New Compound Improves Glucose Tolerance of Diabetes without Associated Nausea

Chemist Robert Doyle in the College of Arts and Sciences (A&S) at Syracuse University has figured out how to control glucose levels in the bloodstream without the usual side effects of nausea, vomiting or malaise.

Robert Doyle, the Laura J. and L. Douglas Meredith Professor of Teaching Excellence and professor of chemistry, is the inventor of a new compound that triggers the secretion of insulin in the pancreas without associated nausea. Working with colleagues at the University of Pennsylvania (Penn), the Seattle Children’s Hospital and SUNY Upstate Medical University, he has designed a conjugate of vitamin B12 that is bound to an FDA-approved drug known as Ex4.

Doyle’s compound, called B12-Ex4, expects to offer a broader scope of available treatment options for diabetes because of its ability to improve glucose tolerance without the associated side effects.

His findings are part of a groundbreaking paper he has co-authored in Diabetes, Obesity and Metabolism (John Wiley & Sons, 2018). A related paper of his addressing glucoregulation and appetite suppression is scheduled to run in Scientific Reports (Nature Publishing Group, 2018).

“This represents an interesting new paradigm for the treatment of Type 2 diabetes, using so-called GLP1-R agonist drugs, which make up a multi-billion dollar industry,” says Doyle, also an associate professor of medicine at SUNY Upstate. “Our findings highlight the potential clinical utility of B12-Ex4 conjugates as therapeutics to treat Type 2 diabetes, with reduced incidence of adverse effects.”

Type 2 diabetes is marked by increased levels of glucose in the blood or urine, when the body is unable to use or produce enough insulin. Long-term complications include eye, kidney or nerve damage; heart attack or stroke; or problems with the wound-healing process.

Doyle’s discovery stems from his work with exenatide, a drug that causes the pancreas to secrete insulin when glucose levels are high. (Insulin is a hormone that moves glucose from the blood to various cells and tissues, where the sugar turns into energy.) Used to treat Type 2 diabetes, exenatide is part of a large class of medications called incretin mimetics. These injectable drugs bind to glucagon-like peptide receptors (GLP1-R) to stimulate the release of insulin.

A drawback of exenatide is that GLP1-R is found in the pancreas and brain. Stimulating the receptor in the pancreas leads to positive aspects of glucose control, but doing so in the hypothalamus (the part of the brain coordinating the nervous system and pituitary gland) causes malaise and nausea.

“We were able to mitigate the side effects of exenatide by preventing it from entering the brain, while allowing it to penetrate other areas of the body, such as the pancreas,” says Doyle, whose research focuses on the chemistry of B12, exploiting its properties and dietary pathway for drug delivery. “Our ability to ‘fix’ Ex-4 as a proof of concept could impact obesity and cancer treatment, since we can use our drug system to prevent or modulate central nervous system [CNS]-mediated side effects. In the case of Ex-4, this [side effect] was chronic nausea.”

Critical to Doyle’s research are GLP-1R agonists–synthetic, peptide-based chemicals that bind to organs or cells, causing them to produce a biological response. These peptide conjugates of insulin are the only known hormones able to decrease blood-sugar levels by enhancing the secretion of insulin. They do this by reducing food intake and body weight.

Doyle says these drugs are effective for treating obesity, but many Type 2 diabetics are not obese or overweight: “In fact, they should avoid losing weight altogether.”

Add to that the prevalence of nausea or vomiting, and the chances of skipping doses or discontinuing treatment increase considerably. “These adverse effects are surprisingly under-investigated, and they limit the full, widespread use and efficacy of GLP-1R agonists for the treatment of metabolic disease,” he continues.

In response to critical need, Doyle’s lab has spearheaded the development of a next-generation incretin therapeutic that controls blood sugar without causing a reduction in food intake or change in eating behavior. “This method of conjugation is ideal for the future treatment of Type 2 diabetes,” says Doyle, adding that Syracuse University owns the patent on this work. “It also may be broadly beneficial to other therapeutics that would benefit from reduced CNS penetrance.”

Doyle collaborated with Matthew Hayes, associate professor of neuroscience in the Department of Psychiatry in Penn’s Perelman School of Medicine, in the project’s experimental design and execution.

Source: EurekAlert!


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Diabetes Doubles Chance of Developing Cataract

People with diabetes are twice as likely to develop cataract as the general population and the relative risk is highest in those aged between 45 and 54, according to a new study published in the journal Eye.

Researchers analysed medical records from 56,510 UK-based diabetes patients aged 40 or over and found that cataract was diagnosed at an overall rate of 20.4 per 1,000 people. This compares to a rate in the general population of 10.8 per 1,000.

Diabetics aged between 45 and 54 were considerably more likely than non-sufferers to develop cataract. Those diabetic patients aged between 45 and 49 were 4.6 times more likely to, and diabetics aged between 50 and 54 were 5.7 times more at risk than their healthy counterparts.

The study used data from the Clinical Practice Research Datalink, which covers around 7% of the UK population and is representative of the overall demographic with regard to age, sex and geographic distribution.

Cataract is one of the main causes of global sight loss. In a previous study by the Vision Loss Expert Group, it was revealed that the condition accounted for significant vision loss or blindness in 65million people worldwide.

Co-author Rupert Bourne, Professor of Ophthalmology at Anglia Ruskin University’s Vision and Eye Research Unit, said: “The report has shown that having diabetes doubles your risk of being diagnosed with a cataract, and that this risk is six times higher if a diabetic patient has significant diabetic retinal disease, called diabetic maculopathy.

“This is only the second such report on cataract incidence in the UK’s diabetic patients since the 1980s and it further emphasises the importance of the NHS Diabetic Eye Screening programme in early identification and treatment of diabetic eye disease to prevent sight loss.

“This is an interesting example of how a very large primary care dataset of electronic patient data, in this case the Clinical Practice Research Datalink, can be used to investigate risk factors for eye disease.”

Source: EurekAlert!


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Friendships May Be Your Defense Against Diabetes

Serena Gordon wrote . . . . . . . .

You probably lean on your friends in tough times. Now, new research suggests your pals might even help you prevent one very big health problem — type 2 diabetes.

In a study of nearly 3,000 middle-aged to elderly people in the Netherlands, researchers found that people who had social networks of 10 to 12 people were less likely to develop type 2 diabetes than people with only seven to eight close friends.

Each drop in a social network member was tied to a 5 percent to 12 percent higher risk of diabetes, the study found.

The investigators also found that men living alone were more likely to have type 2 diabetes, while living alone didn’t seem to affect a woman’s risk of having the blood sugar disease.

“A larger network size may have an important impact on an individual’s lifestyle,” said the study’s lead author, Stephanie Brinkhues. She’s a doctoral candidate at Maastricht University in the Netherlands.

“A larger network also means more access to social support when it is needed, more contacts outside the house, and therefore being more socially active. The larger social network may help people to improve their lifestyle, eat more healthy and be more physically active,” she said.

Those are important steps for preventing type 2 diabetes, which is linked to sedentary behavior and being overweight.

As to why men living alone might not do as well, the study’s senior author, Miranda Schram, suggested several possibilities.

“Potentially, men living alone may not take care of themselves as much as women in this situation,” said Schram, an associate professor at Maastricht University.

“They may have more unhealthy lifestyles, for instance, eating less fresh vegetables and fruit, being less physically active and, in general, health may be less an issue for them, compared to women living alone,” she added.

Schram’s advice to anyone at high risk of type 2 diabetes? Consider making new friends, volunteering or joining special-interest groups.

Both authors noted that this study wasn’t designed to prove a cause-and-effect relationship. However, other research has also found a link between type 2 diabetes and living alone or with less social support, which suggests that these factors might contribute to type 2 diabetes, they said.

But at least one doctor thinks that if isolation or social networks play some role in type 2 diabetes, it’s a small role.

Dr. Joel Zonszein is director of the Clinical Diabetes Center at Montefiore Medical Center in New York City.

“This was a very large and very impressive study, but there are still a lot of problems with the study,” he said.

One issue is with the design of the study itself. It only looks at one moment in time, and doesn’t account for changes that might have occurred in people’s lives.

Zonszein said there are so many other factors that can contribute to diabetes, it’s difficult to tease out the effect each one has, if any. The study authors did try to control for such factors, but it’s hard to account for all of them. Zonszein said more research is needed to see if these findings can be replicated.

In the meantime, he won’t be recommending extra social gatherings to his patients. “I don’t think having more friends or being less isolated will slow down the progression of diabetes,” he concluded.

However, the study authors stressed that people should be encouraged to expand their social network. Doing so could have additional health benefits, they said.

Study participants ranged in age from 40 to 75, with an average age of 60. About half were female, and 29 percent had type 2 diabetes.

The study was published online in BMC Public Health.

Source: HealthDay


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Study: Weight Management Programme Can Put Type 2 Diabetes into Remission

Almost half of participants achieved and maintained diabetes remission at one year without antidiabetic medications

Type 2 diabetes can be reversed following an intensive weight management programme, according a randomised trial in adults who have had the condition for up to 6 years, published in The Lancet.

The study showed that after 1 year, participants had lost an average of 10kg, and nearly half had reverted to a non-diabetic state without using any diabetes treatment. The findings lend support to the widespread use of this type of intervention in the routine care of type 2 diabetes across health services.

“Our findings suggest that even if you have had type 2 diabetes for 6 years, putting the disease into remission is feasible”, says Professor Michael Lean from the University of Glasgow who co-led the study. “In contrast to other approaches, we focus on the need for long-term maintenance of weight loss through diet and exercise and encourage flexibility to optimise individual results.”

Worldwide, the number of people with type 2 diabetes has quadrupled over 35 years, rising from 108 million in 1980 to 422 million in 2014. This is expected to climb to 642 million by 2040. This increase has been linked to rising levels of obesity and the accumulation of intra-abdominal fat. Type 2 diabetes affects almost 1 in 10 adults in the UK and costs the NHS around £14 billion a year.

“Rather than addressing the root cause, management guidelines for type 2 diabetes focus on reducing blood sugar levels through drug treatments. Diet and lifestyle are touched upon but diabetes remission by cutting calories is rarely discussed”, explains Professor Roy Taylor from Newcastle University, UK, who co-led the study.

“A major difference from other studies is that we advised a period of dietary weight loss with no increase in physical activity, but during the long-term follow up increased daily activity is important. Bariatric surgery can achieve remission of diabetes in about three-quarters of people, but it is more expensive and risky, and is only available to a small number of patients.”

Previous research by the same team confirmed the Twin Cycle Hypothesis-that type 2 diabetes is caused by excess fat within the liver and pancreas-and established that people with the disease can be returned to normal glucose control by consuming a very low calorie diet. But whether this type of intensive weight management is practicable and can achieve remission of type 2 diabetes in routine primary care was not known until now.

The Diabetes Remission Clinical Trial (DiRECT), published today, included 298 adults aged 20-65 years who had been diagnosed with type 2 diabetes in the past 6 years from 49 primary care practices across Scotland and the Tyneside region of England between July 2014 and August 2016. Practices were randomly assigned to provide either the Counterweight-plus weight management programme delivered by practice dieticians or nurses (149 individuals) or best practice care under current guidelines (control; 149 individuals).

The weight management programme began with a diet replacement phase, consisting of a low calorie formula diet (825-853 calories/day for 3 to 5 months), followed by stepped food reintroduction (2-8 weeks), and ongoing support for weight loss maintenance including cognitive behavioural therapy combined with strategies to increase physical activity. Antidiabetic and blood pressure-lowering drugs were all stopped at the start of the programme.

The primary outcomes were weight loss of 15 kg or more (sufficient to achieve remission of diabetes in most cases), and remission of diabetes. Remission was defined as achievement of a glycated haemoglobin A1c (HbA1c) level of less than 6.5% at 12 months, off all medications.

The weight loss programme was acceptable to most participants, with a dropout rate of 21%, mainly for social reasons (e.g., bereavement, change or loss of job, moving house). 128 (86%) participants in the weight management group and 147 (99%) participants in the control group attended the 12 month assessment. For those whose measurements of weight and HbA1c level were not available it was assumed that no remission had occurred.

Almost a quarter (36/149) of the weight management group achieved weight loss of 15 kg or more at 12 months, compared with none in the control group. Additionally, nearly half of the weight management group (68/149) achieved diabetes remission at 1 year, compared with six (4%) in the control group.

On average, participants in the weight management group shed 10 kg of bodyweight compared to 1 kg in the control group. Importantly, the results showed that remission was closely linked with the degree of weight loss and occurred in around 9 out of 10 people who lost 15 kg or more, and nearly three quarters (47/64) of those who lost 10 kg or more.

The researchers also noted an improvement in average triglyceride (blood lipid) concentrations in the weight management group, and almost half remained off all antihypertensive drugs with no rise in blood pressure. Furthermore, the weight management group reported substantially improved quality of life at 12 months, with a slight decrease reported in the control group.

Overall, one person experienced serious adverse events possibly related to the treatment (biliary colic and abdominal pain) but continued in the study.. Some participants experienced constipation, headache, and dizziness.

The authors note that the vast majority of participants were white and British, meaning that the findings may not apply to other ethnic and racial groups such as south Asians, who tend to develop diabetes with less weight gain.

According to Professor Taylor: “Our findings suggest that the very large weight losses targeted by bariatric surgery are not essential to reverse the underlying processes which cause type 2 diabetes. The weight loss goals provided by this programme are achievable for many people. The big challenge is long-term avoidance of weight re-gain. Follow-up of DiRECT will continue for 4 years and reveal whether weight loss and remission is achievable in the long-term.”

Writing in a linked Comment, Professor Emeritus Matti Uusitupa from the University of Eastern Finland discusses whether these findings should change treatment options for type 2 diabetes. He writes, “Lean and colleagues’ results, in addition to those from other studies of type 2 diabetes prevention and some smaller interventions in this setting, indicate that weight loss should be the primary goal in the treatment of type 2 diabetes… The DiRECT study indicates that the time of diabetes diagnosis is the best point to start weight reduction and lifestyle changes because motivation of a patient is usually high and can be enhanced by the professional health-care providers. However, disease prevention should be maintained as the primary goal that requires both individual-level and population-based strategies, including taxation of unhealthy food items to tackle the epidemic of obesity and type 2 diabetes.”

Source : Alpha Galileo


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For Older Adults with Diabetes, Losing Weight through Diet and Exercise Can Improve Blood Circulation in the Brain

Type 2 diabetes affects blood circulation. The disease stiffens blood vessels and reduces the amount of oxygen that circulates throughout your body. This includes your brain. When blood flow in the brain is impaired, it can affect the way we think and make decisions.

People who have type 2 diabetes are often overweight or obese. These are conditions that may also be linked to cognitive problems (problems with thinking abilities). Lowering calorie intake and increasing physical activity are known to reduce the negative effects of type 2 diabetes on the body. However, the effects of these interventions on cognition and the brain are not clear.

Recently, researchers examined information from a 10-year-long study called Action for Health in Diabetes (Look AHEAD). In this study, participants learned how to adopt healthy, long-term behavior changes. In their new study, the researchers focused on whether participants with type 2 diabetes who lowered calories in their diet and increased physical activity had better blood flow to the brain. The researchers published their findings in the Journal of the American Geriatrics Society.

Researchers assigned participants to one of two groups. The first group was called the Intensive Lifestyle Intervention. In this group, participants were given a daily goal of eating between 1200 to 1800 calories in order to lose weight, based on their initial weight. They also had a goal of 175 minutes of physical activity during the week, through activities such as brisk walking.

Participants were seen weekly for the first six months, and three times a month for the next six months. During years 2 through 4, they were seen at least once a month and were regularly contacted by phone or email. They were also encouraged to join group classes. At the study’s end, participants were encouraged to continue individual monthly sessions and other activities.

The second group was called the “control group”. The control group attended Diabetes Support and Education classes. The researchers compared the control group to the group that participated in the lifestyle intervention.

About ten years after enrollment, 321 participants completed an MRI brain scan. (An MRI scan is a non-invasive medical test that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed pictures of the brain.) 97 percent of those MRIs met quality control standards set by the researchers for their study.

During the study, the participants had their mental functions tested, including their verbal learning, memory, decision-making ability, and other cognitive functions.

The researchers looked at the group of adults who were overweight or obese at the beginning of the study. They concluded that in that group, those who did the long-term behavioral intervention had greater blood flow in the brain. Furthermore, blood flow tended to be greatest among those who did not do as well on tests of mental functions. This may show how the brain may adapt in response to cognitive decline.

However, the researchers also found that for the heaviest individuals, the intervention may have worked differently. This suggests that the intervention may have been most effective in increasing or maintaining blood flow in the brain for individuals who were overweight but not obese.

This summary is from “Long Term Impact of Intensive Lifestyle Intervention on Cerebral Blood Flow.” It appears online ahead of print in the Journal of the American Geriatrics Society.

Source: The AGS Foundation for Health in Aging


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