Posts tagged insulin resistance
Articles and news from the latest research reports.
Set of molecules found to link insulin resistance in the brain to diabetes
A key mechanism behind diabetes may start in the brain, with early signs of the disease detectable through rising levels of molecules not previously linked to insulin signaling, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai published today in the journal Cell Metabolism.
(Image: Shutterstock)
New Link Found Between Obesity and Insulin Resistance
Obesity is the main culprit in the worldwide avalanche of type 2 diabetes. But how excess weight drives insulin resistance, the condition that may lead to the disease, is only partly understood. Scientists at Joslin Diabetes Center now have uncovered a new way in which obesity wreaks its havoc, by altering the production of proteins that affect how other proteins are spliced together. Their finding, published in Cell Metabolism, may point toward novel targets for diabetes drugs.
Scientists in the lab of Mary-Elizabeth Patti, M.D., began by examining the levels of proteins in the livers of obese people, and finding decreases in number for certain proteins that regulate RNA splicing.
“When a gene is transcribed by the cell, it generates a piece of RNA,” explains Dr. Patti, who is also an Assistant Professor of Medicine at Harvard Medical School. “That piece of RNA can be split up in different ways, generating proteins that have different functions.”
“In the case of these proteins whose production drops in the livers of obese people, this process changes the function of other proteins that can cause excess fat to be made in the liver,” she adds. “That excess fat is known to be a major contributor to insulin resistance.”
Additionally, the researchers showed that these RNA splicing proteins are diminished in samples of muscle from obese people.
The investigators went on to examine a representative RNA-splicing protein called SFRS10 whose levels drop in muscle and liver both in obese people and in over-fed mice. Working in human cells and in mice, they demonstrated that SFRS10 helps to regulate a protein called LPIN1 that plays an important role in synthesizing fat. Among their results, mice in which they suppressed production of SFRS10 made more triglycerides, a type of fat circulating in the blood.
“More broadly, this work adds a novel insight into how obesity may induce insulin resistance and diabetes risk by changing critical functions of cells, including splicing,” says Dr. Patti. “This information should stimulate the search for other genes for which differences in splicing may contribute to risk for type 2 diabetes. Ultimately, we hope that modifying these pathways with nutritional or drug therapies could limit the adverse consequences of obesity.”
(Source: joslin.org)
High Sugar Intake Linked to Low Dopamine Release in Insulin Resistant Patients
PET study led by Stony Brook Professor indicates that overeating and weight gain contributing to onset of diabetes could be related to a deficit in reward circuits in the brain
Using positron emission tomography (PET) imaging of the brain, researchers have identified a sweet spot that operates in a disorderly way when simple sugars are introduced to people with insulin resistance, a precursor to type 2 diabetes. For those who have the metabolic syndrome, a sugar drink resulted in a lower-than-normal release of the chemical dopamine in a major pleasure center of the brain. This chemical response may be indicative of a deficient reward system, which could potentially be setting the stage for insulin resistance. This research could revolutionize the medical community’s understanding of how food-reward signaling contributes to obesity, according to a study presented at the Society of Nuclear Medicine and Molecular Imaging’s 2013 Annual Meeting.
"Insulin resistance is a significant contributor to obesity and diabetes," said Gene-Jack Wang, MD, lead author of the study and Professor of Radiology at Stony Brook University and researcher at the U.S. Department of Energy’s Brookhaven National Laboratory in Upton, N.Y. "A better understanding of the cerebral mechanisms underlying abnormal eating behaviors with insulin resistance would help in the development of interventions to counteract the deterioration caused by overeating and subsequent obesity. We suggest that insulin resistance and its association with less dopamine release in a central brain reward region might promote overeating to compensate for this deficit."
An estimated one-third of Americans are obese, according to the U.S. Centers for Disease Control and Prevention. The American Diabetes Association estimates that about 26 million Americans are living with diabetes and another 79 million are thought to be prediabetic, including those with insulin resistance.
The tendency to overeat may be caused by a complex biochemical relationship, as evidenced by preliminary research with rodents. Dr. Wang’s research marks the first clinical study of its kind with human subjects.
"Animal studies indicated that increased insulin resistance precedes the lack of control associated with pathological overeating," said Wang. "They also showed that sugar ingestion releases dopamine in brain regions associated with reward. However, the central mechanism that contributes to insulin resistance, pathological eating and weight gain is unknown."
He continued, “In this study we were able to confirm an abnormal dopamine response to glucose ingestion in the nucleus accumbens, where much of the brain’s reward circuitry is located. This may be the link we have been looking for between insulin resistance and obesity. To test this, we gave a glucose drink to an insulin-sensitive control group and an insulin-resistant group of individuals and we compared the release of dopamine in the brain reward center using PET.”
In this study, a total of 19 participants-including 11 healthy controls and eight insulin-resistant subjects-consumed a glucose drink and, on a separate day, an artificially sweetened drink containing sucralose. After each drink, PET imaging with C-11 raclopride-which binds to dopamine receptors-was performed. Researchers mapped lit-up areas of the brain and then gauged striatal dopamine receptor availability (which is inversely related to the amount of natural dopamine present in the brain). These results were matched with an evaluation in which patients were asked to document their eating behavior to assess any abnormal patterns in their day-to-day lives. Results showed agreement in receptor availability between insulin-resistant and healthy controls after ingestion of sucralose. However, after patients drank the sugary glucose, those who were insulin-resistant and had signs of disorderly eating were found to have remarkably lower natural dopamine release in response to glucose ingestion when compared with the insulin-sensitive control subjects.
"This study could help develop interventions, i.e., medication and lifestyle modification, for early-stage insulin-resistant subjects to counteract the deterioration that leads to obesity and/or diabetes," said Wang. "The findings set a path for future clinical studies using molecular imaging methods to assess the link of peripheral hormones with brain neurotransmitter systems and their association with eating behaviors."
Circadian clock linked to obesity, diabetes and heart attacks
Disruption in the body’s circadian rhythm can lead not only to obesity, but can also increase the risk of diabetes and heart disease.
That is the conclusion of the first study to show definitively that insulin activity is controlled by the body’s circadian biological clock. The study, which was published on Feb. 21 in the journal Current Biology, helps explain why not only what you eat, but when you eat, matters.
The research was conducted by a team of Vanderbilt scientists directed by Professor of Biological Sciences Carl Johnson and Professors of Molecular Physiology and Biophysics Owen McGuinness and David Wasserman.
“Our study confirms that it is not only what you eat and how much you eat that is important for a healthy lifestyle, but when you eat is also very important,” said postdoctoral fellow Shu-qun Shi, who performed the experiment with research assistant Tasneem Ansari in the Vanderbilt University Medical Center’s Mouse Metabolic Phenotyping Center.
In recent years, a number of studies in both mice and men have found a variety of links between the operation of the body’s biological clock and various aspects of its metabolism, the physical and chemical processes that provide energy and produce, maintain and destroy tissue. It was generally assumed that these variations were caused in response to insulin, which is one of the most potent metabolic hormones. However, no one had actually determined that insulin action follows a 24-hour cycle or what happens when the body’s circadian clock is disrupted.
Because they are nocturnal, mice have a circadian rhythm that is the mirror image of that of humans: They are active during the night and sleep during the day. Otherwise, scientists have found that the internal timekeeping system of the two species operate in nearly the same way at the molecular level. Most types of cells contain their own molecular clocks, all of which are controlled by a master circadian clock in the suprachiasmatic nucleus in the brain.
“People have suspected that our cells’ response to insulin had a circadian cycle, but we are the first to have actually measured it,” said McGuinness. “The master clock in the central nervous system drives the cycle and insulin response follows.”
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.”
Research shows diabetes drug improves memory
An FDA-approved drug initially used to treat insulin resistance in diabetics has shown promise as a way to improve cognitive performance in some people with Alzheimer’s disease.
Working with genetically engineered mice designed to serve as models for Alzheimer’s, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer’s on the behavior of a key brain-signaling molecule.
The molecule, called extracellular signal-regulated kinase (ERK), becomes hyperactive both in the brains of Alzheimer’s patients and in the mice at a disease stage corresponding to mild cognitive impairment in human Alzheimer’s. This excessive activity leads to improper synaptic transmission between neurons, interfering with learning and memory.
Rosiglitazone brings ERK back into line by activating what’s known as the peroxisome proliferator-activated receptor gamma (PPARγ) pathway, which interacts with genes that respond to both PPARγ and ERK.
“Using this drug appears to restore the neuronal signaling required for proper cognitive function,” said UTMB professor Larry Denner, the lead author of a paper describing this work now online (posted Nov. 21) in the Journal of Neuroscience. “It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer’s patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer’s.”
Key protein interactions involved in neurodegenerative disease revealed
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative disease and insulin resistance. The enzymes in question, which play a critical role in nerve cell (neuron) survival, are among the most prized targets for drugs to treat brain disorders such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).
The study was published online ahead of print on November 8, 2012, by the journal Structure.
The new study reveals the structure of a class of enzymes called c-jun-N-terminal kinases (JNK) when bound to three peptides from different protein families; JNK is an important contributor to stress-induced apoptosis (cell death), and several studies in animal models have shown that JNK inhibition protects against neurodegeneration.
"Our findings have long-range implications for drug discovery," said TSRI Professor Philip LoGrasso, who, along with TSRI Associate Professor Kendall Nettles, led the study. "Knowing the structure of JNK bound to these proteins will allow us to make novel substrate competitive inhibitors for this enzyme with even greater specificity and hopefully less toxicity."
The scientists used what they called structure class analysis, looking at groups of structures, which revealed subtle differences not apparent looking at them individually.
"From a structural point of view, these different proteins appear to be very similar, but the biochemistry shows that the results of their binding to JNK were very different," he said.
LoGrasso and his colleagues were responsible for creating and solving the crystal structures of the three peptides (JIP1, SAB, and ATF-2) with JNK3 using a technique called x-ray crystallography, while Nettles handled much of the data analysis.
All three peptides have important effects, LoGrasso said, inducing two distinct inhibitory mechanisms—one where the peptide caused the activation loop to bind directly in the ATP pocket, and another with allosteric control (that is, using a location on the protein other than the active site). Because JNK signaling needs to be tightly controlled, even small changes in it can alter a cell’s fate.
"Solving the crystal structures of these three bound peptides gives us a clearer idea of how we can block each of these mechanisms related to cell death and survival," LoGrasso said. "You have to know their structure to know how to deal with them."
(Source: medicalxpress.com)
Alzheimer’s triggered by “type three diabetes”
An unhealthy diet could lead to Alzheimer’s disease by triggering a form of insulin resistance dubbed “type three diabetes”, scientists claim.
Photo: Getty Images/Peter Macdiarmid
High levels of the hormone insulin, brought on by a bad diet, may harm the brain in the same way that the muscle, liver and fat cells are affected by type two diabetes. Exposing the brain to too much insulin could cause it to stop responding to the hormone, hampering our ability to think and create new memories and ultimately leading to permanent damage, researchers said.
A diet high in fat and sugar has long been linked to a higher risk of Alzheimer’s, while studies of health among large populations have shown that a healthy Mediterranean diet may offer some protection. In type two diabetes, eating too much fatty and sugary food raises our insulin levels to such a consistently high degree that our muscles, fat and liver cells are no longer affected by the hormone.
This means that the amount of glucose and fat in our blood is allowed to increase unchecked, forcing the pancreas to produce even more insulin to try to cope. Ultimately it becomes exhausted and production drops to very low levels.
A small-scale trial on human patients at Washington University found that those who were given a nasal spray containing insulin were better at remembering details of stories, had longer attention spans and were more independent. A further trial on 240 volunteers showing early signs of dementia will provide further clues as to whether the spray can protect memory and learning ability and keep track of brain changes in patients.
A study on rats by experts from Brown University suggest that a similar process could affect the brain, which relies on insulin to regulate nerve signals related to memory and learning and to produce energy from glucose. Researchers found that blocking insulin from rats’ brains made them disorientated and unable to find their way out of a maze because they could not remember where they were.
Examination of their brains showed the same pattern of deterioration seen in Alzheimer’s patients, including increased levels of the amyloid plaque which is a key hallmark of the condition. If the theory is correct, it means eating more healthy foods and exercising more could reduce the risk of Alzheimer’s, and potentially reverse or slow down the memory loss in patients with the condition.
Dr Suzanne de la Monte, who led the study, told New Scientist magazine: “[The rats] were demented. They couldn’t learn or remember. “I believe [Alzheimer’s] starts with insulin resistance. If you can avoid brain diabetes you’ll be fine. But once it gets going you are going to need to attack on multiple fronts.”
(Source: telegraph.co.uk)