Genes Play A Role In Glycemic Control In People With Type 1 Diabetes

Main Category: Diabetes
Article Date: 08 Jun 2009 - 7:00 PST

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Researchers have proven that glycemic control in type 1 diabetes is not fully dependent on the individual's behavior, but is in part subject to genetic influence, according to a presentation here today at the American Diabetes Association's 69th Scientific Sessions.

"We identified four genes related to glycemic control in type 1 diabetes," said Andrew D. Paterson, MBChB, Senior Scientist in the Program for Genetics and Genome Biology, Hospital for Sick Children in Toronto, and lead author of the study. "Two of these genes also affect risk for complications -- kidney, eye, and cardiovascular disease -- and one gene has a strong effect on the rate of hypoglycemia."

"This finding does not give people with diabetes the freedom to slack off on their careful nutrition, exercise, and medication regimens because behavior clearly plays the major role in glycemic control," cautioned Dr. Paterson. "Eventually, the genetic variations we found may be used to identify individuals at risk for poor glycemic control and for diabetic complications, so that steps could be taken to intensify control or implement other measures. But in the interim, this knowledge may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications and lead us in new research directions to better understand the mechanisms of glycemic control."

Nearly 24 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputation. It is a leading cause of death by disease in the United States.

Type 1 is an immune-mediated form of diabetes involving destruction of the insulin-producing beta cells in the pancreas that typically leads to absolute insulin deficiency. Type 1 diabetes accounts for 5% to 10% of all diagnosed cases of diabetes and usually strikes children or young adults, although disease onset can occur at any age.

The first data suggesting that A1C, a measure of average glucose control over the prior two to three months, might be influenced by genetics came in 2001 in a British study looking at identical twins, where one twin had type 1 and the other did not, called discordance. "It was found that when the twin without diabetes had an A1C in the high normal range, the twin with diabetes would have an A1C in the high range for someone with diabetes," said Dr. Paterson. "Essentially, they were playing to the same drummer but in a different key."

In the current study, the researchers mined the extensive data available from one of the world's most well-documented studies of people with type 1 diabetes: the Diabetes Control and Complications Trial (DCCT) -- an NIH-sponsored study. It was initiated over 25 years ago and enrolled 1,441 people in a comparison of intensive versus conventional control of blood glucose. Conventional control during the DCCT required only one or two insulin injections and blood checks daily, with the aim of preventing overt diabetes symptoms, and typically yields A1C levels of 9% or more. Intensive control to bring A1C levels as close to normal as possible (6% or less) required at least three insulin injections a day or treatment with an insulin pump, guided by at least four glucose self-monitoring checks a day. The initial results, reported in 1993, demonstrated dramatic reductions in the development of eye, nerve, and kidney damage. Intensive control also lowered the risk of heart disease according to data published in 2005 as part of the follow-up study of DCCT participants, called the Epidemiology of Diabetes Interventions and Complications (EDIC) observation study, which is still continuing.

The researchers in this genetic study had access to every quarterly A1C test performed on people in the original DCCT over the course of an average of 6 1/2 years. To identify important genetic loci (the positions that genes occupy on a chromosome) influencing glycemic control in type 1, they performed high resolution genome-wide studies using the mean A1C values and capillary glucose of people in the conventional treatment group and compared loci of interest to people in the intensive treatment group.

They determined the genotypes of a million SNPs across the genome for over 1,300 participants in the DCCT. (SNPs are single-nucleotide polymorphisms, pronounced "snips" -- DNA sequence variations in the genome.) Each of these SNPs was tested for association with the participants' average A1Cs over the course of the trial.

They identified four major gene loci related to A1C levels. One in both treatment groups reached genome-wide significance -- SORCS1 gene 10q25.1. Three achieved close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups; and 15q21.3 (WDR72) in the intensive group. Further, evidence indicated that SORCS1 was associated with hypoglycemia (low blood glucose), and BNC2 was associated with kidney and eye complications.

"While this information gives us insight into the mechanisms influencing glycemic control in people with type 1, it is important to remember that the overall influence of genes is small and may vary from person to person and, perhaps, in response to behavior," Dr. Paterson explained. "For example, while the SORCS1 gene accounted for about 5% of the variability in glycemic control in the conventional treatment arm of the DCCT, A1C levels in people with type 1 diabetes have improved since those days as diabetes care teams and patients have learned about the value of more intensive control," he said. "So we don't know whether that number would be the same in a contemporary treatment setting." For example, in the EDIC study, A1C levels of the former conventional control group dropped from 9% to 8.1% after they were taught intensive control at the end of the DCCT.

Source
American Diabetes Association

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