Body clock receptor linked to diabetes in new genetic study

A study published in Nature Genetics today has found new evidence for a link between the body clock hormone melatonin and type 2 diabetes. The study found that people who carry rare genetic mutations in the receptor for melatonin have a much higher risk of type 2 diabetes.

People who carry rare genetic mutations in the receptor for melatonin have a much higher risk of type 2 diabetes, according a study published in Nature Genetics

The findings should help scientists to more accurately assess personal diabetes risk and could lead to the development of personalised treatments.

Previous research has found that people who work night shifts have a higher risk of type 2 diabetes and heart disease. Studies have also found that if volunteers have their sleep disrupted repeatedly for three days, they temporarily develop symptoms of diabetes.

The body's sleep-wake cycle is controlled by the hormone melatonin, which has effects including drowsiness and lowering body temperature. In 2008, a genetic study led by Imperial College London discovered that people with common variations in the gene for MT2, a receptor for melatonin, have a slightly higher risk of type 2 diabetes.

The new study reveals that carrying any of four rare mutations in the MT2 gene increases a person's risk of developing type 2 diabetes six times. The release of insulin, which regulates blood sugar levels, is known to be regulated by melatonin. The researchers suggest that mutations in the MT2 gene may disrupt the link between the body clock and insulin release, leading to abnormal control of blood sugar.

Professor Philippe Froguel, from the School of Public Health at Imperial College London, who led the study, said: "Blood sugar control is one of the many processes regulated by the body's biological clock. This study adds to our understanding of how the gene that carries the blueprint for a key component in the clock can influence people's risk of diabetes.

"We found very rare variants of the MT2 gene that have a much larger effect than more common variants discovered before. Although each mutation is rare, they are common in the sense that everyone has a lot of very rare mutations in their DNA. Cataloguing these mutations will enable us to much more accurately assess a person's risk of disease based on their genetics."

In the study, the Imperial team and their collaborators at several institutions in the UK and France examined the MT2 gene in 7,632 people to look for more unusual variants that have a bigger effect on disease risk. They found 40 variants associated with type 2 diabetes, four of which were very rare and rendered the receptor completely incapable of responding to melatonin. The scientists then confirmed the link with these four variants in an additional sample of 11,854 people.

Professor Froguel and his team analysed each mutation by testing what effect they have on the MT2 receptor in human cells in the lab. The mutations that completely prevented the receptor from working proved to have a very big effect on diabetes risk, suggesting that there is a direct link between MT2 and the disease.

Source: Imperial College London [January 29, 2012]

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Molecular link between diabetes and cancer described

The fact that diabetes raises the risk of certain types of cancer is already well known, but the reasons have been unclear. Now researchers at Lund University in Sweden have mapped a molecular link that explains the connection between the two widespread diseases. 

Developing type 2 diabetes is a lengthy process. An early sign that it has begun is high levels of insulin in the blood. As long as the insulin-producing beta cells are able to compensate for the increased demand, for example when the individual is overweight, the blood sugar levels remain normal. It is not until the capacity for insulin secretion falls below the level needed that type 2 diabetes becomes a fact. The latter stage generally goes quickly, as the stressed beta cells work themselves to death. 

“We have worked with the most well-known risk gene for type 2 diabetes, a variant of the TCF gene, and have studied its function in the beta cells”, says Yuedan Zhou, a doctoral student at the Lund University Diabetes Centre and principal author of the published study. 

The risk variant of TCF is common, 25 per cent of the population carry it and 31 per cent of diabetics, according to figures from the Malmo Preventive Project population survey. 

An equally well-established risk gene in cancer research is p53. The gene has been called the “protector of the genome” because it prevents the uncontrolled cell division that takes place in cancer. The p53 gene has been linked to protection against colon and liver cancer, among others. 

“The function of the TCF gene in the beta cells is to protect the cells against high, stressful blood sugar levels. If that function fails, the beta cells die, which leads to diabetes”, says Ola Hansson, researcher and principal author of the survey. 

The two genes work in concert, TCF protects against cell death, while p53 prevents excessive cell division. 

“It is here that the connection between diabetes and cancer arises. When the blood sugar levels are high, the TCF gene is activated and this impedes the activity of the p53 gene thereby protecting the beta cells from cell death”. 

The research group began working with the TCF gene two years ago to understand its role in insulin production. The discovery of the link with p53 and cancer was mostly by chance. 

“Or good intuition”, they say. 

The mapping of the TCF gene is continuing, this time in collaboration with the European Bioinformatics Institute in Cambridge. 

Cancer researchers are working to try and influence p53 so that its tumour-preventing function is restored. 

“In a similar way, strengthening the protective function of TCF against beta cell death in connection with high blood sugar would work as a drug for type 2 diabetes, or as a treatment before the disease has even developed fully”, says Ola Hansson. 

Note: The full name of the risk variant is TCF7L2.  

Source: Lund University [November 15, 2011]

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Researchers identify diabetes link to cognitive impairment in older adults

Many complications of diabetes, including kidney disease, foot problems and vision problems are generally well recognized. But the disease's impact on the brain is often overlooked. 

For the past five years, a team led by Beth Israel Deaconess Medical Center (BIDMC) neurophysiologist Vera Novak, MD, PhD, has been studying the effects of diabetes on cognitive health in older individuals and has determined that memory loss, depression and other types of cognitive impairment are a serious consequence of this widespread disease. 

Now, Novak's team has identified a key mechanism behind this course of events. In a study published in the November 2011 issue of the journal Diabetes Care, they report that in older patients with diabetes, two adhesion molecules – sVCAM and sICAM – cause inflammation in the brain, triggering a series of events that affect blood vessels and, eventually, cause brain tissue to atrophy. Importantly, they found that the gray matter in the brain's frontal and temporal regions -- responsible for such critical functions as decision-making, language, verbal memory and complex tasks – is the area most affected by these events. 

"In our previous work, we had found that patients with diabetes had significantly more brain atrophy than did a control group," explains Novak, Director of the Syncope and Falls in the Elderly (SAFE) Program in the Division of Gerontology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "In fact, at the age of 65, the average person's brain shrinks about one percent a year, but in a diabetic patient, brain volume can be lowered by as much as 15 percent." 

Diabetes develops when glucose builds up in the blood instead of entering the body's cells to be used as energy. Known as hyperglycemia, this condition often goes hand-in-hand with inflammation. Novak wanted to determine if chronic inflammation of the blood vessels was causing altered blood flow to the brain in patients with diabetes. 

To test this hypothesis, Novak's team recruited 147 study subjects, averaging 65 years of age. Seventy one of the subjects had type 2 diabetes and had been taking medication to manage their conditions for at least five years. The other 76 were age and sex-matched non-diabetic controls. 

Study subjects underwent a series of cognitive tests, balance tests and standard blood-pressure and blood-glucose tests. Serum samples were also collected to measure adhesion molecules and several other markers of systemic inflammation. To determine perfusion (blood flow) measures in the brain, patients also underwent functional MRI testing, in which a specialized imaging technique known as arterial spin labeling (developed by BIDMC MR physicist David Alsop, PhD) was used in conjunction with a standard MRI to measure vascular reactivity in several brain regions and to show changes in blood flow. 

As predicted, the scans showed that the diabetic patients not only had greater blood vessel constriction than the control subjects, but they also had more atrophied brain tissue, particularly gray matter. The results also showed that, in the patients with diabetes, the frontal, temporal and parietal regions of the brain were most affected. Similarly, the team's measurements of serum markers confirmed that high glucose levels were strongly correlated with higher levels of inflammatory cytokines. 

"It appears that chronic hyperglycemia and insulin resistance – the hallmarks of diabetes – trigger the release of adhesion molecules [sVCAM and sICAM] and set off a cascade of events leading to the development of chronic inflammation," says Novak. "Once chronic inflammation sets in, blood vessels constrict, blood flow is reduced, and brain tissue is damaged. " 

This discovery now provides two biomarkers of altered vascular reactivity in the brain. "If these markers can be identified before the brain is damaged, we can take steps to try and intervene," says Novak, explaining that some data indicates that medications may improve vascoreactivity. 

But more important, she says, the new findings provide still more reason for doctors and patients to focus greater attention on the management – and prevention – of diabetes. 

"Cognitive decline affects a person's ability to successfully complete even the simplest of everyday tasks, such as walking, talking or writing," says Novak. "There are currently 25.8 million cases of type 2 diabetes in the United States alone, which is more than eight percent of our total population. The effects of diabetes on the brain have been grossly neglected, and, as our findings confirm, are issues that need to be addressed." 

Source: Beth Israel Deaconess Medical Center [November 08, 2011]

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Your stroke risk profile may also help predict your risk of memory problems

A new study shows a person's stroke risk profile, which includes high blood pressure, smoking, and diabetes, may also be helpful in predicting whether a person will develop memory and thinking problems later in the life. The research is published in the Nov. 8, 2011, issue of Neurology®, the medical journal of the American Academy of Neurology. 

Researchers in the REGARDS study followed 23,752 people with an average age of 64 who were free of stroke and cognitive problems at the start of the study. Participants underwent a Framingham Stroke Risk Profile, which is used to determine a person's risk of stroke by measuring their age, blood pressure, education level, history of heart disease, smoking and diabetes status, and whether they have left ventricular hypertrophy (a thickening of the heart muscle) and an abnormal heart rhythm. 

After an average of four years of follow-up, 1,907 people had developed memory and thinking problems. 

The study found the higher a person's score on the Stroke Risk Profile, the greater the chance of developing cognitive problems four years later. Fifteen percent of people who scored among the highest 25 percent on the Stroke Risk Profile test (greater than 11.99 points) had cognitive problems compared to three percent of those who scored among the bottom 25 percent with a score below 3.4 points. 

"Overall, it appears that the total Stroke Risk Profile score, while initially created to predict stroke, is also useful in determining the risk of cognitive problems," said study author Frederick Unverzagt, PhD, of Indiana University School of Medicine in Indianapolis. 

The study found older age and the presence of thickening in the heart muscle, which is a result of long-term high blood pressure, were the only Stroke Risk Profile factors independently associated with future cognitive problems. This association remained even after controlling for age, sex, race, where a person lived and education. In addition, the study also found high systolic blood pressure was related to cognitive problems in people without a thickening of the heart muscle. 

"Our findings suggest that elevated blood pressure and thickening of the heart muscle may provide a simple way for doctors to identify people at risk for memory and thinking problems," said Unverzagt. "Increased focus on preventing and treating high blood pressure may be needed to preserve cognitive health." 

Source: American Academy of Neurology [November 07, 2011]

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