Can fat 'feel' fat? Size-sensing protein controls glucose uptake and storage in fat cells
by University of Iowa
Researchers at the University of Iowa have discovered that a molecule which can sense the swelling of fat cells also controls a signaling pathway that allows fat cells to take up and store excess glucose. Mice missing this protein, known as SWELL1, gain less weight (fat) than normal mice on a high-fat diet, but also develop diabetes.
"Although we have created a mouse that is resistant to weight gain by removing the SWELL1 protein, the mouse is not healthy; it has insulin resistance and glucose intolerance," says Rajan Sah, MD, PhD, assistant professor of internal medicine at the University of Iowa Carver College of Medicine and senior author of the study.
Type 2 diabetes is one of the more serious health problems associated with obesity. The disease makes cells less sensitive to insulin and causes blood sugar levels to become abnormally high. It is healthier for the body to store excess glucose as fat rather than have it circulating in the blood where it can damage blood vessels and nerves.
In healthy people, insulin released in response to high glucose levels acts on many different tissues to coordinate use or storage of the glucose. It triggers fat cells to take up excess glucose and store it as fat.
Sah's study, which was published recently in Nature Cell Biology, found that removing SWELL1 from fat cells in mice disrupts this insulin signaling pathway and prevents fat cells from taking up glucose.
Sah and his team homed in on SWELL1 because of several pieces of converging evidence. Fat cells have a tremendous capacity to expand - up to 30 times their normal volume in the context of obesity. It's also long been known that changes in fat cell size alters fat cell signaling.
Through exploratory experiments investigating cell swelling in fat cells from lean and obese mice as well as fat cells obtained from bariatric surgery patients, Sah and his team serendipitously identified SWELL1 protein as an essential component of fat cells' volume-sensing mechanism. From unrelated work by other researchers, they also knew that this protein was involved in a signaling pathway common to all cells. In fat cells this pathway regulates glucose uptake in response to insulin.
"We thought maybe this SWELL1 protein is what links the two pieces together - the size-sensing mechanism and the signaling pathway that responds to size changes by altering insulin sensitivity," explains Sah, who also is a member of the Fraternal Order of Eagles Diabetes Research Center, and the Abboud Cardiovascular Research Center at the UI.
The team's study showed that swelling of mouse or human fat cells, either artificially in a petri dish, or because the cells have expanded due to obesity, activates SWELL1 signaling. Removing SWELL1 from mouse fat cells knocks out this volume-sensing signal and disrupts the insulin signaling pathway used by fat cells to take up and store excess glucose. Mice missing SWELL1 have smaller fat cells, but also develop insulin resistance and glucose intolerance.
Interestingly, on a regular diet, mice missing SWELL1 had body weights, fat composition, and metabolism that were all essentially the same as a normal mouse. The only difference was they had no SWELL1 activity in their fat cells, as well as reduced ability to clear glucose from the blood and impaired insulin sensitivity (insulin resistance).
When the mice were put on a high-fat diet, the mice missing SWELL1 did not gain weight as fast as the normal mice but the insulin resistance and glucose intolerance became worse.
"The idea that fat is bad is not necessarily true," Sah says. "Too much fat is bad, and fat in the wrong places is bad, but fat in the right place and allowed to expand normally may be somewhat protective against diabetes.
"If fat cells can sense their own expansion, then SWELL1 protein might be the mechanism for that," he continues. "What we see here is what the cell does with the information that it is getting bigger. It turns on a signaling pathway that modulates glucose uptake and insulin sensitivity. From this discovery, we can start to look at whether we can target this modulation of insulin sensitivity in a therapeutic way."
Your muscles can 'taste' sugar, research finds
by Stephanie King, University of Michigan
An illustration of the Baf60c-Deptor-AKT signaling pathway identified as a target of myocyte glucose sensing that augments muscle insulin action. Credit: Stephanie King/LSI
It's obvious that the taste buds on the tongue can detect sugar. And after a meal, beta cells in the pancreas sense rising blood glucose and release the hormone insulin—which helps the sugar enter cells, where it can be used by the body for energy.
Now researchers at the University of Michigan Life Sciences Institute have uncovered an unexpected mechanism of glucose sensing in skeletal muscles that contributes to the body's overall regulation of blood sugar levels.
"We found that skeletal muscle cells have machinery to directly sense glucose—in a certain sense it's like the muscles can taste sugar, too," said senior study author Jiandie Lin, a faculty member at the LSI, where his lab is located.
This ability of muscles to sense blood glucose is a separate and parallel process that augments the insulin-driven response. Together they work as a rheostat to maintain steady glucose levels in the body, particularly after a meal, according to findings published May 4 in Molecular Cell.
Continuing to develop this in-depth understanding of how the body self-regulates blood sugar at the molecular level could shed new light on obesity and diabetes, as well as point toward new therapeutic targets, said Zhuoxian Meng, the study's lead author and a research investigator in Lin's lab.
The researchers were able to examine the contributions of the glucose-sensing pathway in skeletal muscle by silencing a key gene—BAF60C—in cell cultures and in laboratory mice.
"When we did that, the mice lacking BAF60C looked absolutely normal, but after we gave them a high-fat diet to induce obesity, they developed trouble disposing of the additional glucose after a meal," Lin said. "The well-known insulin mechanism was not sufficient to process the glucose on its own."
Elevated blood sugar following a meal is a key symptom of Type 2 diabetes. And chronic high blood sugar, also known hyperglycemia, can lead to serious health issues.
"We found that the molecular pathway that's engaged by glucose in muscle cells, at least the initial steps, is very similar to what happens in the beta cells in the pancreas," said Lin, who is also a professor of cell and developmental biology at the U-M Medical School. "This is very interesting because there's a very important class of diabetes drugs known as sulfonylureas that act by closing a potassium channel and causing the beta cells to secrete more insulin.
"Our research shows that this glucose-sensing pathway in muscle cells likely also plays a role in the drugs' overall glucose-lowering action. The extent of the pathway's contribution will need to be studied further."
Additionally, Lin said, there are two steps within the glucose-sensing pathway that could serve as potential targets for modulation with therapeutic compounds.
"It's amazing how subtle changes in glucose can be detected throughout the body," Lin said. "Beta cells respond, nerve cells respond, and now we know that muscle cells respond directly, too."
Pathways leading to beta cell division identified, may aid diabetes treatment
by University of California - San Diego
Researchers at UC San Diego School of Medicine identified pathways that regulate pancreatic beta cell (pictured in green) growth. These cells help maintain normal blood glucose levels by producing the hormone insulin. Credit: UC San Diego Health
Pancreatic beta cells help maintain normal blood glucose levels by producing the hormone insulin—the master regulator of energy (glucose). Impairment and the loss of beta cells interrupts insulin production, leading to type 1 and 2 diabetes. Using single-cell RNA sequencing, researchers at University of California San Diego School of Medicine have, for the first time, mapped out pathways that regulate beta cell growth that could be exploited to trick them to regenerate.
The findings are published in the May 2 issue of the journal Cell Metabolism.
"If we can find a drug that makes beta cells grow, it could improve blood sugar levels in people with diabetes," said Maike Sander, MD, professor in the Department of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine. "These people often have residual beta cells but not enough to maintain normal blood glucose levels."
The body generates beta cells in utero and they continue to regenerate after birth, but as people age, cell regeneration diminishes. The predominant way to grow new beta cells is through cell division, but beta cells capable of dividing are rare, compromising less than 1 percent of all beta cells. Scientists have been investigating molecular pathways that govern beta cell growth in hopes of finding new therapies that would help people regain blood glucose control after the onset of diabetes.
In their study, Sander's team identified the pathways that are active when beta cells divide providing insight into possible drug targets. Using single-cell RNA sequencing, the team was able to profile molecular features and metabolic activity of individual beta cells to determine how dividing beta cells differ from non-dividing cells.
"No one has been able to do this analysis because the 1 percent or less of beta cells that are dividing are masked by the 99 percent of beta cells that are not dividing," said Sander. "This in-depth characterization of individual beta cells in different proliferative states was enabled by newer technology. It provides a better picture of what sends beta cells into cell division and clues we can use to try to develop drugs to stimulate certain pathways."
Whether stimulating beta cells to grow will result in therapeutic interventions for diabetes is still to be seen, but this new information opens the door to find out, said Sander.
New type of insulin-producing cell discovered
by Andy Fell, UC Davis
Insulin is made in pancreatic islets by beta cells. In type I diabetes, these cells are lost. Now UC Davis researchers have identified another type of insulin-producing cell in the islets, which appears to be an immature beta cell (shown in red in this image). The discovery shows unexpected flexibility in the system. Greater understanding could lead to better treatments and stem cell therapies for diabetes. Credit: Mark Huising/UC Davis
In people with type I diabetes, insulin-producing beta cells in the pancreas die and are not replaced. Without these cells, the body loses the ability to control blood glucose. Researchers at the University of California, Davis have now discovered a possible new route to regenerating beta cells, giving insight into the basic mechanisms behind healthy metabolism and diabetes. Eventually, such research could lead to better treatment or cures for diabetes.
"We've seen phenomenal advances in the management of diabetes, but we cannot cure it," said Mark Huising, assistant professor of neurobiology, physiology and behavior in the UC Davis College of Biological Sciences. "If you want to cure the disease, you have to understand how it works in the normal situation."
Huising is senior author on a paper on the work published April 4 in the journal Cell Metabolism.
Working with both laboratory mice and human tissue, Huising is studying how the cells in the islets of Langerhans in the pancreas work together to regulate blood glucose. In both mice and people, the islets contain beta cells, which detect glucose and secrete insulin, and other cell types including alpha cells that produce glucagon, a hormone that raises blood sugar. The opposite effects of insulin and glucagon enable the body to regulate blood sugars and store nutrients.
Type I diabetes is a disease with two parts. Firstly, the beta cells are killed by the body's own immune system, and then they fail to regenerate (or those that do are killed). An effective cure for type I diabetes would involve dealing with both problems.
Accepted dogma, Huising said, has been that new beta cells are generated by other beta cells dividing. But now by applying new techniques in microscopy, his team has discovered, scattered around the edges of the islets, another type of cell that looks a lot like an immature beta cell.
These new cells can make insulin, but don't have the receptors to detect glucose, so they can't function as a full beta cell. However, Huising's team was able to observe alpha cells in the islet turn into immature beta cells and then mature into real beta cells.
"There's much more plasticity in the system than was thought," Huising said.
Understanding Fundamentals of Metabolism and Diabetes
It's an exciting result for three reasons, Huising said. Firstly, this is a new beta cell population in both humans and mice that wasn't known before. Secondly, the new population could be a source to replenish beta cells killed off in diabetes. Finally, understanding how these cells mature into functioning beta cells could help in developing stem cell therapies for diabetes. Stem cells have the potential to develop into a wide range of other cells. So far, attempts to grow real beta cells from stem cells have made great strides, but these efforts have not yet reached their full potential because they get hung up at an earlier immature stage.
This basic understanding of cells in the islets could also help in understanding type II diabetes, where beta cells do not die but become inactive and no longer secrete/release insulin.
"JDRF is proud to have supported Dr. Huising in this work and extremely excited about the results shown in the paper. The concept of harnessing the plasticity in the islet to regenerate beta cells has emerged as an intriguing possibility in recent years," said Andrew Rakeman, Ph.D., director of discovery research at JDRF. "The work from Dr. Huising and his team is showing us not only the degree of plasticity in islet cells, but the paths these cells take when changing identity. Adding to that the observations that the same processes appear to be occurring in human islets raises the possibility that these mechanistic insights may be able to be turned into therapeutic approaches for treating diabetes."
Sugar levels are managed by interactions between cells of the Islets of Langerhans in the pancreas. The hormone urocortin (green) is produced and stored in the same cells as insulin in the islets. Cells that make glucagon, which works to raise blood sugar, are stained red. Credit: Mark Huising, UC Davis
Sometimes, listening in on a conversation can tell you a lot. For Mark Huising, an assistant professor in the Department of Neurobiology, Physiology and Behavior at the UC Davis College of Biological Sciences, that crosstalk is between the cells that control your body's response to sugar, and understanding the conversation can help us understand, and perhaps ultimately treat, diabetes.
Huising's lab has now identified a key part of the conversation going on between cells in the pancreas. A hormone called urocortin 3, they found, is released at the same time as insulin and acts to damp down insulin production. A paper describing the work appears online on June 15 in the journal Nature Medicine.
"It's a beautiful system," Huising said. "It turns out that there is a lot of crosstalk going on in the islets to balance insulin and glucagon secretion. The negative feedback that urocortin 3 provides is necessary to tightly control blood sugar levels at all times."
Diabetes affects millions of Americans every year. Both forms of the disease—type 1, "juvenile" or "insulin-dependent" diabetes, and type 2 or "adult-onset" diabetes—occur when the body fails to regulate the level of sugar properly.
Diabetes is tied to structures called the Islets of Langerhans in the pancreas. Within the islets, beta cells make insulin. Increasing blood sugar stimulates insulin production, which causes the body's cells to pull sugar out of circulation.
The islets also house alpha cells, which make another hormone, glucagon, which acts on the liver to release more glucose into the bloodstream.
An islet of Langerhans with urocortin stained green in beta cells. Glucagon-making cells are stained red. Credit: Mark Huising.
An islet of Langerhans with urocortin stained green in beta cells. Glucagon-making cells are stained red. Credit: Mark Huising.
Urocortin 3 was originally identified as a hormone that is related to the signal in our brain that kick-starts our stress response. Instead, urocortin 3 is produced by islet beta cells and stored and released alongside insulin. In a series of experiments, Huising's group showed that urocortin 3 causes another cell type in the islets, delta cells, to release somatostatin, which turns down insulin production and acts as a natural brake on the release of insulin.
Urocortin 3 is reduced in laboratory animal models of diabetes and in beta cells from diabetic patients. Without urocortin 3, islets produce more insulin, but at the same time lose control over how much insulin they release.
By understanding how different cells and systems communicate to regulate blood sugar, Huising hopes to get a better understanding of what happens when this regulation goes wrong, leading to the different forms diabetes. Eventually this approach could lead to new ways to treat or prevent the disease.
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Diseases, Conditions, Syndromes
APRIL 21, 2015
New clues to treat juvenile diabetes
by UC Davis
UC Davis biologist Mark Hulsing will use the Hartwell Foundation grant to explore signals that cause new insulin-making cells to replace those lost in diabetes. (Gregory Urquiaga/UC Davis photo)
UC Davis Assistant Professor Mark Huising is a recipient of The Hartwell Foundation 2014 Individual Biomedical Research Award to support his early-stage research toward a cure for juvenile diabetes. Diabetes affects 10 percent of the entire United States population, including approximately a million children. Remarkably, 40 children every day receive the diagnosis of diabetes.
Huising, who works in the Department of Neurobiology, Physiology and Behavior at the UC Davis College of Biological Sciences, also holds an appointment in the Department of Physiology and Membrane Biology at the UC Davis School of Medicine. He joined UC Davis in November 2014 having previously worked at the Salk Institute in La Jolla, California. He is interested in how certain cells in the pancreas control the body's response to sugar in diabetes. Achieving a balance between reduction of elevated blood sugar levels and the need to prevent potentially fatal low sugar levels is critical to maintaining health.
The Hartwell Foundation award will provide $300,000 in direct cost over three years to support Huising's research looking at the biological signals and triggers affecting a small pool of cells in the pancreas that could be essential in regenerating control of blood sugar in this disease. The Individual Biomedical Research Award to Huising represents the ninth time a researcher from UC Davis has won such recognition from The Hartwell Foundation over the last seven years.
Islets, insulin and diabetes
Diabetes has been a prevalent health problem since ancient times. Two forms of the disease are known—Type 1, or "insulin-dependent" diabetes, and Type 2 diabetes, caused when the body fails to regulate the level of sugar properly, sending it either soaring high or dropping to very low levels.
In juvenile diabetes, the body's own immune system causes damage to a specialized region in the pancreas, called the islets of Langerhans, effectively rejecting the tissue. The damage is significant because the beta cells within the islets make insulin. Normally, increasing blood sugar stimulates insulin production, which causes the body's cells to pull sugar out of circulation. The islets also house alpha cells, which make another hormone, glucagon. When blood sugar falls, alpha cells make more glucagon, which causes the liver to break out stocks of glycogen and turn it into glucose.
New insight on insulin from immature cells
At diagnosis of diabetes, the body's immune system has already destroyed most beta cells and any ability to produce insulin. The remaining alpha cells build up and release glucagon, which causes a serious side-effect of juvenile diabetes. The majority of scientific strategies focus on means to prevent beta cell death and promote beta cell division. However, efforts to restore lost beta cells have been largely unsuccessful.
Huising has discovered that, in laboratory mice, immature beta cells may spontaneously arise from alpha cells. He proposes to identify the biochemical signals that switch alpha cells into beta cells and determine in human tissue whether such beta cells are adequately mature and functional. Huising's approach represents a shift in the current paradigm that after birth beta cells arise exclusively through the division of existing beta cells.
If successful, Huising will harness the intrinsic potential for beta cell regeneration that exists within pancreatic islets. This approach has the benefit of blocking a serious side effect of juvenile diabetes and represents a potential path to a cure for the disease.
Biomedical research that benefits children
"The Hartwell Foundation has a strong commitment to providing financial support to stimulate discovery in early-stage, innovative biomedical research that has potential to benefit children of the United States," said Fred Dombrose, president of The Hartwell Foundation. "Mark Huising typifies the innovative, young investigator we seek to fund. We want to make a difference."
Top Ten Center designation
In addition to the individual award, The Hartwell Foundation designated UC Davis as one of its Top Ten Centers for Biomedical Research for the fifth consecutive year.
In selecting each research center of excellence, The Hartwell Foundation takes into account the shared values the institution has with the foundation relating to children's health, the presence of an associated medical school and biomedical engineering program, and the quality and scope of ongoing biomedical research.
The foundation also considers the institutional commitment to support collaboration, provide encouragement, and extend technical support to the investigator, especially as related to translational approaches and technology transfer that could promote rapid clinical application of research results.
These results, obtained in Lille at the EGID (European Genomic Institute for Diabetes) Laboratory of Excellence, are published in the journal Nature Medicine on 20 April 2015.
The team directed by François Pattou is developing innovative therapies to control the more severe forms of diabetes, a disorder characterised by a high blood sugar levels, i.e. chronic hyperglycaemia. To treat type 1 diabetes, the laboratory is conducting projects based on the production of human islets, which are transplanted into patients. Islet transplantation restores production of insulin, the hormone that controls the level of sugar by storing it when its level in the blood is too high. Analysis of human islets destined for transplantation makes it possible to evaluate the cells and thus improve transplantation. It was in this context that the research team discovered a new mechanism for controlling glucagon secretion in humans, a mechanism that explains a side-effect of a new class of diabetes drugs used to treat type 2 diabetes associated with obesity and characterised by insulin resistance.
When the cells detect a low sugar level (e.g. during fasting), an increase in blood sugar level is required to provide the energy needed by the body. This involves another hormone, glucagon, the role of which is to stimulate sugar production by the liver in order to restore the blood glucose levels to normal as quickly as possible. This hormone, secreted by the alpha cells in the islets of Langerhans in the pancreas, has been somewhat forgotten compared to insulin, which is produced by the beta cells to stimulate storage of sugar. It is, however, an essential part of the physiopathology of diabetes.
In this study, the researchers discovered that a glucose cotransporter, SGLT2, known to reabsorb glucose in the kidney, is present in the alpha cells, and controls glucagon secretion. By measuring the expression of the gene for this transporter in the islets of diabetic donors (type 2), they observed a reduction in SGLT2 expression and an increase in glucagon expression compared with the islets of healthy subjects. This result was confirmed in mice with type 2 diabetes. As they became increasingly obese, expression of the cotransporter declined.
Unexpectedly, by revealing this mechanism, the researchers have explained the paradoxical increase in glucagon level observed in patients using a new class of diabetes drugs, the gliflozins, marketed in the United States and the United Kingdom. This class of drugs targets the glucose transporter located in the kidney, preventing the reabsorption of excess glucose in diabetics and its partial elimination in the urine.
"The diabetes treatment dapagliflozin, by blocking the SGLT2 receptor, stimulates the alpha cells and increases glucagon secretion," explains François Pattou.
This unexpected effect might at least partially limit the hypoglycaemic effect of this diabetes treatment, and, for the researchers, justifies the simultaneous administration of other drugs that limit glucagon secretion, such as the sulfonylureas or GLP-1 analogues. Before it is marketed in France, which is expected in the next few months, this discovery might enable patients receiving this treatment for type 2 diabetes to optimise its efficacy.
Diabetes drug could protect against low blood sugar levels by stimulating insulin production in the body
by Lund University
DPP-4 inhibitors are a group of drugs used to treat type 2 diabetes that lower high blood sugar levels by stimulating insulin production in the body. Researchers at Lund University in Sweden have now discovered that DPP-4 inhibitors are also effective against low blood sugar levels. The study, which was carried out on mice, has been published in the journal Diabetologia.
"If these inhibitors also prove effective in humans against low blood sugar, then this supports the idea that the area of application of these drugs could be broadened to include persons with diabetes that is difficult to control and suffer from frequent hypoglycaemias", said Siri Malmgren, a researcher at Lund University.
Blood sugar levels that are either too high or too low over a long period of time can cause serious harm to the body. Hypoglycaemia (low blood sugar) can occur in people with diabetes when they have eaten too little or after strenuous physical activity, as well as when they have taken too much insulin. It is an unpleasant condition with symptoms including heart palpitations and dizziness that can lead to a life-threatening 'insulin coma'. However, fatalities are extremely rare.
Normally, the body's own defence against hypoglycaemia is the hormone glucagon, which stimulates the liver to produce sugar and thus raise blood sugar levels. For those with diabetes, this regulation process doesn't work, leading to an increased risk of developing hypoglycaemia.
"In order to be able to offer people with diabetes more reliable treatment, it is important that their medication supports the body's own defences against hypoglycaemia", said Siri Malmgren, who conducted the study.
The researchers have therefore investigated whether DPP-4 inhibitors (Januvia, Galvus and others), an existing class of diabetes drugs could fulfil this function.
"One of the advantages of DPP-4 inhibition as a treatment for diabetes is the very low risk of hypoglycaemia. Through Dr Malmgren's important work, a fundamental new principle for this has been identified. We are now beginning to understand why DPP-4 inhibitors reduce the risk of this serious side effect", said Professor Bo Ahrén, the principal investigator for the study.
Mice treated with DPP-4 inhibitors were seen to have much better protection against hypoglycaemia than mice that were not given DPP-4 inhibitors. Their own production of glucagon also increased.
DPP-4 inhibitors stimulate the body's own insulin production - which lowers blood sugar - and work by raising the levels of another hormone - GIP - that is secreted in the intestines when we eat. Giving mice high doses of this hormone also protected them against hypoglycaemia and increased their glucagon levels.
"We believe that DPP-4 inhibitors not only lower blood sugar but also provide direct protection against hypoglycaemia, at least in mice, and that they do this by increasing levels of the hormones GIP and glucagon", said Siri Malmgren.
The researchers also reached the conclusion that GIP, which has previously been considered to lower blood sugar, in fact normalises blood sugar levels.
"Our findings could lead to new areas of application for existing drugs. We don't know all there is to know about the medicines we have, and once we have full insight into their mechanisms of action we can use them more effectively.
Scientists identify key control for blood glucose levels which could improve diabetes treatment
by Joanne Milne, University of Aberdeen
For people suffering from diabetes, managing blood sugar can be like walking a tightrope - if too high they run the risk of serious long term complications such as blindness, kidney failure, limb gangrene and premature heart disease, but allow it to drop too low and it can lead to a loss of consciousness which could be fatal.
Now a team of scientists from the UK and USA, has taken a major step forward in understanding how the brain senses low glucose levels and triggers responses to deal with this, which could help clinicians to devise new strategies to help control diabetes more safely.
They have identified a completely novel and hitherto unsuspected pathway buried deep within a region of the brain called the parabrachial nucleus. Here they found that a brain hormone, cholecystokinin (CCK), is a crucial sensor of blood glucose levels and orchestrates responses around the body when levels drop too low.
Professor Lora Heisler, from the University of Aberdeen Rowett Institute of Nutrition and Health, said: "It is remarkable to find that such an incredibly small set of cells in the brain play such an important role in maintaining normal glucose levels."
Dr Martin Myers, from the University of Michigan, said "We knew that CCK cells in the brain modify things like appetite and anxiety but they had previously been overlooked in terms of any link to blood sugar levels.
"The discovery of the important function of this brain hormone raises the possibility of using drugs targeting the CCK system to boost defences against hypoglycaemia, the clinical syndrome that results from low blood sugar. This can be extremely serious and in the most severe cases can lead to seizures, unconsciousness, brain damage and even death."
Professor Heisler and Dr Myers collaborated with colleagues from the universities of Aberdeen, Michigan, Cambridge, Edinburgh and Chicago to complete the study and their findings are now published in the journal Nature Neuroscience.
Professor Heisler said the identification of the role played by CCK could be of particular significance to around 20% of patients with diabetes who suffer from regular severe debilitating episodes brought on by low blood sugar.
"To allow glucose to enter the cells and provide the body with the energy it needs to carry out all basic functions, insulin is needed," Professor Heisler added.
"For those with diabetes, the effects of insulin on the body are drastically diminished, either because the pancreas doesn't produce enough of it (type 1 diabetes) and/or because cells are less responsive to it (type 2 diabetes).
"As a result, glucose can build up in the bloodstream and may reach dangerously high levels (hyperglycemia) which can result in serious long term complications such as blindness, kidney failure, limb gangrene and amputation and premature heart disease.
"To correct this problem, diabetics take insulin or other drugs designed to lower blood sugar levels but if they take too much insulin relative to the amount of glucose in their bloodstream, it can cause your blood sugar level to drop too low, resulting in hypoglycaemia.
"When patients suffer repeated bouts of hypoglycaemia they can develop 'unawareness' which means they find it difficult to detect symptoms that their blood sugar levels are falling and it is this group particularly that we hope could benefit from our findings in regard to the role played by CCK."
Dr Myers was the lead researcher in the study and now hopes to apply their findings in a clinical environment.
He said: "When blood sugar levels drop, a cascade of events takes place within the body which should boost it back up to normal levels but we did not know what triggered this chain of events.
"By identifying and understanding the basic machinery – CCK – that is organising and orchestrating this cascade of events, the more we can use that mechanism to help treat this disease.
"Further research is now needed to look at how we can target the CCK system as well as the cells upon which CCK acts to prevent or treat hypoglycaemia."
A gut hormone first described in 1928 plays an unanticipated and important role in the remote control of blood sugar production in the liver, according to a report in the August 6th Cell Metabolism, a Cell Press publication. What's more, the researchers show that rats fed a high-fat diet for a few days become resistant to the glucose-lowering hormone known as cholecystokinin (CCK).
"We show for the first time that CCK from the gut activates receptors to regulate glucose levels," said Tony Lam of the University of Toronto. "It does so via a gut-brain-liver neuronal axis."
Researchers already knew that CCK levels rise in the upper intestine in response to nutrients such as lipids to lower food intake, Lam explained. Now, his team shows that the CCK hormone binds local receptors on nerves of the small intestine, sending a powerful signal to the brain. The brain in turn tells the liver to stop producing glucose.
Lam said his group described the gut-brain-liver circuitry in a paper published last year. The new study shows that it is CCK that acts as the trigger.
A primary increase of CCK-8, the biologically active form of CCK, in the upper intestine lowers glucose production independently of any change to circulating insulin levels, they found. CCK-8's effects depend on activation of CCK-A receptors and the signals they send to the brain and on to the liver, where glucose production slows. Those effects of the hormone begin to fail early in the onset of high-fat diet-induced insulin resistance, they report.
The findings suggest that CCK resistance, like insulin resistance, might be a key contributor to the high blood sugar that often comes with a high-fat diet. It also suggests that drugs targeting the CCK receptors in the gut may hold promise for therapy. That's key, Lam said, because such gut-targeted drugs might be expected to have fewer side effects than currently available diabetes drugs that work directly on the liver.
"This raises the possibility that we might be able to tap into the circuitry [to lower blood sugar]," Lam said. "At least now we know where to start."
Drug combinations that could increase sensitivity to both insulin and CCK might better combat diabetes than either could alone, he added. While the magnitude of CCK's influence over glucose levels relative to the effects of insulin aren't yet known, Lam said it's now clear both are important and neither works properly in the case of diabetes or obesity.
The researchers further suggest that CCK's role in the gut might somehow explain why people often show improvements in their blood sugar levels following gastric bypass surgeries, even before they lose any weight.
"Since we described that duodenal CCK normally triggers a gut-brain-liver axis to lower glucose production but fails to do so in high-fat fed rodents, we propose that duodenal bypass surgeries improve glucose tolerance in diabetes and obesity partly because the surgery bypasses an acquired defect involving duodenal CCK resistance in response to high-fat feeding," they wrote. Further studies are needed to explore that notion.
Potential drug target identified for diabetes by studying novel gut-brain-liver circuit
Scientists at the Toronto General Hospital Research Institute have discovered a novel signaling pathway between three organs – the gut, the brain, and the liver – which lowers blood sugar when activated.
A team led by Dr. Tony Lam used a rat model to discover that fats can activate a subset of nerves in the intestine, which then send a signal to the brain and subsequently to the liver to lower glucose or sugar production. But eating a high-fat diet for just three days can interfere with this signal, disabling it so that it does not signal the other organs to lower blood glucose levels.
The research was published in a paper entitled, “Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production” as an advance on-line publication of the international science journal Nature.
“This is a new approach in developing more effective methods to lower glucose or blood sugar levels in those who are obese or have diabetes,” said Dr. Lam, who holds The John Kitson McIvor (1915 – 1942) Chair in Diabetes Research at the University Health Network and University of Toronto. Currently, those with diabetes lower their glucose through diet, exercise, anti-diabetic tablets or insulin injections (usually several times a day) and must regularly monitor blood glucose levels. High glucose levels can result in damage to eyes, nerves and kidneys and increase the risk of heart attack, stroke, blindness, erectile dysfunction, foot problems and amputations. Many laboratories around the world are in a race to find alternative and effective ways in which to lower glucose levels because of the severe complications which can result from high sugar levels.
“We already knew that the brain and liver can regulate blood glucose levels, but the question has been, how do you therapeutically target either of these two organs without incurring side effects?” noted Dr. Lam, who is also an Assistant Professor of Physiology and Medicine at the University of Toronto. “We may have found a way around this problem by suggesting that the gut can be the initial target instead. Much like a remote control device, the gut is able to relay a signal to the brain which in turn signals the liver to lower glucose production. If new medicines can be developed that stimulate this sensing mechanism in the gut, we may have an effective way of slowing down the body’s production of sugar, thereby lowering blood sugar levels in diabetes.”
Dr. Lam emphasized that it will take a number of years of experimental work to determine whether this approach is effective and safe in humans who have diabetes.
More than two million Canadians have diabetes. “Diabetes is an epidemic in Canada and around the world and its numbers are continuing to increase at an alarming rate, consuming our precious health care resources,” says Dr. Gary Lewis, Head of the Division of Endocrinology and Metabolism at the University Health Network and Mount Sinai Hospitals in Toronto and Professor of Medicine and Physiology at the University of Toronto. “We have good evidence from clinical trials which shows that lowering blood glucose levels towards normal in those who develop diabetes has a major impact in preventing its devastating complications, so it is critical that we learn how to control these levels in the most effective and least invasive ways possible. Dr. Lam’s work reveals a new regulatory circuit which provides novel sites and targets to lower these levels in diabetes and obesity.”
Dr. Richard Weisel, Director of the Toronto General Research Institute (TGRI), Professor and Chairman of Cardiac Surgery at the University of Toronto, welcomes any potential interventions which can help lower blood sugar levels. “Studies have shown that people with very high blood glucose levels are more likely to die from heart disease, so anything that we can discover to help lower these levels would help in decreasing the progression of and mortality from cardiovascular disease.”
"Tony's discovery represents an exciting breakthrough that could eventually lead to new ways to treat diabetes," observed Dr. Diane Finegood, Scientific Director of the Institute of Nutrition, Metabolism and Diabetes, part of the Canadian Institutes of Health Research (CIHR). "I am pleased that CIHR played a major role in funding this research".
Working with rats, Dr. Lam and colleagues designed and performed a series of elegant experiments which showed for the first time that the lipids or fats which enter the small intestine trigger the afferent neuronal signal to the brain which then sends signals to the liver to lower glucose production and blood glucose levels in as little as fifteen minutes. No drop in levels occurred when nerves were cut or blocked between the gut and the brain or between the brain and the liver. The trigger to lower glucose was also disabled when rats were fed a high-fat diet for three days prior to the experiment, a finding which may suggest that those who eat a high fat diet lose this beneficial signaling pathway.
Study offers insights on how the timing of dinner and genetics affect individuals' blood sugar control
by Massachusetts General Hospital
Credit: CC0 Public Domain
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, Ph.D., 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, Ph.D., 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, Ph.D., 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."
Melatonin and mealtime: Common genetic difference could put some at greater risk of diabetes
by Brigham and Women's Hospital
Credit: Darren Lewis/public domain
Researchers from Brigham and Women's Hospital (BWH) and the University of Murcia, Spain, have shed new light on why people who carry a common genetic mutation may be more at risk for developing type 2 diabetes. By carefully studying healthy subjects, researchers were able to chart the effect of melatonin supplements on blood sugar control. Their results, reported in Metabolism, suggest that taking melatonin close to mealtimes may put people with a common genetic variant more at risk.
"Our work is the first to show that a person's genetic profile could impact their ability to tolerate glucose when they take melatonin," said co-corresponding author Frank Scheer, PhD, associate professor of medicine at Harvard Medical School and the Director of the Medical Chronobiology at BWH.
"Our results suggest that we may need to exert caution when taking melatonin close to meal times, especially in carriers of the risk variant," said co-corresponding author Marta Garaulet, PhD, a full professor of Physiology at the University of Murcia.
As many as 50 percent of people of European ancestry carry this genetic variation in MTNR1B, a gene that encodes a melatonin receptor. Previous studies have found that this mutation increases a person's risk of diabetes, but exactly how and why it influences blood sugar control has remained poorly understood and has mostly been studied during the daytime, when naturally occurring melatonin concentrations are very low.
Scheer, Garaulet and their colleagues studied members of a female rugby team at the University of Murcia to investigate the effects of taking melatonin supplements on blood sugar levels. By looking at a small group of similar subjects, the research team could narrow in on the effects of melatonin and limit other possible causes of differences in results. Each recipient received either a dose of melatonin or a placebo in the morning (9 a.m.) and evening (9 p.m.), followed by a large dose of glucose, a so called oral glucose tolerance test. Blood samples were taken before and at 30-minute intervals after they received the glucose doses for the next two hours.
Of the 17 participants, 11 were carriers of the genetic risk variant and six were not. The research team found that in the morning, the effects of melatonin on ability to control blood sugar levels differed significantly between the two groups, finding that the carriers' ability to control blood sugar levels was six times worse than non-carriers'. In the evening, no significant differences were found between the two groups. The absence of the effect in the evening may have been due to a limited sample size.
"Our data suggest that when subjects take melatonin, the genetic risk variant in MTNR1B causes a much greater change in glucose tolerance in carriers compared to non-carriers, even in people who are not obese and not diabetic," said Scheer. "Our results suggest that it may be important to take genetics into account when thinking about timing of food consumption and melatonin administration." The team notes that further, large-scale studies will be needed in vulnerable populations before clinical recommendations can be made.
Gene associated with diabetes risk suggests link with body clock
New research shows a link between the body clock and diabetes.
A connection between the body clock and abnormalities in metabolism and diabetes has been suggested in new research by an international team involving the University of Oxford, the Wellcome Trust Sanger Institute and the MRC Epidemiology Unit in Cambridge.
The researchers have identified a gene involved in the way the body responds to the 24 hour day-night cycle that is strongly linked to high blood sugar levels and an increased risk of type 2 diabetes. The results of the genome-wide association scan are published in Nature Genetics.
‘We have extremely strong, incontrovertible evidence that the gene encoding melatonin receptor 1B is associated with high fasting glucose levels and increased risk of type 2 diabetes,’ says Professor Mark McCarthy of the Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford.
Melatonin is a hormone that is strongly tied to control of our sleep-wake cycles, with concentrations in the blood peaking at nighttime and dipping during the day. As a result, melatonin is implicated in conditions like jetlag and sleep disorders.
Disrupted sleep patterns are known to be associated with a range of health problems including metabolic disorders like diabetes, but it is not understood how they are connected. In identifying a link between a melatonin receptor and blood sugar levels, this study provides genetic evidence that mechanisms controlled by our body clock are connected to the machinery that keeps us metabolically healthy. It seems likely that the action of melatonin on the pancreas is being disturbed in this case, the researchers suggest.
The international research collaboration combined ten genome-wide association scans involving a total of over 36,000 individuals of European descent. A variant in the gene encoding melatonin receptor 1B (MTNR1B) showed a rise of 0.07 mmol/l in fasting glucose level on average and a 9% increase in risk of type 2 diabetes for each copy of the gene variant inherited from a parent.
‘High fasting glucose levels are early markers of diabetes and this observation provides important clues about the possible mechanisms linking genes to diabetes risk,’ says Professor Nick Wareham, Director of the MRC Epidemiology Unit in Cambridge.
Other genes have previously been shown to be associated with high blood sugar levels, but have not shown an increase in diabetes risk. The melatonin receptor found in this genome-wide study is the first gene to be linked to both high blood sugar and increased risk of diabetes.
‘Although levels of glucose in the blood are used to diagnose diabetes, most of the genes previously associated with high glucose levels do not increase risk of diabetes,’ says Dr Inês Barroso from the Wellcome Trust Sanger Institute. ‘We have found a variant – a G in the genome in place of a C – in MTNR1B. This single-letter change influences both sugar levels and diabetes. This remarkable result should allow us to gain new insight into this problem.’
Physical activity protects against type 2 diabetes by modifying metabolism
by University of Eastern Finland
Figure 1. The association of physical activity (PA) changes with glucose and insulin concentrations, insulin sensitivity, and insulin secretion in 5867 participants without diabetes at baseline, subjected to oral glucose tolerance tests both at baseline and follow-up visits. The effect sizes (β, SE) are given as the standardized mean differences for participants who decreased their PA (PADec) or increased their PA (PAInc) compared to the reference category of no changes in their PA (PA0). The p-values were adjusted for age, follow-up time, corresponding metabolic trait at baseline, BMI, smoking, alcohol consumption, and PA at baseline. Credit: DOI: 10.3390/metabo12010069
Regular physical activity significantly changes the body's metabolite profile, and many of these changes are associated with a lower risk of type 2 diabetes, a new study from the University of Eastern Finland shows. The study population included more than 7,000 men who were followed up for eight years. Men in the highest physical activity category had a 39% lower risk of type 2 diabetes than men who were physically inactive. Physical activity was associated with the levels of a total of 198 metabolites, i.e., compounds formed as a result of the body's metabolism, and increased physical activity had an impact on some of the same metabolites that have previously been associated with a health-promoting diet. In addition, the study showed that increased physical activity improves insulin secretion.
A total of 1,260 metabolites were analyzed from the study participants' fasting glucose samples. The association of physical activity with the metabolite profile hasn't been studied this comprehensively nor in such an extensive cohort before. Indeed, published in Metabolites, this study is the first to establish an association between many metabolites and physical activity.
The researchers investigated the association of physical activity with metabolite profile, insulin sensitivity, insulin secretion and risk of type 2 diabetes in men participating in the METabolic Syndrome In Men (METSIM) study. None of the participants had diabetes at the onset of the study. A physical activity questionnaire was conducted among the participants at the onset of the study and again eight years later, and they also underwent an oral glucose tolerance test and had their metabolites analyzed from a fasting glucose sample.
Men were classified into four categories based on their physical activity: those who were physically inactive, those who were physically active only occasionally, those who were physically active regularly but no more than twice a week, and those who were physically active regularly at least three times a week. The duration of a single session of physical activity was defined as at least 30 minutes.
Physical activity was associated with the levels of a total of 198 metabolites. Among other things, physical activity changed the levels of several lipids in a manner that in previous studies has been associated with a lower risk of type 2 diabetes. In previous studies, a health-promoting diet has also been observed to have some similar associations with unsaturated fatty acid levels, for example. As completely new metabolic biomarkers associated with physical activity, the researchers identified in particular steroids, amino acids, imidazoles, carboxylic acids, and hydroxy acids.
During the follow-up, the risk of developing type 2 diabetes was 39% lower for men who were physically the most active, and 30% lower even for men who were physically active no more than twice a week, when compared to men who were physically inactive. Lower fasting glucose and insulin levels, and better insulin sensitivity and insulin secretion, were observed in men who increased their physical activity during the follow-up.
The association of physical activity with insulin secretion has remained unclear, despite several studies on the matter. The study published now confirms that increased physical activity improves insulin secretion.
Moderate-to-vigorous physical activity and less sitting reduce the risk of diabetes in older adults
by University of Oulu
Credit: Unsplash/CC0 Public Domain
According to a recent study, moderate-to-vigorous physical activity and less sedentary time improve glucose metabolism and reduce the risk of type 2 diabetes in older adults. Based on the results, it is important to encourage older adults to avoid sedentary time and increase moderate-to-vigorous physical activity to improve their glucose metabolism.
The study is part of the population-based Oulu1945 survey conducted in 2013–2015 by the University of Oulu and Oulu Deaconess Institute's Department of Sports and Exercise Medicine, Finland. The survey involved a total of 660 Oulu residents born in 1945 and between the ages of 67 and 69, at that time. Physical activity and sedentary time were measured with a wrist-worn accelerometer for a period of two weeks, and the glucose metabolism was examined using an oral glucose tolerance test. The subjects were divided into the following four profiles based on the amount of moderate-to-vigorous physical activity and sedentary time: "couch potatoes," "light movers," "sedentary actives" and "actives."
"Active" older adults had a lower incidence of type 2 diabetes and prediabetes than older adults in the 'couch potatoes' profile, one in two of whom were found to have a glucose metabolism disorder. The blood glucose and insulin concentrations in the 'active' profile were lower throughout the glucose tolerance test compared to those in the less physically active groups. Older adults in the 'active' profile had a better glucose tolerance and muscle insulin sensitivity than those in the 'couch potatoes' profile, both clear signs of a reduced risk of diabetes.
"Previous surveys have suggested a link between older adults' physical activity and glucose metabolism, but the use of the accelerometer in studies involving older adults has been negligible. In this study, we were able to make a distinction between moderate-to-vigorous physical activity and sedentary time through accelerometry and to then profile the subjects on that basis in different activity profiles. We analyzed the association between the physical activity profile and glucose metabolism, which is a new perspective. By the activity profiles, we can see that, from the point of view of glucose metabolism, physical activity alone is not enough: you should be active and potter about throughout the day," says researcher Miia Länsitie.
The risk of glucose metabolism disorders increases significantly in older age, making it essential to find ways to prevent diabetes in older adults. Based on this study, an active lifestyle, including moderate-to-vigorous physical activity and limited sedentary time, also promotes older adults' glucose metabolism and can play a significant role in preventing diabetes in older people.
"Older adults with long-term illnesses or functional limitations, who may find it impossible to achieve the recommended level of physical activity, should spend less time sitting down and more pottering about every day to enhance their glucose metabolism," Länsitie says.
Study shows active older adults have better physical and mental health
by American Cancer Society
Credit: CC0 Public Domain
Older adults with higher physical activity and lower sitting time have better overall physical and mental health, according to a new study from the American Cancer Society (ACS). The study, appearing in the journal, CANCER, suggests that higher amounts of regular moderate- to vigorous-intensity physical activity (MVPA) and lower duration of sedentary time is associated with higher global mental and physical health for older cancer survivors and older adults, in general.
With a rapidly aging population and nearly 16.9 million cancer survivors in the United States today, there is a need to identify strategies associated with healthy aging and improving quality of life for aging cancer survivors. Being physically active is related to several health benefits, and in this study, ACS investigators led by Dr. Erika Rees-Punia analyzed self-reported aerobic and muscle-strengthening physical activities, sitting time, and mental and physical health among nearly 78,000 participants in the ACS's Cancer Prevention Study II Nutrition Cohort. Participants (average age 78 years) included older cancer survivors up to 10 years post-diagnosis, and cancer-free adults.
The investigators found that regardless of cancer history, the differences in global mental and physical health between the most and least active, and the least and most sedentary, were clinically meaningful. These findings provide evidence for the importance of engaging in regular MVPA and decreasing sitting time as a reasonable non-pharmacologic strategy to improve quality of life in older men and women, with or without a prior cancer diagnosis. In fact, the recently published ACS physical activity guidelines recommend that adults get 150-300 minutes of moderate-intensity activity or 75-150 minutes of vigorous-intensity activity through the week, and to limit sedentary behaviors such as screen-based entertainment.
"The findings reinforce the importance of moving more and sitting less for both physical and mental health, no matter your age or history of cancer," said Rees-Punia. "This is especially relevant now as so many of us, particularly cancer survivors, may be staying home to avoid COVID-19 exposure, and may be feeling a little isolated or down. A simple walk or other physical activity that you enjoy may be good for your mind and body."
Replacing sitting time with physical activity associated with lower risk of death
by American Cancer Society
Credit: CC0 Public Domain
For those who get the least amount of physical activity, replacing a half hour of sitting time with physical activity was associated with up to a nearly 50% reduction in mortality, according to a new study from the American Cancer Society. The study, appearing in the American Journal of Preventive Medicine, suggests that replacing modest amounts of sitting time with even light physical activity may have the potential to reduce the risk of premature death among less active adults.
Regular moderate- to vigorous-intensity physical activity (MVPA) is associated with a lower risk of cardiovascular disease; certain cancers; and premature death. In addition, the amount of time spent sedentary-distinct from physical inactivity—is associated with a higher risk of death and disease. That may be a result, at least in part, from sedentary behavior displacing physical activity.
Most previous studies have explored the potential effect of sedentary time without considering the physical activity it displaces, leaving a gap in the understanding of the issue. To explore further, investigators led by Erika Rees-Punia, Ph.D., analyzed self-reported sitting time, light physical activity, and moderate/vigorous physical activity among 92,541 participants in the ACS's Cancer Prevention Study II Nutrition Cohort.
The analysis reviewed sedentary time and activity levels over 14 years. It found among those who were the least active at baseline (?17 minutes/day moderate to vigorous physical activity), replacing 30 minutes/day of sitting with light physical activity was associated with a 14% reduced risk of death, while replacement with moderate to vigorous physical activity was associated with a 45% reduced risk of death.
The investigators found similar but smaller associations among moderately active participants: replacing a half hour of sedentary time with light physical activity was associated with a 6% reduction in mortality among those who were moderately active; replacing 30 minutes of sitting time with moderate to vigorous physical activity was associated with a 17% mortality reduction in this group. However, for the most active (>38 minutes/day of MVPA), substitution of sitting time with light physical activity or MVPA was not associated with a reduction in mortality risk.
Participants reporting more moderate/vigorous physical activity were leaner, had a higher educational attainment, and were less likely to be current smokers. For all participants, sitting time largely included watching TV (39%) and reading (20%).
The study did have some limitations: it relied on self-reported physical activity and sitting time; it lacked information on certain activities of daily living (e.g., cleaning, self-care, cooking) that are particularly common for older adults. And participants were predominately white and educated, so may not represent the general U.S. population.
"These findings suggest that the replacement of modest amounts of sitting time with even light physical activity may have the potential to reduce the risk of premature death among less active adults," conclude the authors.
Behavioral intervention ups physical activity in T2DM
(HealthDay)—A behavioral intervention results in a sustained increase in physical activity and decrease in sedentary time among patients with type 2 diabetes, according to a study published in the March 5 issue of the Journal of the American Medical Association.
Stefano Balducci, M.D., from "La Sapienza" University in Rome, and colleagues enrolled 300 physically inactive and sedentary patients with type 2 diabetes to receive a behavioral intervention or standard of care for three years. One individual theoretical counseling session and eight biweekly theoretical and practical counseling sessions were provided each year to participants in the behavioral intervention group. In the standard care group, participants received only general physician recommendations.
Participants were followed for a median of 3.0 years. The researchers found that in the behavioral intervention and standard care groups, respectively, participants accumulated 13.8 and 10.5 metabolic equivalent-hours per week of physical activity volume, 18.9 and 12.5 minutes/day of moderate-to-vigorous intensity physical activity, 4.6 and 3.8 hours/day of light-intensity physical activity, and 10.9 and 11.7 hours/day of sedentary time. Throughout the study, the significant between-group differences were maintained; during the third year, the between-group difference in moderate-to-vigorous intensity physical activity decreased.
"This behavioral intervention strategy was successful in increasing physical activity volume by reallocating sedentary time to light-intensity physical activity and, to a lesser extent, moderate- to vigorous-intensity physical activity," the authors write.
Several authors disclosed financial ties to the pharmaceutical industry.
Once-yearly counseling tied to more physical activity in T2DM
(HealthDay)—Theoreti cal and practical once-yearly counseling for three years is associated with increased physical activity (PA) and reduced sedentary (SED) time in patients with type 2 diabetes, according to a study published online Aug. 18 in Diabetes Care.
Stefano Balducci, M.D., from La Sapienza University in Rome, and colleagues randomized 300 physically inactive and sedentary patients with type 2 diabetes to receive theoretical and practical counseling once yearly for three years (intervention group [INT]) or standard care (control group). The authors reported the four-month effects on objectively measured daily light-intensity PA (LPA), moderate-to-vigorous PA (MVPA), and SED time, as well as cardiovascular risk factors.
The researchers observed increases in LPA and MVPA in both groups, and decreases in SED time, although the changes were significantly more marked in INT participants. In INT participants only there was a significant reduction in hemoglobin A1c (HbA1c). There was an association for an increase in LPA >0.92 hours/day and in MVPA >7.33 min/day, and a decrease in SED time >1.05 hours/day, with an average decrease of about 1 percent in HbA1c and with significant improvements in fasting glucose, body weight, waist circumference, and high sensitivity C-reactive protein. PA and SED time changes independently predicted improvement in HbA1c.
"Significant improvements in cardiometabolic risk profiles were observed in subjects experiencing the most pronounced changes in PA and SED time, even if below the recommended level," the authors write.
Several authors disclosed financial ties to the pharmaceutical industry.
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