Posts tagged diabetes

The rare disorder Wolfram syndrome is caused by mutations in a single gene, but its effects on the body are far reaching. The disease leads to diabetes, hearing and vision loss, nerve cell damage that causes motor difficulties, and early death.

Now, researchers at Washington University School of Medicine in St. Louis, the Joslin Diabetes Center in Boston and the Novartis Institutes for BioMedical Research report that they have identified a mechanism related to mutations in the WFS1 gene that affects insulin-secreting beta cells. The finding will aid in the understanding of Wolfram syndrome and also may be important in the treatment of milder forms of diabetes and other disorders.

The study is published online in the journal Nature Cell Biology

“We found something we didn’t expect,” says researcher Fumihiko Urano, MD, PhD, associate professor of medicine in Washington University’s Division of Endocrinology, Metabolism and Lipid Research. “The study showed that the WFS1 gene is crucial to producing a key molecule involved in controlling the metabolic activities of individual cells.” That molecule is called cyclic AMP (cyclic adenosine monophosphate).

Insulin-secreting beta cells in the pancreas (above) cannot make enough cyclic AMP in patients with Wolfram syndrome. As a result, the pancreas produces and secretes less insulin, and the cells eventually die.

In insulin-secreting beta cells in the pancreas, for example, cyclic AMP rises in response to high blood sugar, causing those cells to produce and secrete insulin.

“I would compare cyclic AMP to money,” Urano says. “You can’t just take something you make to the store and use it to buy food. First, you have to convert it into money. Then, you use the money to buy food. In the body, external signals stimulate a cell to make cyclic AMP, and then the cyclic AMP, like money, can ‘buy’ insulin or whatever else may be needed.”

The reason patients with Wolfram syndrome experience so many problems, he says, is because mutations in the WFS1 gene interfere with cyclic AMP production in beta cells in the pancreas.

“In patients with Wolfram syndrome, there is no available WFS1 protein, and that protein is key in cyclic AMP production,” he explains. “Then, because levels of cyclic AMP are low in insulin-secreting beta cells, those cells produce and secrete less insulin. And in nerve cells, less cyclic AMP can lead to nerve cell dysfunction and death.”

By finding that cyclic AMP production is affected by mutations in the WFS1 gene, researchers now have a potential target for understanding and treating Wolfram syndrome.

“I don’t know whether we can find a way to control cyclic AMP production in specific tissues,” he says. “But if that’s possible, it could help a great deal.”

Meanwhile, although Wolfram syndrome is rare, affecting about 1 in 500,000 people, Urano says the findings also may be important to more common disorders.

“It’s likely this mechanism is related to diseases such as type 2 diabetes,” he says. “If a complete absence of the WFS1 protein causes Wolfram syndrome, perhaps a partial impairment leads to something milder, like diabetes.”

(Source: news.wustl.edu)

A drug designed for diabetes sufferers could have the potential to treat neurodegenerative diseases like Alzheimer’s, a study by scientists at the University of Ulster has revealed.

Type II diabetes is a known risk factor for Alzheimer’s and it is thought that impaired insulin signalling in the brain could damage nerve cells and contribute to the disease.

Scientists believe that drugs designed to tackle Type II diabetes could also have benefits for keeping our brain cells healthy.

To investigate this, Prof Christian Hölscher and his team at the Biomedical Sciences Research Institute on the Coleraine campus used an experimental drug called (Val8)GLP-1.

This drug simulates the activity of a protein called GLP-1, which can help the body control its response to blood sugar. The scientists treated healthy mice with the drug and studied its effects in the brain.

Although it is often difficult for drugs to cross from the blood into the brain, the team found that (Val8)GLP-1 entered the brain and appeared to have no side-effects at the doses tested.

The drug promoted new brain cells to grow in the hippocampus, an area of the brain known to be involved in memory. This finding suggests that as well as its role in insulin signalling, GLP-1 may also be important for the production of new nerve cells in the mouse brain.

The team found that blocking the effect of GLP-1 in the brain made mice perform more poorly on learning and memory task, while boosting it with the drug seemed to have no effect on behaviour.

The new findings, published this week in the journal Brain Research, are part of ongoing research funded by Alzheimer’s Research UK, the leading dementia research charity.

Prof Hölscher, said: “Here at the Biomedical Sciences Research Institute, we are really interested in the potential of diabetes drugs for protecting brain cells from damage and even promoting new brain cells to grow. This could have huge implications for diseases like Alzheimer’s or Parkinson’s, where brain cells are lost.

“It is very encouraging that the experimental drug we tested, (Val8)GLP-1, entered the brain and our work suggests that GLP-1 could be a really important target for boosting memory. While we didn’t see benefits on learning and memory in these healthy mice, we are keen to test the drugs in mice with signs of Alzheimer’s disease, where we could see real improvements.”

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, said: “We are pleased to have supported this early stage research, suggesting that this experimental diabetes drug could also promote the growth of new brain cells. While we know losing brain cells is a key feature of Alzheimer’s, there is a long way to go before we would know whether this drug could benefit people with the disease.

"This research will help us understand the factors that keep nerve cells healthy, knowledge that could hold vital clues to tackling Alzheimer’s. With over half a million people in the UK living with the disease, learning more about how to keep our brain cells healthy is of vital importance. Funding for dementia research lags far behind that of other common diseases, but is essential if we are to realise the true potential of research like this.”

(Source: alphagalileo.org)

September 3, 2012

People whose blood sugar is on the high end of the normal range may be at greater risk of brain shrinkage that occurs with aging and diseases such as dementia, according to new research published in the September 4, 2012, print issue of Neurology, the medical journal of the American Academy of Neurology.

"Numerous studies have shown a link between type 2 diabetes and brain shrinkage and dementia, but we haven’t known much about whether people with blood sugar on the high end of normal experience these same effects," said study author Nicolas Cherbuin, PhD, with Australian National University in Canberra.

The study involved 249 people age 60 to 64 who had blood sugar in the normal range as defined by the World Health Organization. The participants had brain scans at the start of the study and again an average of four years later.

Those with higher fasting blood sugar levels within the normal range and below 6.1 mmol/l (or 110 mg/dL) were more likely to have a loss of brain volume in the areas of the hippocampus and the amygdala, areas that are involved in memory and cognitive skills, than those with lower blood sugar levels. A fasting blood sugar level of 10.0 mmol/l (180 mg/dL) or higher was defined as diabetes and a level of 6.1 mmol/l (110 mg/dL) was considered impaired, or prediabetes.

After controlling for age, high blood pressure, smoking, alcohol use and other factors, the researchers found that blood sugar on the high end of normal accounted for six to 10 percent of the brain shrinkage.

"These findings suggest that even for people who do not have diabetes, blood sugar levels could have an impact on brain health," Cherbuin said. "More research is needed, but these findings may lead us to re-evaluate the concept of normal blood sugar levels and the definition of diabetes."

Source: medicalxpress.com

An unhealthy diet could lead to Alzheimer’s disease by triggering a form of insulin resistance dubbed “type three diabetes”, scientists claim.

Photo: Getty Images/Peter Macdiarmid

High levels of the hormone insulin, brought on by a bad diet, may harm the brain in the same way that the muscle, liver and fat cells are affected by type two diabetes. Exposing the brain to too much insulin could cause it to stop responding to the hormone, hampering our ability to think and create new memories and ultimately leading to permanent damage, researchers said.

A diet high in fat and sugar has long been linked to a higher risk of Alzheimer’s, while studies of health among large populations have shown that a healthy Mediterranean diet may offer some protection. In type two diabetes, eating too much fatty and sugary food raises our insulin levels to such a consistently high degree that our muscles, fat and liver cells are no longer affected by the hormone.

This means that the amount of glucose and fat in our blood is allowed to increase unchecked, forcing the pancreas to produce even more insulin to try to cope. Ultimately it becomes exhausted and production drops to very low levels.

A small-scale trial on human patients at Washington University found that those who were given a nasal spray containing insulin were better at remembering details of stories, had longer attention spans and were more independent. A further trial on 240 volunteers showing early signs of dementia will provide further clues as to whether the spray can protect memory and learning ability and keep track of brain changes in patients.

A study on rats by experts from Brown University suggest that a similar process could affect the brain, which relies on insulin to regulate nerve signals related to memory and learning and to produce energy from glucose. Researchers found that blocking insulin from rats’ brains made them disorientated and unable to find their way out of a maze because they could not remember where they were.

Examination of their brains showed the same pattern of deterioration seen in Alzheimer’s patients, including increased levels of the amyloid plaque which is a key hallmark of the condition. If the theory is correct, it means eating more healthy foods and exercising more could reduce the risk of Alzheimer’s, and potentially reverse or slow down the memory loss in patients with the condition.

Dr Suzanne de la Monte, who led the study, told New Scientist magazine: “[The rats] were demented. They couldn’t learn or remember. “I believe [Alzheimer’s] starts with insulin resistance. If you can avoid brain diabetes you’ll be fine. But once it gets going you are going to need to attack on multiple fronts.”

(Source: telegraph.co.uk)

ScienceDaily (Aug. 9, 2012) — Manipulating a group of hormone-producing cells in the brain can control blood sugar levels in the body — a discovery that has dramatic potential for research into weight-loss drugs and diabetes treatment.

Erik Johnson uses the fruit fly, Drosophila, to look at an enzyme called AMP-activated kinase and its role in signaling the hormone that elevates the level of sugar in the blood. (Credit: Image courtesy of Wake Forest University)

In a paper published in the October issue of Genetics and available online now, neurobiologists at Wake Forest University examine how fruit flies (Drosophila) react when confronted with a decreased diet.

Reduced diet or starvation normally leads to hyperactivity in fruit flies — a hungry fly buzzes around feverishly, looking for more food. That happens because an enzyme called AMP-activated kinase stimulates the secretion of the adipokinetic hormone, which is the functional equivalent of glucagon. This hormone acts opposite of insulin, as it tells the body to release the sugar, or food, needed to fuel that hyperactivity. The body uses up its energy stores until it finds food.

But when Wake Forest’s Erik Johnson, an associate professor of biology, and his research team turned off AMP-activated kinase, the cells decreased sugar release and the hyperactive response stopped almost completely — even in the face of starvation.

"Since fruit flies and humans share 30 percent of the same genes and our brains are essentially wired the same way, it suggests that this discovery could inform metabolic research in general and diabetes research specifically," said Johnson, the study’s principal investigator. "The basic biophysical, biochemical makeup is the same. The difference in complexity is in the number of cells. Why flies are so simple is that they have approximately 100,000 neurons versus the approximately 11 billion in humans."

Medical advances as a result of this research might include:

• Diabetes research: Adipokinetic hormone is the insect equivalent to the hormone glucagon in the human pancreas. Glucagon raises blood sugar levels; insulin reduces them. However, it is difficult to study glucagon systems because the pancreatic cells are hard to pull apart. Studying how this similar system works in the fruit fly could pave the way to a drug that targets the cells that cause glucagon to tell the body to release sugar into the blood — thus reducing the need for insulin shots in diabetics.

• Weight-loss drugs: An “exercise drug” would turn on all AMP-activated kinase in the body and trick the body into thinking it was exercising. “Exercise stimulates AMP-activated kinase, so manipulation of this molecule may lead to getting the benefits of exercise without exercising,” Johnson said. In previous research published in the online journal PLoS ONE, Johnson and his colleagues found that, when you turn off AMP-activated kinase, you get fruit flies that “eat a lot more than normal flies, move around a lot less, and end up fatter.”

Source: Science Daily

ScienceDaily (Aug. 1, 2012) — Scientists have known for some time that throwing off the body’s circadian rhythm can negatively affect body chemistry. In fact, workers whose sleep-wake cycles are disrupted by night shifts are more susceptible to chronic inflammatory diseases such as diabetes, obesity and cancer.

Researchers at the Salk Institute for Biological Studies have now found a possible molecular link between circadian rhythm disturbances and an increased inflammatory response. In a study published July 9 in Proceedings of the National Academy of Sciences, the Salk team found that the absence of a key circadian clock component called cryptochrome (CRY) leads to the activation of a signaling system that elevates levels of inflammatory molecules in the body.

"There is compelling evidence that low-grade, constant inflammation could be the underlying cause of chronic diseases such as diabetes, obesity and cancer," says senior author Inder Verma, a professor in Salk’s Laboratory of Genetics and the Irwin and Joan Jacobs Chair in Exemplary Life Science. "Our results strongly indicate that an arrhythmic clock system, induced by the absence of CRY proteins, alone is sufficient to increase the stress level of cells, leading to the constant expression of inflammatory proteins and causing low-grade, chronic inflammation."

Cryptochrome serves as a break to slow the circadian clock’s activity, signaling our biological systems to wind down each evening. In the morning, CRY stops inhibiting the clock’s activity, helping our physiology ramp up for the coming day.

To gain insight into the role of circadian clock components on immune function, the Salk scientists measured the expression of inflammatory mediators in the hypothalamus (the area of the brain responsible for sleep-wake cycle regulation) of mice with deleted CRY genes. Through a variety of tests, these knockout mice showed a significant increase in the expression of certain inflammatory proteins known as cytokines, including interleukin-6 and tumor necrosis factor-α, compared to mice with CRY genes.

"Our findings demonstrate that a lack of cryptochrome activates these proinflammatory molecules, indicating a potential role for cryptochrome in the regulation of inflammatory cytokine expression," says Satchidananda Panda, an associate professor in Salk’s Regulatory Biology Laboratory and one of the senior authors of the study.

In addition, the researchers found that a lack of CRY activated the NF-kB pathway, a molecular signaling conduit that controls many genes involved in inflammation. NF-kB is a protein complex in a cell’s cytoplasm, “just happily doing nothing,” says Verma. In response to stimuli, it is transferred to the cell’s nucleus, where it binds to inflammation genes and turns them on. The regulation of these genes is tightly controlled, but NF-kB does not completely shut off their expression. This lingering expression causes inflammation.

"Every time this pathway is turned on, there is a residual amount of inflammation left in the body," says Rajesh Narasimamurthy, a research associate in Verma’s laboratory and the paper’s first author. "That adds up over time, contributing to inflammation-related diseases like obesity and diabetes."

Previous research has shown that suppressing the activity of the NF-kB pathway might be a suitable therapy for some diseases. For example, NF-kB is activated automatically in cancer cells of multiple myeloma, which affects infection-fighting plasma cells in the bone marrow and allows the cells to proliferate. Drugs that inhibit this activity might be able to degrade NF-kB to the point that it may kill off the disease.

The researchers say the goal now is to find out how to suppress NF-kB activation in the short term to treat diseases like diabetes. They caution that any long-term suppression of the pathway could lead to chronic infection. “We would like to find molecules that modify this activity and focus on those small-molecule inhibitors to treat disease,” Verma adds.

Source: Science Daily