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Type 2 Diabetes Accelerates Brain Aging and Cognitive Decline

Scientists have demonstrated that normal brain aging is accelerated by approximately 26% in people with progressive type 2 diabetes compared with individuals without the disease, reports a study published today in eLife.

The authors evaluated the relationship between typical brain aging and that seen in type 2 diabetes, and observed that type 2 diabetes follows a similar pattern of neurodegeneration as aging, but which progresses faster. One important implication of this finding is that even typical brain aging may reflect changes in the brain’s regulation of glucose by insulin.

The results further suggest that by the time type 2 diabetes is formally diagnosed, there may already be significant structural damage to the brain. Sensitive ways to detect diabetes-associated changes to the brain are therefore urgently needed.

There is already strong evidence linking type 2 diabetes with cognitive decline, yet few patients currently undergo a comprehensive cognitive assessment as part of their clinical care. It can be difficult to distinguish between normal brain aging that begins in middle age, and brain aging caused or accelerated by diabetes. To date, no studies have directly compared neurological changes in healthy people over the course of their lifespan with changes to those experienced by people of the same age with diabetes.

“Routine clinical assessments for diagnosing diabetes typically focus on blood glucose, insulin levels and body mass percentage,” says first author Botond Antal, a PhD student at the Department of Biomedical Engineering, Stony Brook University, New York, US. “However, the neurological effects of type 2 diabetes may reveal themselves many years before they can be detected by standard measures, so by the time type 2 diabetes is diagnosed by conventional tests, patients may have already sustained irreversible brain damage.”

To define the impact of diabetes on the brain over and above normal aging, the team made use of the largest available brain structure and function dataset across human lifespan: UK Biobank data from 20,000 people aged 50 to 80 years old. This dataset includes brain scans and brain function measurements and holds data for both healthy individuals and those with a type 2 diabetes diagnosis. They used this to determine which brain and cognitive changes are specific to diabetes, rather than just aging, and then confirmed these results by comparing them with a meta-analysis of nearly 100 other studies.

Their analysis showed that both aging and type 2 diabetes cause changes in executive functions such as working memory, learning and flexible thinking, and changes in brain processing speed. However, people with diabetes had a further 13.1% decrease in executive function beyond age-related effects, and their processing speed decreased by a further 6.7% compared to people of the same age without diabetes. Their meta-analysis of other studies also confirmed this finding: people with type 2 diabetes had consistently and markedly lower cognitive performance compared to healthy individuals who were the same age and similarly educated.

The team also compared brain structure and activity between people with and without diabetes using MRI scans. Here, they found a decrease in grey brain matter with age, mostly in a region called the ventral striatum – which is critical to the brain’s executive functions. Yet people with diabetes had even more pronounced decreases in grey matter beyond the typical age-related effects – a further 6.2% decrease in grey matter in the ventral striatum, but also loss of grey matter in other regions, compared with normal aging.

Together, the results suggest that the patterns of type 2 diabetes-related neurodegeneration strongly overlap with those of normal aging, but that neurodegeneration is accelerated. Moreover, these effects on brain function were more severe with increased duration of diabetes. In fact, progression of diabetes was linked with a 26% acceleration of brain aging.

“Our findings suggest that type 2 diabetes and its progression may be associated with accelerated brain aging, potentially due to compromised energy availability causing significant changes to brain structure and function,” concludes senior author Lilianne Mujica-Parodi, Director of the Laboratory for Computational Neurodiagnostics, Stony Brook University. “By the time diabetes is formally diagnosed, this damage may already have occurred. But brain imaging could provide a clinically valuable metric for identifying and monitoring these neurocognitive effects associated with diabetes. Our results underscore the need for research into brain-based biomarkers for type 2 diabetes and treatment strategies that specifically target its neurocognitive effects.”


Source: elife

How the Timing of Dinner and Genetics Affect Individuals’ Blood Sugar Control

Michael Morrison wrote . . . . . . . . .

Blood sugar control, which is impaired in individuals with diabetes, is affected by various factors—including the timing of meals relative to sleep as well as levels of melatonin, a hormone primarily released at night that helps control sleep-wake cycles. In research published in Diabetes Care, a team led by investigators at Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH) and the University of Murcia in Spain conducted a clinical trial to look for connections between these two factors.

“We decided to test if late eating that usually occurs with elevated melatonin levels results in disturbed blood sugar control,” says senior author Richa Saxena, PhD, a principal investigator at the Center for Genomic Medicine at MGH.

For the randomized crossover study that included 845 adults from Spain, each participant fasted for eight hours and then for the next two evenings had first an early meal and then a late meal relative to their typical bedtime. The investigators also analyzed each participant’s genetic code within the melatonin receptor-1b gene (MTNR1B) because previous research has linked a variant (called the G-allele) in MTNR1B with an elevated risk of type 2 diabetes.

“In natural late eaters, we simulated early and late dinner timing by administering a glucose drink and compared effects on blood sugar control over two hours,” explains Saxena. “We also examined differences between individuals who were carriers or not carriers of the genetic variant in the melatonin receptor.”

The team found that melatonin levels in participants’ blood were 3.5-fold higher after the late dinner. The late dinner timing also resulted in lower insulin levels and higher blood sugar levels. (This connection makes sense because insulin acts to decrease blood sugar levels.) In the late dinner timing, participants with the MTNR1B G-allele had higher blood sugar levels than those without this genetic variant.

“We found that late eating disturbed blood sugar control in the whole group. Furthermore, this impaired glucose control was predominantly seen in genetic risk variant carriers, representing about half of the cohort,” says lead author Marta Garaulet, PhD, a professor of physiology and nutrition in the Department of Physiology at the University of Murcia.

Experiments revealed that the high melatonin levels and carbohydrate intake associated with late eating impairs blood sugar control through a defect in insulin secretion.

“Our study results may be important in the effort towards prevention of type 2 diabetes,” says co-senior author Frank A.J.L. Scheer, PhD, MSc, director of the Medical Chronobiology Program at BWH. “Our findings are applicable to about a third of the population in the industrialized world who consume food close to bedtime, as well as other populations who eat at night, including shift workers, or those experiencing jetlag or night eating disorders, as well as those who routinely use melatonin supplements close to food intake.”

The authors note that for the general population, it may be advisable to abstain from eating for at least a couple of hours before bedtime. “Genotype information for the melatonin receptor variant may further aid in developing personalized behavioral recommendations,” says Saxena. “Notably, our study does not include patients with diabetes, so additional studies are needed to examine the impact of food timing and its link with melatonin and receptor variation in patients with diabetes.”


Source: Massachusetts General Hospital

Chart: Where Diabetes Burdens Are Rising

Source : Statista

Statins: Good for the Heart, Maybe Not So Good for Diabetes

Steven Reinberg wrote . . . . . . . . .

Statins are proven to lower cholesterol, but they may also come with a downside for patients with diabetes: A new study finds they may make the blood sugar disease worse.

Researchers found that among those taking statins, 56% saw their diabetes progress, compared with 48% of those not taking statins. And the higher the dose of the statin, the faster the progression of the diabetes.

“This study should be a start to more research examining the balance of benefits and harms of statins in patients with diabetes,” said senior researcher Dr. Ishak Mansi. He is a professor in the Departments of Medicine and Data and Population Science at the University of Texas Southwestern in Dallas.

“We know well about the benefits of statins, but the harms are much less investigated,” Mansi said. “Specifically, what is the population that may benefit less from the use of statins for primary prevention or be harmed? Answering these questions impact hundreds of millions of patients and cannot be postponed.”

He cautioned that based solely on this one finding, no patient should stop taking their statins and that association does not prove causation.

For the study, Mansi and his colleagues collected data on more than 83,000 diabetic patients who used statins and more than 83,000 who didn’t.

Those who were taking statins were more likely to see their diabetes progress and need to start using insulin and other types of drugs to lower high blood sugar levels sooner than those who weren’t taking statins.

“The study may alert clinicians that they may need to pay close attention and expect to adjust anti-diabetes medications when they initiate statins,” Mansi said.

Dr. Joel Zonszein, an emeritus professor of medicine at the Albert Einstein College of Medicine in New York City, said that blood sugar is not the only key to managing type 2 diabetes.

“Management of type 2 diabetes is not centered on lowering blood sugars,” explained Zonszein, who wasn’t part of the study. “In addition to lifestyle changes, medications are often necessary to prevent or attenuate complications. Statins are highly effective in lowering cholesterol and protecting against heart attacks and strokes.”

Statins do not cause diabetes and the modestly increased rate in precipitating new-onset diabetes is well-known, though the exact mechanism remains unknown, he said.

“The benefits of statins in patients with type 2 diabetes are far greater than the potential side effects,” Zonszein added.

Millions of people have been treated with statins, and its widespread application has been a major public health advance, he noted.

Treatment of obesity, hypertension and high cholesterol is as important as improving glycemic control, Zonszein added, and statins are one of the best medications for these in patients with type 2 diabetes.

“When prescribing any medication, a careful balance between benefits and side effects is discussed between the health care provider and the patient,” Zonszein said. “In the case of statins, the benefits, particularly in patients with type 2 diabetes, are by far better than potential side effects.”

The report was published online in the journal JAMA Internal Medicine.


Source: HealthDay

Diabetes and Dementia Risk: Another Good Reason to Keep Blood Sugar in Check

Laura Williamson wrote . . . . . . . . .

There are many reasons to avoid getting diabetes, or to keep it controlled if you already have it: Higher risks for heart disease, stroke and for having a foot or leg amputation. But here’s another one: It’s a major risk factor for dementia.

While researchers are still investigating what causes that increased risk, one thing they do know is it’s linked to highs – and lows – in the body’s blood sugar levels.

“Whether it’s Type 1 or Type 2 diabetes, glycemic control is very important” for maintaining good brain health, said Rachel Whitmer, chief of the division of epidemiology at University of California, Davis and associate director of the school’s Alzheimer’s Disease Research Center. “This is another motivation to have good control.”

Good management of blood glucose levels is one of seven lifestyle changes people can make to support better heart and brain health, called Life’s Simple 7 by the American Heart Association. It’s a step that could potentially help more than 34.2 million people in the U.S. living with diabetes.

According to the Centers for Disease Control and Prevention, the vast majority of people with diabetes have Type 2, which becomes more prevalent as people get older, as does dementia. It happens when the body can’t properly use the insulin it makes to control blood sugar levels. It develops over many years and is often associated with being overweight or obese. Type 1 diabetes is an autoimmune disease in which the body stops making insulin.

Most of the research on the diabetes-dementia link involves Type 2 diabetes, which studies show roughly doubles the dementia risk and may cause it to develop a few years earlier. For people with Type 1 diabetes, treatment advances have led to longer lifespans, allowing researchers to begin delving into how the disease affects their cognitive abilities as they age.

“They are now living to ages to be at risk for diseases that happen later in life,”

said Whitmer, who is also an adjunct investigator at the Division of Research for Kaiser Permanente Northern California.

Whitmer led a study for Kaiser that showed older adults with Type 1 diabetes who were hospitalized for just one blood sugar extreme were at higher risk for dementia – and those who were hospitalized for both highs and lows were six times more likely to later develop dementia.

Shannon Macauley, an assistant professor of gerontology and geriatric medicine at Wake Forest School of Medicine, studies the relationship between Type 2 diabetes and Alzheimer’s disease in her lab in Winston-Salem, North Carolina.

“Glucose is unbelievably important for the brain,” Macauley said. Though it makes up just 2% of the body’s weight, the brain uses 20%-30% of circulating blood glucose. “People don’t appreciate how much the brain sucks glucose out of the blood; it’s a big user of your glucose supply.”

Unlike other organs, the brain can’t store excess glucose, she said. That makes it vulnerable to highs and lows. “It needs it on demand in a rapid fashion but that puts the brain at excess risk when glucose levels hit one extreme or another.”

Macauley’s research in mice suggests too much glucose may be causing rapid production of beta-amyloid, proteins that clump together to form amyloid plaques in the brain. Beta-amyloid has been implicated in the development of Alzheimer’s disease.

When the brain suddenly produces excess beta-amyloid, it’s “like throwing a Jersey barrier out onto I-95,” Macauley said. “All the cars have to figure out how to get around it. The cells can’t get to where they need to go, they can’t communicate properly with other cells and lose their efficiency.”

Conversely, too little glucose in the brain robs it of the energy it needs to perform tasks, she said. “You need energy on hand for every task – to talk, think, button your shirt. Energy also goes to keeping the cells and brain alive. If you go low, you are starving the brain, and it can’t do what it needs to do.”

Preventing dementia isn’t the only way good blood glucose control helps the brain, Whitmer said.

“It also helps to prevent stroke,” she said. “There are lots of blood vessels in the brain. Good glycemic control equates with good blood vessel health. What’s good for your heart is good for your brain.”

Whether a person has Type 1 or Type 2 diabetes, there are many steps they can take to keep blood sugar levels on an even keel.

First, it’s important to know your numbers. Even blood sugar levels slightly higher than normal – a condition known as prediabetes – can start to do damage, Macauley said. To be in the healthy range, levels should be lower than 100 mg/dl, with measurements from 100-125 mg/dl considered prediabetes.

“If you are in that realm, there are clues you are becoming unhealthy,” Macauley said. A person may be overweight, eating an unhealthy diet, smoking or not getting enough sleep or physical exercise. “Exercise causes you to use that extra glucose.”

If diet and exercise don’t help enough, medication may be needed, she said.

People with Type 1 diabetes need to check blood sugar levels throughout the day because what they eat and how much physical activity they get can cause levels to rise or fall. Health experts recommend they keep supplies such as hard candy, fruit juice or glucose tablets with them to boost levels should they get too low.

As people with Type 1 live longer, Whitmer said, researchers need to focus on other ways to ensure their years are healthy ones. “We really need to step back and think about how we can increase this patient population’s chances of successful aging.”


Source: American Heart Association

Which Blood Sugar Meds Work Best Against Type 2 Diabetes?

Steven Reinberg wrote . . . . . . . . .

You have type 2 diabetes, and you are already taking an old standby drug, metformin. But you still need help controlling your blood sugar levels. Which medication would be the best?

New research pitted several diabetes drugs against each other and came up with an answer: The diabetes drugs Lantus and Victoza were better at controlling blood sugar over time than Amaryl or Januvia.

“We’ve known that type 2 diabetes is a progressive disease, and these medications, in general, do not reduce or obliterate progression, and that the ability of these medications to slow the rise in glucose varies amongst them,” explained Dr. Steven Kahn, a professor of medicine, metabolism, endocrinology and nutrition at the University of Washington in Seattle. He is a member of the executive committee that oversaw the trial.

The goal was to see which of these drugs kept average blood sugar levels in the recommended target range, at an A1C level of less than 7%. A1C blood tests are a standard means of gauging long-term blood sugar control.

“When we look at the rise in A1C over time, it’s clear that there are initial beneficial impacts of one drug over the other, but they tend to fail at a very similar rate,” Kahn said. “So, beyond the first couple of years, all the failure seems to be occurring at the same rate, but overall failure was less with Lantus and Victoza.”

Lantus (insulin glargine) and Victoza (liraglutide) are both injectable drugs, while Amaryl (glimepiride) and Januvia (sitagliptin) are pills.

The study, which was funded by the U.S. National Institutes of Health, included more than 5,000 people with type 2 diabetes, average age 57. The participants, 20% of whom were Black and 18% of whom were Hispanic, were randomly assigned to one of the four drugs along with metformin in the trial, which ran an average of four years.

The researchers found that Lantus and Victoza were the most effective in keeping A1C levels under 7%, while Amaryl or Januvia had the lowest effect and higher odds of letting A1C levels rise above 7%.

The results were similar across gender, race, ethnicity and age group.

  • Patients given Victoza and Januvia were more likely to lose weight than those taking Amaryl. Those taking Lantus maintained a stable weight.
  • Victoza caused more gastrointestinal side effects, such as nausea, abdominal pain and diarrhea, than the other drugs. Amaryl was linked to a higher risk for low blood sugar than the other drugs.
  • Victoza was linked to a lower risk of heart attack, stroke and other heart and vascular complications than the other drugs.

Dr. Caroline Messer, an endocrinologist at Lenox Hill Hospital in New York City, said the study confirms that these medications are appropriate and should be used as a second-line treatment after metformin, or as a first-line treatment if metformin isn’t tolerated.

Messer noted that although some of the newer drugs are expensive, they are covered by most health insurance plans.

“I think the only disservice of the study is that I don’t want people to start thinking that you should be using insulin [Lantus] as a second-line treatment,” she explained. “I think that it does a disservice, because if people are reaching for insulin too quickly because of this trial, that would be a shame.”

The findings were presented Monday at the virtual annual meeting of the American Diabetes Association. Findings presented at medical meetings should be considered preliminary until published in a peer-reviewed journal.

Dr. Joel Zonszein, an emeritus professor of medicine at Albert Einstein College of Medicine in New York City, was not surprised by the findings, but thinks the trial is outdated.

“It certainly proves that Victoza and Lantus are better medications to improve blood sugar control when metformin is not enough,” he said.

The problem with the study is that it didn’t include other drugs that were approved by the U.S. Food and Drug Administration when the study began, so there may be more effective drug combinations that are yet to be tested, Zonszein said.

“We need to know what the best combination is for treatment of diabetes early in the disease and not to use the antiquated step-up approach — what to do when the medication fails? We have an excellent choice of medications, and there is no reason to have individuals with diabetes not well-treated,” he added.

And when managing diabetes, treating blood sugar is not the only consideration, Zonszein noted.

“We treat each patient and individualize regimens accordingly. Treatment includes obesity, high cholesterol and hypertension, among others. We aim to improve and prolong a good quality of life,” he said. “For instance, the weight loss found with Victoza is important for many, and not found with the other agents in the study. Victoza’s gastrointestinal side effects are also well-known, and these are decreased when using newer weekly drugs.”

Although blood sugar levels are important, treatment aims to avoid or delay the complications of diabetes, Zonszein said.

Because stroke and heart attack are the common causes of death among diabetes patients, treatment should include medications that prevent heart attack, stroke and other heart and vascular complications, as well as kidney disease.

“The… trial is therefore outdated, and doesn’t help people or their health care providers to make decisions in 2021 — the train has left the station,” Zonszein said.

“Treatment of diabetes has shifted towards individualizing therapy, using proper medications from the get-go. We now use medications that do not cause low blood sugar or need frequent blood sugar checking. Certainly, we use medications that can help with weight loss and cause less cardiovascular complications,” he explained.

Kahn said he is all for individualized treatment for type 2 diabetes. He also wishes that drug companies would do head-to-head trials of the newer drugs to determine the best combination treatment.


Source: HealthDay

Diabetes Can Lead to Amputations, But Stem Cell Treatment Offers Hope

Amy Norton wrote . . . . . . . . .

One of the most dangerous complications of diabetes is a foot ulcer that won’t heal, but now a preliminary study finds that a type of stem cell found in body fat may be a powerful remedy for these severe foot wounds.

The study included 63 patients with non-healing diabetic foot ulcers who were given injections of cells from their own body fat. Over the next year, the treatment healed the ulcers in most patients.

Researchers said the study — conducted in Nicaragua — lays the groundwork for a similar trial in the United States, to replicate the findings.

Diabetic foot ulcers are open sores or wounds that affect roughly 15% of people with diabetes, according to the American Podiatric Medical Association (APMA). For some, the wounds refuse to heal and can become infected — sometimes leading to amputation.

In the United States alone, studies show that more than half of all amputations are diabetes-related — and non-healing foot ulcers are usually the reason why.

People with diabetes are vulnerable to foot ulcers for several reasons, explained study author Dr. Michael Carstens.

Over time, chronically high blood sugar can damage nerves in the feet, leading to a loss of sensation. That means sores or cuts can go unnoticed until they worsen and become infected. Making matters worse, diabetes damages the body’s small blood vessels, which impairs blood flow to the feet — interfering with the natural wound-healing process.

On top of that, many people with diabetes also have blockages in larger arteries, including those in the legs, said Carstens, of Wake Forest University’s Institute for Regenerative Medicine, in Winston-Salem, N.C.

Diabetic foot ulcers can often be treated with measures like applying medication or dressings to the wound, as well as surgical debridement — where a doctor removes dead skin and tissue to create a “new” wound that may heal better.

Still, the APMA says, around 6% of people with diabetic ulcers end up in the hospital due to an infection or other complication.

For their study, Carstens’ team turned to stem cells to try to heal severe wounds in diabetes patients who were candidates for amputation.

“They had critical-size wounds,” Carstens noted. “There was no way they were going to heal on their own.”

Specifically, researchers harvested a collection of cells called stromal vascular fraction from patients’ body fat. Among that collection is a type of “adult” stem cell called mesenchymal stem cells (MSCs).

MSCs give rise to certain more mature cell types, including cartilage and muscle.

Researchers injected the cells into and around patients’ wounds, and along arteries in the lower leg. Six months later, 51 of the 63 patients were showing complete closure of the ulcer, while another eight had at least a 75% closure.

Of the remaining four, three needed amputations and one died — from heart complications unrelated to the treatment, the researchers said.

One year out, 50 patients had completely healed wounds, while another four had at least 85% healing. The remaining five patients had died — also from heart-related causes.

According to Carstens, MSCs appear to work by producing chemicals that spur new blood vessel growth, allowing for wound repair.

The findings were recently published in the journal Stem Cells Translational Medicine.

The general tactic of using stem cells for diabetic foot ulcers is not new; doctors can already use cells derived from the amniotic membrane of the placenta.

Dr. Jeffrey Ross, an APMA spokesman, said he’s personally found amniotic membrane cells to be very effective in wound healing.

The cells are retrieved from the placenta of babies born by cesarean section, explained Ross, who is also an associate professor of surgery at Baylor College of Medicine in Houston.

Various companies market products containing frozen or dehydrated amniotic membrane cells that can be applied to diabetic foot ulcers.

Ross did say the wound healing in the new study was “impressive.” In three patients who’d had wounds so severe their tendons were exposed, the newly developed tissue was capable of covering the tendons — which he pointed out is difficult to achieve.

Ross added, though, that he would have liked to see more intensive follow-up of the patients. The intervals between evaluations were “too far apart,” he said.

It’s not clear whether cells derived from patients’ fat could be any better than the amniotic cells already on the market, according to Ross. It would take head-to-head studies to determine that, he said.

But in general, Ross said, cell-based therapies — harnessing the body’s own healing powers — are the wave of the future.

But they are costly, he noted, and right now insurance coverage of the available cell therapies for foot ulcers varies.

Carstens agreed the approach is expensive, but made another point: The investment would have to be balanced against the high cost — and suffering — caused by severe diabetic foot ulcers and amputations.


Source: HealthDay