
The NIDDK, part of the NIH, also conducts and supports research on other
endocrine and metabolic diseases; digestive diseases, nutrition, and obesity;
and kidney, urologic and hematologic diseases. Spanning the full spectrum of
medicine and afflicting people of all ages and ethnic groups, these diseases
encompass some of the most common, severe, and disabling conditions affecting
Americans.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov. |