Posts tagged diabetes
Posts tagged diabetes
A new University of Arizona study, published in the journal Neurology, suggests a possible link between elevated blood sugar levels and risk for developing Alzheimer’s disease.
About 5 percent of men and women, ages 65 to 74, have Alzheimer’s disease, and it is estimated that nearly half of those age 85 and older may have the disease, according to the U.S. Centers for Disease Control and Prevention. Among the known factors that contribute to the disease are age and genetics. Scientists also think that high blood pressure, high cholesterol and diabetes may increase risk.
Although the link between diabetes and Alzheimer’s has been studied, UA researchers wondered if elevated blood sugar levels in non-diabetic individuals also might indicate a higher risk for developing Alzheimer’s disease.
“There have been studies that have linked diabetes to Alzheimer’s disease as a risk factor,” said Alfred Kaszniak, UA professor of psychology and a co-author on the study. “What was not known when we began this work is whether that risk was only at levels of blood sugar that qualify for diagnoses of diabetes, or in the borderline or pre-diabetic range, or would we also see a relationship across the so-called normal range of blood glucose?”
The researchers used fluorodeoxyglucose (18F) positron electron tomography, or FDG PET, a medical imaging technique that produces three-dimensional images of metabolic activity in the brain. Fasting serum glucose levels – blood sugar levels following several hours of not eating – are routinely acquired as part of the FDG PET protocol.
“When compared to those without the disease, Alzheimer’s disease patients demonstrate a pattern of reduced brain metabolism in particular brain regions,” explained Christine Burns, lead author on the study and a UA pre-doctoral student in psychology. “What we show is an association between elevated fasting serum glucose levels and a similar pattern of reduced metabolism in these same AD-related brain regions in cognitively healthy adults.”
The researchers studied data on 124 cognitively normal, non-diabetic adults with a family history of Alzheimer’s disease. The individuals, who ranged in age from 47 to 68, were among participants in a larger study, led by Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix, looking at a variety of Alzheimer’s risk factors, including genetic risk.
The link between high blood sugar and reduced brain metabolism existed regardless of whether individuals carried the Apolipoprotein E4 gene variant, an established risk factor for the development of Alzheimer’s disease.
In addition to suggesting a link between elevated blood sugar levels and Alzheimer’s risk in non-diabetic individuals, the study also shows promise for the use of brain imaging techniques like PET in identifying Alzheimer’s risk and developing early preventative interventions, researchers say.
“Right now, if you want to develop a drug or evaluate some other kind of a preventive measure for Alzheimer’s disease, the labor and expense is prohibitive,” Kaszniak said. “If you recruit people who may be at some risk, but are 20 years away from developing signs of the illness, what drug company or governmental agency is going to fund research that follows people for 20 years to see whether something is effective in prevention?
“However, if you have a biologic marker, it suggests what areas you should really focus on in those very expensive longitudinal studies,” he said.
Burns said she hopes the findings will inform ongoing work designed to help develop early Alzheimer’s interventions.
“A lot of valuable research is focused on treatment and slowing decline in Alzheimer’s patients,” she said. “I’m interested in complementing this work with interventions that can be implemented earlier on, perhaps at middle age.”
New research in The FASEB Journal using mice suggests that disrupting our internal clocks can lead to a complete absence of 24-hour bodily rhythms and an immediate gain in body weight
If you’re pulling and all-nighter to finish a term paper, a new parent up all night with a fussy baby, or simply can’t sleep like you once could, then you may be snoozing on good health. That’s because new research published in The FASEB Journal used mice to show that proper sleep patterns are critical for healthy metabolic function, and even mild impairment in our circadian rhythms can lead to serious health consequences, including diabetes and obesity.
“We should acknowledge the unforeseen importance of our 24-hour rhythms for health,” said Claudia Coomans, Ph.D., a researcher involved in the work from the Department of Molecular Cell Biology in the Laboratory of Neurophysiology at Leiden University Medical Center in Leiden, Netherlands. “To quote Seneca ‘We should live according to nature (secundum naturam vivere).’”
To make this discovery, Coomans and colleagues exposed mice to constant light, which disturbed their normal internal clock function, and observed a gradual degradation of their bodies’ internal clocks until it reached a level that normally occurs when aging. Eventually the mice lost their 24-hour rhythm in energy metabolism and insulin sensitivity, indicating that relatively mild impairment of clock function had severe metabolic consequences.
“The good news is that some of us can ‘sleep it off’ to avoid obesity and diabetes,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “The bad news is that we can all get the metabolic doldrums when our normal day/night cycle is disrupted.”
A research team led by Robert Nagele, PhD, of the New Jersey Institute for Successful Aging (NJISA) at the University of Medicine and Dentistry of New Jersey (UMDNJ)-School of Osteopathic Medicine, has demonstrated that the anti-atherosclerosis drug darapladib can significantly reduce leaks in the blood brain barrier. This finding potentially opens the door to new therapies to prevent the onset or the progression of Alzheimer’s disease. Writing in the Journal of Alzheimer’s Disease (currently in press), the researchers describe findings involving the use of darapladib in animal models that had been induced to develop diabetes mellitus and hypercholesterolemia (DMHC), which are considered to be major risk factors for Alzheimer’s disease.
“Diabetes and hypercholesterolemia are associated with an increased permeability of the blood-brain barrier, and it is becoming increasingly clear that this blood-brain barrier breakdown contributes to neurodegenerative diseases such as Alzheimer’s,” Nagele said. “Darapladib appears to be able to reduce this permeability to levels comparable to those found in normal, non-DMHC controls, and suggests a link between this permeability and the deposition of amyloid peptides in the brain.”
The study involved 28 animal (pig) models that were divided into three groups – DMHC animals treated with a 10 mg/day dose of darapladib; DMHC animals that received no treatment; and non-DMHC controls. Post-mortem analysis of the brains of the darapladib-treated animals showed significant decreases in blood-brain barrier leakage and in the density of amyloid-positive neurons in the cerebral cortices. Interestingly, the amyloid peptides that leaked into the brain tissue were found almost exclusively in the pyramidal neurons of the cerebral cortex, one of the earliest pathologies of the development of Alzheimer’s disease.
“Because our results suggest that these metabolic disorders can trigger neurodegenerative changes through blood-brain barrier compromise, therapies – such as darapladib – that can reduce vascular leaks have great potential for delaying the onset or slowing the progression of diseases like Alzheimer’s,” said the study’s lead author, Nimish Acharya, PhD, of the NJISA and the UMDNJ-Graduate School of Biomedical Sciences. “The clinical, caregiving and financial impact of such an effect cannot be overestimated.”
Scientists at Queen’s University Belfast are hoping to develop a novel approach that could save the sight of millions of diabetes sufferers using adult stem cells.
Currently millions of diabetics worldwide are at risk of sight loss due to a condition called Diabetic Retinopathy. This is when high blood sugar causes the blood vessels in the eye to become blocked or to leak. Failed blood flow harms the retina and leads to vision impairment and if left untreated can lead to blindness.
The novel REDDSTAR study (Repair of Diabetic Damage by Stromal Cell Administration) involving researchers from Queen’s Centre for Vision and Vascular Science in the School of Medicine, Dentistry and Biomedical Sciences, will see them isolating stem cells from donors, expanding them in a laboratory setting and re-delivering them to a patient where they help to repair the blood vessels in the eye. This is especially relevant to patients with diabetes were the vessels of the retina become damaged.
At present there are very few treatments available to control the progression of diabetic complications. There are no treatments which will improve glucose levels and simultaneously treat the diabetic complication.
The €6 million EU funded research is being carried out with NUI Galway and brings together experts from Northern Ireland, Ireland, Germany, the Netherlands, Denmark, Portugal and the US.
Professor Alan Stitt, Director of the Centre for Vision and Vascular Science in Queen’s and lead scientist for the project said: “The Queen’s component of the REDDSTAR study involves investigating the potential of a unique stem cell population to promote repair of damaged blood vessels in the retina during diabetes. The impact could be profound for patients, because regeneration of damaged retina could prevent progression of diabetic retinopathy and reduce the risk of vision loss.
“Currently available treatments for diabetic retinopathy are not always satisfactory. They focus on end-stages of the disease, carry many side effects and fail to address the root causes of the condition. A novel, alternative therapeutic approach is to harness adult stem cells to promote regeneration of the damaged retinal blood vessels and thereby prevent and/or reverse retinopathy.”
“This new research project is one of several regenerative medicine approaches ongoing in the centre. The approach is quite simple: we plan to isolate a very defined population of stem cells and then deliver them to sites in the body that have been damaged by diabetes. In the case of some patients with diabetes, they may gain enormous benefit from stem cell-mediated repair of damaged blood vessels in their retina. This is the first step towards an exciting new therapy in an area where it is desperately needed.”
The research focuses on specific adult stem-cells derived from bone-marrow. Which are being provided by Orbsen Therapeutics, a spin-out from the Science Foundation Ireland-funded Regenerative Medicine Institute (REMEDI) at NUI Galway.
The project will develop ways to grow the bone-marrow-derived stem cells. They will be tested in several preclinical models of diabetic complications at centres in Belfast, Galway, Munich, Berlin and Porto before human trials take place in Denmark.
Further information on the Centre for Vision and Vascular Science at Queen’s is available online at http://www.qub.ac.uk/research-centres/CentreforVisionandVascularScience/
Researchers at the University of Michigan’s Life Sciences Institute have found that amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes and fatty liver in mice.
The findings from the lab of Alan Saltiel, the Mary Sue Coleman director of the Life Sciences Institute, were published online Feb. 10 in the journal Nature Medicine.
“One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are ‘defending’ their body weight,” Saltiel said. “Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice.”
Different formulations of amlexanox are currently prescribed to treat asthma in Japan and canker sores in the United States. Saltiel is teaming up with clinical-trial specialists at U-M to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists at U-M to develop a new compound based on the drug that optimizes its formula.
The study appears to confirm and extend the notion that the genes IKKE and TBK1 play a crucial role for maintaining metabolic balance, a discovery published by the Saltiel lab in 2009 in the journal Cell.
“Amlexanox appears to work in mice by inhibiting two genes—IKKE and TBK1—that we think together act as a sort of brake on metabolism,” Saltiel said. “By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy.”
Researchers from the Universitat Autònoma de Barcelona (UAB), led by Fàtima Bosch, have shown for the first time that it is possible to cure diabetes in large animals with a single session of gene therapy. As published this week in Diabetes, the principal journal for research on the disease, after a single gene therapy session, the dogs recover their health and no longer show symptoms of the disease. In some cases, monitoring continued for over four years, with no recurrence of symptoms.
The therapy is minimally invasive. It consists of a single session of various injections in the animal’s rear legs using simple needles that are commonly used in cosmetic treatments. These injections introduce gene therapy vectors, with a dual objective: to express the insulin gene, on the one hand, and that of glucokinase, on the other. Glucokinase is an enzyme that regulates the uptake of glucose from the blood. When both genes act simultaneously they function as a “glucose sensor”, which automatically regulates the uptake of glucose from the blood, thus reducing diabetic hyperglycemia (the excess of blood sugar associated with the disease).
As Fàtima Bosch, the head researcher, points out, “this study is the first to demonstrate a long-term cure for diabetes in a large animal model using gene therapy.”
This same research group had already tested this type of therapy on mice, but the excellent results obtained for the first time with large animals lays the foundations for the clinical translation of this gene therapy approach to veterinary medicine and eventually to diabetic patients.
The study was led by the head of the UAB’s Centre for Animal Biotechnology and Gene Therapy (CBATEG) Fàtima Bosch, and involved the Department of Biochemistry and Molecular Biology of the UAB, the Department of Medicine and Animal Surgery of the UAB, the Faculty of Veterinary Science of the UAB, the Department of Animal Health and Anatomy of the UAB, the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), the Children’s Hospital of Philadelphia (USA) and the Howard Hughes Medical Institute of Philadelphia (USA).
A research team in Israel has devised a novel approach to identifying the molecular basis for designing a drug that might one day decrease the risk diabetes patients face of developing Alzheimer’s disease. The team will present its work at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.
A recent study suggests that people who suffer from type 2 diabetes face twice the risk of developing Alzheimer’s disease later in life compared to those who do not have diabetes. The link these diseases share relates to the formation of two types of peptide deposits that aggregate, or clump together. Peptides are chains of amino acids; longer chains form proteins. One type of peptide, called amyloid beta, is found in Alzheimer plaques in neurons of the brain. The other type, amylin, is found in the pancreas and the brain. Two years ago, researchers found both molecules in the pancreas of diabetic patients, and in both diseases their presence has been linked to the progression of the disease state.
To explore the hypothesis that interactions between the two molecules might play a critical role in the self-assembly of peptides that leads to protein aggregation, Yifat Miller, assistant professor from Ben-Gurion University of the Negev, Beer-Sheva, Israel, characterized the way the two protein molecules interact with each other through an examination of their structure. It was the first analysis of its kind.
“By identifying the specific ‘hot regions’ of these peptides that strongly interact with each other, our study may provide insight into the link between type 2 diabetes and Alzheimer’s disease,” Miller says. “We believe that preventing these interactions by developing a drug will decrease the risk that type 2 diabetes patients face of developing Alzheimer’s disease later life.”
Joslin scientists report the first generation of human induced pluripotent stem cells from patients with an uncommon form of diabetes, maturity onset diabetes of the young (MODY). These cells offer a powerful resource for studying the role of genetic factors in the development of MODY and testing potential treatments. The findings appear in the Journal of Biological Chemistry.
Human induced pluripotent stem cells (hiPSCs) are adult cells that have been genetically reprogrammed to exhibit the characteristics of embryonic stem cells, including the ability to differentiate into specialized cell types. The generation of hiPSCs, which was first reported in 2006, was a major scientific breakthrough with the potential to increase understanding of many diseases and aid in drug development.
Maturity onset diabetes of the young (MODY) is a form of diabetes that mainly affects individuals age 25 or younger and accounts for about 1 to 5 percent of all diabetes cases in the United States. Unlike type 1 and type 2 diabetes, which are polygenic and result from alterations in genetic and environmental factors, MODY is a monogenic disease that results from mutations in a single gene. To date, eight types of MODY and eleven MODY genes have been identified. Some types of MODY produce only mild symptoms and are often treated solely with oral diabetic medications.
Joslin Diabetes Center is one of a limited number of research institutes with the capability to generate hiPSCs from patients with diabetes. The cells used to produce the hiPSCs were obtained from patients with five different types of MODY at Joslin Diabetes Center and Haukeland University Hospital, Bergen, Norway. The MODY-hiPSCs are morphologically, molecularly and functionally indistinguishable from human pluripotent stem cells (hPSCs).
As a monogenic disease, MODY provides “a valuable opportunity to directly study in more detail the genetic mechanisms underlying the disease and not be influenced by other factors, such as insulin resistance,” says senior author Rohit N. Kulkarni, M.D., Ph.D., a Principal Investigator in the Section on Islet Cell and Regenerative Biology at Joslin and Associate Professor of Medicine at Harvard Medical School.
The scientists will first induce the MODY-hiPSCs to differentiate towards beta cells and in the process learn more about the potential blocks in their ability to differentiate. Using the iPSC-derived beta cells, they plan to study how MODY genes regulate the insulin secretory function. “Generating hiPSCs is an important step forward because we cannot obtain beta cells from living patients. These cells will allow us to do many experiments that otherwise would not be possible,” says Dr. Kulkarni.
The scientists also plan to explore ways to correct the genetic defect and use the beta cells derived from the “repaired” hiPSCs to test various treatments. “If we find medications that improve beta cell function, we can go back to the clinic and use them to treat patients,” says Dr. Kulkarni. “It will allow us to tailor treatments to a patient’s unique characteristics and provide personalized medicine to diabetes patients.”
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.”
Medical researchers at the University of Alberta have discovered a drug intended for diabetes appears to restore memory in Alzheimer’s brain cells.
Jack Jhamandas, a researcher with the Faculty of Medicine & Dentistry at the U of A, is the principal investigator with the team whose research results were recently published in the peer-reviewed publication The Journal of Neuroscience. He works in the Division of Neurology.
The team took brain tissue from animal models with Alzheimer’s disease and tested the tissue in the lab, looking specifically at the cells’ memory capacity. When brain cells are shocked by a barrage of electrical impulses, the cells “remember” the experience and this is a typical way to test or measure memory in the lab setting.
Amyloid protein, which is found in abnormally large amounts in the memory and cognition parts of the brains of Alzheimer’s patients, diminishes memory. A sister protein, known as amylin, which comes from the pancreas of diabetic patients, has the same impact on memory cells.
Jhamandas and his team demonstrated last year that a diabetes drug that never made it to market, known as AC253, could block the toxic effects of amyloid protein that lead to brain cell death.
In the lab, Jhamandas and his teammates, which included Ryoichi Kimura, a visiting scientist from Japan, tested the memory of normal brain cells and those with Alzheimer’s—both from animal models. When the drug AC253 was given to brain cells with Alzheimer’s and the shock memory tests were redone, memory was restored to levels similar to those in normal cells.
“This is very important because it tells us that drugs like this might be able to restore memory, even after Alzheimer’s disease may have set in,” says Jhamandas.