Posts tagged glucose
Articles and news from the latest research reports.
A long childhood feeds the hungry human brain
A five-year old’s brain is an energy monster. It uses twice as much glucose (the energy that fuels the brain) as that of a full-grown adult, a new study led by Northwestern University anthropologists has found.
The study helps to solve the long-standing mystery of why human children grow so slowly compared with our closest animal relatives.
It shows that energy funneled to the brain dominates the human body’s metabolism early in life and is likely the reason why humans grow at a pace more typical of a reptile than a mammal during childhood.
Results of the study will be published the week of Aug. 25 in the journal Proceedings of the National Academy of Sciences.
"Our findings suggest that our bodies can’t afford to grow faster during the toddler and childhood years because a huge quantity of resources is required to fuel the developing human brain," said Christopher Kuzawa, first author of the study and a professor of anthropology at Northwestern’s Weinberg College of Arts and Sciences. "As humans we have so much to learn, and that learning requires a complex and energy-hungry brain."
Kuzawa also is a faculty fellow at the Institute for Policy Research at Northwestern.
The study is the first to pool existing PET and MRI brain scan data — which measure glucose uptake and brain volume, respectively — to show that the ages when the brain gobbles the most resources are also the ages when body growth is slowest. At 4 years of age, when this “brain drain” is at its peak and body growth slows to its minimum, the brain burns through resources at a rate equivalent to 66 percent of what the entire body uses at rest.
The findings support a long-standing hypothesis in anthropology that children grow so slowly, and are dependent for so long, because the human body needs to shunt a huge fraction of its resources to the brain during childhood, leaving little to be devoted to body growth. It also helps explain some common observations that many parents may have.
"After a certain age it becomes difficult to guess a toddler or young child’s age by their size," Kuzawa said. "Instead you have to listen to their speech and watch their behavior. Our study suggests that this is no accident. Body growth grinds nearly to a halt at the ages when brain development is happening at a lightning pace, because the brain is sapping up the available resources."
It was previously believed that the brain’s resource burden on the body was largest at birth, when the size of the brain relative to the body is greatest. The researchers found instead that the brain maxes out its glucose use at age 5. At age 4 the brain consumes glucose at a rate comparable to 66 percent of the body’s resting metabolic rate (or more than 40 percent of the body’s total energy expenditure).
"The mid-childhood peak in brain costs has to do with the fact that synapses, connections in the brain, max out at this age, when we learn so many of the things we need to know to be successful humans," Kuzawa said.
"At its peak in childhood, the brain burns through two-thirds of the calories the entire body uses at rest, much more than other primate species," said William Leonard, co-author of the study. "To compensate for these heavy energy demands of our big brains, children grow more slowly and are less physically active during this age range. Our findings strongly suggest that humans evolved to grow slowly during this time in order to free up fuel for our expensive, busy childhood brains."
The role of lactate in boosting memory
Everyone knows that neurons are the key to how the brain operates. But it turns out they aren’t the only stars in the show; neighboring cells called astrocytes are quickly gaining increasing respect for the critical role they play in memory and learning. EPFL scientists have recently outlined the molecular mechanics of this process in an article published in Proceedings of the National Academy of Sciences (PNAS). Lactate produced by the star-shaped astrocytes accelerates the memorization process. This result, surprising until very recently, opens up new possibilities for treating cognitive and memory disorders, as well as psychiatric conditions such as depression.
Our brains are greedy, gobbling up as much as 25% of our daily energy consumption. Neurons and astrocytes thrive on glucose. Neurons use it to protect themselves from the buildup of toxic products resulting from their activity. Astrocytes, which are glial cells (as opposed to neurons), manufacture lactate; this was long thought to be a byproduct of glucose metabolism, and then as a simple energy source for neurons.
In 2011, research published in the journal Cell by EPFL’s Laboratory of Neuroenergetics and Cellular Dynamics in collaboration with a U.S. team unveiled the critical role of lactate. “In vivo, when the transfer of lactate from astrocytes to neurons is blocked, we found that the memorization process was also blocked,” explains EPFL professor Pierre Magistretti, head of the lab. “We thus knew that it was an essential fuel for that process.”
Focusing their attention on the molecular mechanism, the scientists discovered that lactate provides more than just energy. It acts as a moderator of one type of glutamate receptor (NMDA receptors), the nervous system’s primary neurotransmitter. This glutamate receptor is involved in the memorization process, and the research demonstrates that lactate gives them what amounts to a turbo-boost. “Glutamate lets you drive in first gear; with lactate, you can shift into fourth and travel at 100 km/h,” says Magistretti.
Palliating cognitive deficits
The scientists did their initial research in vitro. They exposed mice neurons to various substances and measured their effect on the expression of genes involved in memory. Glucose and pyruvate (another glucose derivative) didn’t have any effect. A lactate supplement, on the other hand, triggered the expression of four genes involved in cerebral plasticity that are essential to memorization.
They followed this work with in vivo studies, which confirmed their results. They administered lactate into the brains of living mice, and then extracted the tissues and measured gene expression. Once again, the expression of genes involved in cerebral plasticity increased significantly.
Could we take lactate supplements and develop encyclopedic memory? Magistretti’s lab has just received a grant to study the effects of artificial lactate supplementation. “We have identified a series of molecules that can make astrocytes produce more lactate. Now the idea is to see in vivo if we can mitigate cognitive deficits and memory disorders.” In addition, since conditions such as depression are often accompanied by cognitive problems, “lactate could also have an antidepressant effect,” says Magistretti, who also conducts research at the National Center for Competence in Research Synapsy, dedicated to the understanding of the synaptic basis of psychiatric disease.
(Source: actu.epfl.ch)
Medicinal oil reduces debilitating epileptic seizures associated with Glut 1 deficiency, trial shows
Two years ago, the parents of Chloe Olivarez watched painfully as their daughter experienced epileptic seizures hundreds of times a day. The seizures, caused by a rare metabolic disease that depleted her brain of needed glucose, left Chloe nearly unresponsive, and slow to develop.
Within hours, treatment with an edible oil dramatically reduced the number of seizures for then-4-year-old Chloe, one of 14 participants in a small UT Southwestern Medical Center clinical trial.
“Immediately we noticed fewer seizures. From the Chloe we knew two years ago to today, this is a completely different child. She has done amazingly well,” said Brandi Olivarez, Chloe’s mother.
For Chloe and the other trial participants who suffer from the disease called Glut1 deficiency (G1D), seizure frequency declined significantly. Most showed a rapid increase in brain metabolism and improved neuropsychological performance, findings that suggested the oil derived from castor beans called triheptanoin, ameliorated the brain glucose-depletion associated with this genetic disorder, which is often undiagnosed.
“This study paves the way for a medical food designation for triheptanoin, thus significantly expanding therapeutic options for many patients,” said Dr. Juan Pascual, Associate Professor of Neurology and Neurotherapeutics, Physiology, and Pediatrics at UT Southwestern and lead author of a study on the findings, published in JAMA Neurology.
For the estimated 38,000 Americans suffering from this disease, the only proven treatment has been a high-fat ketogenic diet, which only works for about two-thirds of patients. In addition, this diet carries long-term risks, such as development of kidney stones and metabolic abnormalities.
Based on the results of this trial, triheptanoin appears to work as efficiently as the ketogenic diet; however, more research needs to be done before the oil is made available as a medical food therapy, researchers said.
“Triheptanoin byproducts produced in the liver and also in the brain refill brain chemicals that we found are preferentially diminished in the disorder, and this effect is precisely what defines a medical food rather than a drug,” said Dr. Pascual, who heads UT Southwestern’s Rare Brain Disorders Program, maintains an appointment in the Eugene McDermott Center for Human Growth and Development, and holds The Once Upon a Time Foundation Professorship in Pediatric Neurologic Diseases.
The oil, approved for use in research only, is an ingredient in some cosmetic products and is added to butter in some European countries. It is not commercially available in the U.S. for clinical use.
Triheptanoin’s success as an experimental treatment for other metabolic diseases, along with preclinical success in G1D mice, led Dr. Pascual and his trial collaborator, Dr. Charles Roe, Clinical Professor of Neurology and Neurotherapeutics, to first conceive the idea and then launch this trial for G1D patients. The 14 pediatric and adult patients in the study consumed varying amounts of the oil, based on their body weight, four times a day. Given the trial’s success, Dr. Pascual plans further research to refine the optimal dosage toward the goal of facilitating medical food designation of triheptanoin as a new G1D treatment.
While some trial participants reported mild stomach upset as a side effect, for Chloe the oil has been a miracle medicine without negative effects. Her parents, Brandi and Josh Olivarez of Waco, Texas, continue to be amazed by her progress.
“Before, she was having so many seizures a day that she couldn’t even talk. Now she sings all the time, she can eat whatever she wants, and her speech is greatly improved. She still has some learning delays, but has come a long way,” said Mrs. Olivarez.
Many Glut1 patients suffer from movement disorders that limit their physical capabilities, but that does not appear to be the case with Chloe. As for the seizures, she still has minor ones occasionally, but they are not debilitating.
“She is now able to run a solid mile without stopping. This would not have been possible without the oil,” Mrs. Olivarez said. “Before, she had almost no muscle tone, was lethargic and had a very wide gait due to trying to balance herself while walking, which was very tiring for her.”
To better understand this disease, UT Southwestern established a patient-completed registry to track G1D incidence and what treatments work or do not work for those registered.
Glucose ‘control switch’ in the brain key to both types of diabetes
Researchers at Yale School of Medicine have pinpointed a mechanism in part of the brain that is key to sensing glucose levels in the blood, linking it to both type 1 and type 2 diabetes. The findings are published in the July 28 issue of Proceedings of the National Academies of Sciences.
“We’ve discovered that the prolyl endopeptidase enzyme — located in a part of the hypothalamus known as the ventromedial nucleus — sets a series of steps in motion that control glucose levels in the blood,” said lead author Sabrina Diano, professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences, Comparative Medicine, and Neurobiology at Yale School of Medicine. “Our findings could eventually lead to new treatments for diabetes.”
The ventromedial nucleus contains cells that are glucose sensors. To understand the role of prolyl endopeptidase in this part of the brain, the team used mice that were genetically engineered with low levels of this enzyme. They found that in absence of this enzyme, mice had high levels of glucose in the blood and became diabetic.
Diano and her team discovered that this enzyme is important because it makes the neurons in this part of the brain sensitive to glucose. The neurons sense the increase in glucose levels and then tell the pancreas to release insulin, which is the hormone that maintains a steady level of glucose in the blood, preventing diabetes.
“Because of the low levels of endopeptidase, the neurons were no longer sensitive to increased glucose levels and could not control the release of insulin from the pancreas, and the mice developed diabetes.” said Diano, who is also a member of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.
Diano said the next step in this research is to identify the targets of this enzyme by understanding how the enzyme makes the neurons sense changes in glucose levels. “If we succeed in doing this, we could be able to regulate the secretion of insulin, and be able to prevent and treat type 2 diabetes,” she said.
Understanding the unique nature of children’s bodies and brains
With the increase in childhood obesity and the associated increase in type 2 diabetes among children and adolescents, there is growing interest in how children’s bodies process the foods they eat and how obesity and diabetes begin to develop at early ages. Two studies presented at the American Diabetes Association’s 74th Scientific Sessions® help to shed light on this topic.
One study, by researchers at the Yale School of Medicine, compared how the brains of adolescents and adults differed in their response to ingestion of a glucose drink. It found that in adolescents, glucose increased the blood flow in the regions of the brain implicated in reward-motivation and decision-making, whereas in adults, it decreased the blood flow in these regions.
"While we cannot speculate directly about how glucose ingestion may influence behavior, certainly we have shown that there are differences in how adults and adolescents respond to glucose," said lead researcher Ania Jastreboff, MD, PhD, an Assistant Professor of Medicine and Pediatrics at the Yale School of Medicine. "This is important because adolescents are the highest consumers of dietary added sugars. This is just the first step in understanding what is happening in the adolescent brain in response to consumption of sugary drinks. Ultimately, it will be important to investigate whether such exposure to sugar during adolescence impacts food and drink consumption, and whether it relates to the development of obesity."
Another study, by researchers in Germany at the University Children’s Hospital in Leipzig, compared fat cell composition and biology in lean and obese children and adolescents. They found that when children become obese, beginning as early as age six, there was an increase in the number of adipose cells, and that they are larger in size than the cells found in the bodies of lean children. The researchers also found evidence of dysfunction of the fat cells of obese children, including signs of inflammation, which can lead to insulin resistance, diabetes and other problems, such as high blood pressure.
"Our research shows that obese children start to have not only more but also larger adipocytes, or fat cells, at a very young age and that this is associated with increased inflammation and is linked to impaired metabolic function," said lead researcher Antje Körner, MD, Professor of Pediatrics and Pediatric Researcher at the Pediatric Research Center, University Children’s Hospital, Leipzig. "What we were interested in was seeing whether something was already going on with the adipose tissue itself if the children become obese at an early age, and it appears that there is. It’s important because this can contribute to the development of comorbidities of obesity in children, such as diabetes."
Infections damage our ability to form spatial memories
Increased inflammation following an infection impairs the brain’s ability to form spatial memories – according to new research. The impairment results from a decrease in glucose metabolism in the brain’s memory centre, disrupting the neural circuits involved in learning and memory.
Inflammation has long been linked to disorders of memory like Alzheimer’s disease. Severe infections can also impair cognitive function in healthy elderly individuals. The new findings published in the journal Biological Psychiatry help explain why inflammation impairs memory and could spur the development of new drugs targeting the immune system to treat dementia.
In the first trial to image how inflammation impairs human memory, the team at Brighton and Sussex Medical School scanned 20 participants before and after either a benign salty water injection or typhoid vaccination, used to induce inflammation. Positron emission tomography (PET) was used to measure the effects of inflammation on the consumption of glucose in the brain and after each scan participants tested their spatial memory by performing a series of tasks in a virtual reality.
A reduction in glucose metabolism within the brain’s memory centre, known as the Medial Temporal Lobe (MTL), was seen following inflammation. Participants also performed less well in spatial memory tasks, an effect that appeared to be directly mediated by the change in MTL metabolism.
"We have known for some time that severe infections can lead to long-term cognitive impairment in the elderly. Infections are also a common trigger for acute decline in function in patients with dementia and Alzheimer’s disease," explains Dr Neil Harrison, a Wellcome Trust Intermediate Clinical Fellow at BSMS who led the study. "This study suggests that catching a cold or the flu, which leads to inflammation in the brain, could impair our memory."
Infections are unlikely to cause long-term detrimental impact in the young and healthy but the findings are of great significance in the elderly. The team now plan to investigate the role of inflammation in dementia, including insight into how acute infections such as influenza influence the rate of progression and decline.
"Our findings suggest that the brain’s memory circuits are particularly sensitive to inflammation and help clarify the association between inflammation and decline in dementia," says Dr Harrison. "If we can control levels of inflammation, we may be able to reduce the rate of decline in patients’ cognition."
(Source: eurekalert.org)
High blood sugar makes Alzheimer’s plaque more toxic to the brain
High blood-sugar levels, such as those linked with Type 2 diabetes, make beta amyloid protein associated with Alzheimer’s disease dramatically more toxic to cells lining blood vessels in the brain, according to a new Tulane University study published in latest issue of the Journal of Alzheimer’s Disease.
The study supports growing evidence pointing to glucose levels and vascular damage as contributors to dementia.
“Previously, it was believed that Alzheimer’s disease was due to the accumulation of ‘tangles’ in neurons in the brain from overproduction and reduced removal of beta amyloid protein,” said senior investigator Dr. David Busija, regents professor and chair of pharmacology at Tulane University School of Medicine. “While neuronal involvement is a major factor in Alzheimer’s development, recent evidence indicates damaged cerebral blood vessels compromised by high blood sugar play a role. Even though the links among Type 2 diabetes, brain blood vessels and Alzheimer’s progression are unclear, hyperglycemia appears to play a role.”
Drs. Cristina Carvalho and Paula Moreira from the University of Coimbra in Portugal were co-investigators in the study.
Researchers studied cell cultures taken from the lining of cerebral blood vessels, one from normal rats and another from mice with uncontrolled chronic diabetes. They exposed the cells to beta amyloid and different levels of glucose and later measured their viability. Cells exposed to high glucose or beta amyloid alone showed no changes in viability. However, when exposed to hyperglycemic conditions and beta amyloid, viability decreased by 40 percent. Researchers suspect the damage is due to oxidative stress from the mitochondria of the cell.
The cells from diabetic mice were more susceptible to damage and death to beta amyloid protein − even at normal glucose levels. The increased toxicity of beta amyloid may damage the blood-brain barrier, disrupt normal blood flow to the brain and decrease clearance of beta amyloid protein.
The study’s findings underscore the need to aggressively control blood sugar levels in diabetic individuals, Busija said.
(Source: tulane.edu)
Lower Blood Sugars May Be Good for the Brain
Even for people who don’t have diabetes or high blood sugar, those with higher blood sugar levels are more likely to have memory problems, according to a new study published in the October 23, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
The study involved 141 people with an average age of 63 who did not have diabetes or pre-diabetes, which is also called impaired glucose tolerance. People who were overweight, drank more than three-and-a-half servings of alcohol per day, and those who had memory and thinking impairment were not included in the study.
The participants’ memory skills were tested, along with their blood glucose, or sugar, levels. Participants also had brain scans to measure the size of the hippocampus area of the brain, which plays an important role in memory.
People with lower blood sugar levels were more likely to have better scores on the memory tests. On a test where participants needed to recall a list of 15 words 30 minutes after hearing them, recalling fewer words was associated with higher blood sugar levels. For example, an increase of about 7 mmol/mol of a long-term marker of glucose control called HbA1c went along with recalling 2 fewer words. People with higher blood sugar levels also had smaller volumes in the hippocampus.
“These results suggest that even for people within the normal range of blood sugar, lowering their blood sugar levels could be a promising strategy for preventing memory problems and cognitive decline as they age,” said study author Agnes Flöel, MD, of Charité University Medicine in Berlin, Germany. “Strategies such as lowering calorie intake and increasing physical activity should be tested.”
Clot buster and brain protector
Ever since its introduction in the 1990s, the “clot-busting” drug tPA has been considered a “double-edged sword” for people experiencing a stroke. It can help restore blood flow to the brain, but it also can increase the likelihood of deadly hemorrhage. In fact, many people experiencing a stroke do not receive tPA because the window for giving the drug is limited to the first few hours after a stroke’s onset.
But Emory neurologist Manuel Yepes may have found a way to open that window. Even when its clot-dissolving powers are removed, tPA can still protect brain cells in animals from the loss of oxygen and glucose induced by a stroke, Yepes’ team reported in the Journal of Neuroscience (July 2012).
"We may have been giving the right medication, for the wrong reason," Yepes says. "tPA is more than a clot-busting drug. It functions naturally as a neuroprotectant."
The finding suggests that a modified version of the drug could provide benefits to patients who have experienced a stroke, without increasing the risk of bleeding.
"This would be a major breakthrough in the care of patients with stroke, if it could be developed," says Michael Frankel, director of the Marcus Stroke and Neuroscience Center at Grady Memorial Hospital.
tPA is a protein produced by the body and has several functions. One is to activate the enzyme plasmin, which breaks down clots. But Yepes’ team has discovered that the protein has additional functions. For example, in cultured neurons, it appears to protect neurons in the brain, turning on a set of genes that help cells deal with a lack of oxygen and glucose. This result contradicts previous reports that the protein acts as a neurotoxin in the nervous system.
Tweaking tPA so that it is unable to activate plasmin—while keeping intact the rest of its functions—allowed the researchers to preserve its protective effect on neurons in culture. This modified tPA also reduced the size of the damaged area of the brain after simulated stroke in mice, with an effect comparable in strength to regular tPA. The next step is to test the modified version of tPA in a pilot clinical trial.
The possibility that tPA may be working as a neuroprotectant may explain why, in large clinical studies, tPA’s benefits sometimes go unobserved until several weeks after treatment, Yepes says. “If it was just a matter of the clot, getting rid of the clot should make the patient better quickly,” he says. “It’s been difficult to explain why you should have to wait three months to see a benefit.”
(Source: emoryhealthmagazine.emory.edu)
A landmark discovery about how insulin docks on cells could help in the development of improved types of insulin for treating both type 1 and type 2 diabetes.
For the first time, researchers have captured the intricate way in which insulin uses the insulin receptor to bind to the surface of cells. This binding is necessary for the cells to take up sugar from the blood as energy.
The research team was led by the Walter and Eliza Hall Institute and used the Australian Synchrotron in Melbourne. The study was published in the journal Nature.
For more than 20 years scientists have been trying to solve the mystery of how insulin binds to the insulin receptor. A research team led by Associate Professor Mike Lawrence, Dr Colin Ward and Dr John Menting have now found the answer.
Associate Professor Lawrence from the institute’s Structural Biology division said the team was excited to reveal for the first time a three-dimensional view of insulin bound to its receptor. “Understanding how insulin interacts with the insulin receptor is fundamental to the development of novel insulins for the treatment of diabetes,” Associate Professor Lawrence said. “Until now we have not been able to see how these molecules interact with cells. We can now exploit this knowledge to design new insulin medications with improved properties, which is very exciting.”
The Australian Synchrotron’s MX2 microcrystallography beamline was critical to the project’s success. “If we did not have this fantastic facility in Australia and their staff available to help us, we would simply not have been able to complete this project,” Associate Professor Lawrence said.
Associate Professor Lawrence assembled an international team of project collaborators, including researchers from Case Western Reserve University, the University of Chicago, the University of York and the Institute of Organic Chemistry and Biochemistry in Prague. “Collaborations in this field are essential,” he said. “No one laboratory has all the resources, expertise and experience to take on a project as difficult as this one.”
“We have now found that the insulin hormone engages its receptor in a very unusual way,” Associate Professor Lawrence said. “Both insulin and its receptor undergo rearrangement as they interact – a piece of insulin folds out and key pieces within the receptor move to engage the insulin hormone. You might call it a ‘molecular handshake’.”
Australia is facing an increasing epidemic of type 2 diabetes. There are now approximately one million Australians living with diabetes and around 100,000 new diagnoses each year.
“Insulin controls when and how glucose is used in the human body,” Associate Professor Lawrence said. “The insulin receptor is a large protein on the surface of cells to which the hormone insulin binds. The generation of new types of insulin have been limited by our inability to see how insulin docks into its receptor in the body.
“Insulin is a key treatment for diabetics, but there are many ways that its properties could potentially be improved,” Associate Professor Lawrence said. “This discovery could conceivably lead to new types of insulin that could be given in ways other than injection, or an insulin that has improved properties or longer activity so that it doesn’t need to be taken as often. It may also have ramifications for diabetes treatment in developing nations, by creating insulin that is more stable and less likely to degrade when not kept cold, an angle being pursued by our collaborators. Our findings are a new platform for developing these kinds of medications.”