Posted on Diabetes

Scientists unveil promising new approach to diabetes prevention

Scripps Research scientists unveil promising new approach to diabetes prevention


A Scripps Research team found a compound that protects against diabetes-like metabolic changes in obese mice, including the reduction in liver fat deposits of treated obese mice (right) compared to untreated (left). CREDIT Scripps Research

A team of scientists from Scripps Research has conducted promising early tests of a new strategy that might one day be used to prevent or treat type 2 diabetes.

The scientists, whose results are reported in Nature Communications, tested an experimental compound called IXA4 in obese mice. They showed that the compound activates a natural signaling pathway that protects the animals from harmful, obesity-driven metabolic changes that would normally lead to diabetes.

“We were able to activate this pathway in both the liver and the pancreas with this one compound, and that added up to a significant overall improvement in metabolic health of obese animals,” says Scripps Research’s Luke Wiseman, PhD.

“This is the first time anyone has shown that a small molecule activating this pathway in this manner works to treat disease in a live animal,” adds Enrique Saez, PhD.

The study was a collaboration between the laboratories of Saez and Wiseman, who are both professors in the Department of Molecular Medicine at Scripps Research and co-senior authors on the new paper.

Type 2 diabetes remains a major public health problem: about 30 million people are estimated to have it in the U.S. alone. Driven largely by overweight and obesity, it features the loss of normal blood sugar regulation, and brings a multitude of health issues including higher risks of heart disease, stroke, kidney disease, nerve damage, retinal degeneration, and some cancers. There are many drugs for treating type 2 diabetes, but none that works well for every patient.

For several years, Wiseman’s lab has been studying a signaling pathway involving two proteins called IRE1 and XBP1s. When activated by a certain type of cellular stress, IRE1 activates XBP1s, which in turn alters the activity of a host of genes, including many metabolic genes, in an effort to reduce the cellular stress. Prior studies suggest that the activity of this pathway, at least in the short-term, can protect liver and fat cells from stresses caused by obesity—stresses that can harm these cells in ways that promote diabetes.

The IRE1/XBP1s pathway is not a straightforward diabetes drug target, however. Past research has shown that keeping IRE1/XBP1 switched on chronically ends up harming cells, triggering inflammation and worsening overall metabolic dysfunction.

“IRE1/XBP1s signaling is a response to cellular stress, and keeping it on all the time essentially tells the cell that the stress can’t be resolved—so the cell in effect kills itself,” Wiseman says.

In the new study, the researchers showed that a compound they identified a few years ago, IXA4, activates IRE1/XBP1s for just a few hours at a time. Because it otherwise allows IRE1 to turn off, it can in principle be given daily without triggering the deleterious signaling seen with constant IRE1 activation, making it a promising candidate to explore for human treatments.

The team used IXA4 to treat mice that were obese from a high-fat, high-calorie diet. After just eight weeks, the treated mice had improved glucose metabolism and insulin activity, less fat buildup and inflammation in the liver, and no loss of insulin-producing cells in the pancreas, compared to untreated obese mice.

IXA4 can reach only a limited set of tissues including the liver and pancreas, and so the team is now developing other compounds that can get into a broader set of cells including fat cells.

“We’re also continuing to work with IXA4 as a potential treatment for other metabolic disorders such as fatty liver disease,” Saez says.

Posted on Patient Talk

Pictorial warnings could reduce purchases of sugary drinks

Pictorial warnings could reduce purchases of sugary drinks

Photographs of UNC Mini Mart during a trial evaluating graphic health warnings for sugary drinks. CREDIT Hall MG et al., 2022, PLOS Computational Biology

Purchases of sugary drinks could be reduced by pictorial health warnings, reports research publishing February 1st in the open access journal PLOS Medicine. A trial in a naturalistic store setting found parents bought fewer sugary drinks when products displayed pictorial warnings about type 2 diabetes or heart damage, as compared with barcode labels. The study suggests that policies requiring pictorial health warnings on sugary drinks could reduce purchases of these products.

Children in the US consume more than the recommended levels of sugary drinks, increasing their risk of a variety of chronic diseases, including type 2 diabetes and heart disease. Research has found that text warnings can reduce sugary drink consumption, but the effects of pictorial warnings remain largely uninvestigated.

Marissa G Hall and colleagues at the University of North Carolina at Chapel Hill randomly assigned 325 parents of children aged 2-12 to an intervention arm or control arm and asked them to choose a drink and a snack for their child plus a household item in a naturalistic store laboratory. The intervention group had pictorial health warnings about type 2 diabetes or heart disease displayed on drinks, while controls had barcode labels.

In the control group 45% of parents bought a sugary drink for their child, compared to 28% in the pictorial warning group. Calories (kcal) from purchased sugary drinks were also reduced, with an average of 82 kcal for controls vs. 52 kcal for the pictorial warnings group. Parents in the intervention arm reported thinking more about their decision and the impacts of sugary drinks as well as lower intentions to serve sugary drinks to their child. Pictorial warnings could be a promising option for reducing purchases of sugary drinks for children, and related health outcomes.

Corresponding author Lindsey Smith Taillie adds, “Kids in the US consume too many sugary drinks, increasing their risk of a variety of health problems, from dental caries to chronic diseases like type 2 diabetes. We know from tobacco control research that warnings that include images are effective for reducing consumption. Our study is one of the first to show that this type of policy works for sugary drinks, too. This data provides evidence to support policies to require strong front-of-package warnings as a strategy to reduce children’s intake of sugary drinks.”

Posted on Autism

Different autism risk genes, same effects on brain development

Brain organoid showing different cell types


Microscopy image of a brain organoid showing neuron precursors (magenta) and deep-layer projection neurons (green), which are one of the cell types affected by autism risk gene mutations. CREDIT Paola Arlotta laboratory at Harvard University and Kwanghun Chung laboratory at MIT.

Autism has been associated with hundreds of different genes, but how these distinct genetic mutations converge on a similar pathology in patients has remained a mystery. Now, researchers at Harvard University and the Broad Institute of MIT and Harvard have found that three different autism risk genes actually affect similar aspects of neural formation and the same types of neurons in the developing human brain. By testing the genetic mutations in miniature 3D models of the human brain called “brain organoids,” the researchers identified similar overall defects for each risk gene, although each one acted through unique underlying molecular mechanisms.

The results, published in the journal Nature, give researchers a better understanding of autism and are a first step toward finding treatments for the condition.

“Much effort in the field is dedicated to understanding whether commonalities exist among the many risk genes associated with autism. Finding such shared features may highlight common targets for broad therapeutic intervention, independent from the genetic origin of disease. Our data show that multiple disease mutations indeed converge on affecting the same cells and developmental processes, but through distinct mechanisms.
These results encourage the future investigation of therapeutic approaches aimed at the modulation of shared dysfunctional brain properties,” said senior author of the study Paola Arlotta, who is the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University and an institute member in the Stanley Center for Psychiatric Research at the Broad Institute.

The Arlotta lab focuses on organoid models of the human cerebral cortex, the part of the brain responsible for cognition, perception, and language. The models start off as stem cells, then grow into a 3D tissue that contains many of the cell types of the cortex, including neurons that are able to fire and connect into circuits. “In 2019, we published a method to allow the production of organoids with the unique ability to grow reproducibly. They consistently form the same types of cells, in the same order, as the developing human cerebral cortex,” said Silvia Velasco, a senior postdoctoral fellow in the Arlotta lab and a co-lead author in the new study. “It is a dream come true to now see that organoids can be used to discover something unexpected and very new about a disease as complex as autism.”

In the new study, the researchers generated organoids with a mutation in one of three autism risk genes, which are named SUV420H1, ARID1B, and CHD8. “We decided to start with three genes that have a very broad hypothetical function. They don’t have a clear function that could easily explain what is happening in autism , so we were interested in seeing if these genes were somehow doing similar things,” said Bruna Paulsen, a postdoctoral fellow in the Arlotta lab and co-lead author.

The researchers grew the organoids over the course of several months, closely modeling the progressive stages of how the human cerebral cortex forms. They then analyzed the organoids using several technologies: single-cell RNA sequencing and single-cell ATAC-sequencing to measure the changes and regulation in gene expression caused by each disease mutation; proteomics to measure responses in proteins; and calcium imaging to check whether molecular changes were reflected in abnormal activity of the neurons and their networks.

“This study was only possible as a collaboration of several labs that came together, each with their own expertise, to attack a complex problem from multiple angles,” said co-author Joshua Levin, an institute scientist in the Stanley Center and the Klarman Cell Observatory at the Broad Institute.

The researchers found that the risk genes all affected neurons in a similar way, either accelerating or slowing down neural development. In other words, the neurons developed at the wrong time. Also, not all cells were affected — rather, the risk genes all impacted the same two populations of neurons, an inhibitory type called GABAergic neurons and an excitatory type called deep-layer excitatory projection neurons. This pointed at selected cells that may be special targets in autism.

“The cortex is made in a very orchestrated way: each type of neuron appears at a specific moment, and they start to connect very early. If you have some cells forming too early or too late compared to when they are supposed to, you might be changing the way circuits are ultimately wired,” said Martina Pigoni, a former postdoctoral fellow in the Arlotta lab and co-lead author.

In addition to testing different risk genes, the researchers also produced organoids using stem cells from different donor individuals. “Our goal was to see how changes in the organoids might be impacted by an individual’s unique genetic background,” said Amanda Kedaigle, an Arlotta lab computational biologist and co-lead author.

When looking at organoids made from different donors, the overall changes in neural development were similar, yet the level of severity varied across individuals. The risk genes’ effects were fine-tuned by the rest of the donor genome.

“It is puzzling how the same autism risk gene mutations often show variable clinical manifestations in patients. We found that different human genomic contexts can modulate the manifestation of disease phenotypes in organoids, suggesting that we may be able to use organoids in the future to disentangle these distinct genetic contributions and move closer to more a complete understanding of this complex pathology,” Arlotta said.

“Genetic studies have been wildly successful at identifying alterations in the genome associated with autism and other neurodevelopmental conditions. The difficult next step on the path to discovering new treatments is to understand exactly what these mutations do to the developing brain,” said Steven Hyman, who is a Harvard University Distinguished Service Professor of Stem Cell and Regenerative Biology, the director of the Stanley Center at the Broad, and a Broad Institute core member. “By mapping the alterations in brain circuits when genetic variations are present, we can take the tentative next step in the direction of better diagnoses and uncover new avenues for therapeutic exploration.”

Posted on Cognitive dysfunction, Obesity

Greater body fat a risk factor for reduced thinking and memory ability

Sonia Anand


Lead author Sonia Anand is a professor of medicine of McMaster University’s Michael G. DeGroote School of Medicine and a vascular medicine specialist at Hamilton Health Sciences (HHS). CREDIT McMaster University

 A new study has found that greater body fat is a risk factor for reduced cognitive function, such as processing speed, in adults.

Even when the researchers took cardiovascular risk factors (such as diabetes or high blood pressure) or vascular brain injury into account, the association between body fat and lower cognitive scores remained. This suggests other not yet confirmed pathways that linked excess body fat to reduced cognitive function.

In the study, 9,166 participants were measured by bioelectrical impedance analysis to assess their total body fat.

As well, 6,733 of the participants underwent magnetic resonance imaging (MRI) to measure abdominal fat packed around the organs known as visceral fat, and the MRI also assessed vascular brain injury – areas in the brain affected by reduced blood flow to the brain.


“Our results suggest that strategies to prevent or reduce having too much body fat may preserve cognitive function,” said lead author Sonia Anand, a professor of medicine of McMaster University’s Michael G. DeGroote School of Medicine and a vascular medicine specialist at Hamilton Health Sciences (HHS). She is also a senior scientist of the Population Health Research Institute of McMaster and HHS.

She added that “the effect of increased body fat persisted even after adjusting for its effect on increasing cardiovascular risk factors like diabetes and high blood pressure, as well as vascular brain injury, which should prompt researchers to investigate which other pathways may link excess fat to reduced cognitive function.”

Co-author Eric Smith, a neurologist, scientist and an associate professor of clinical neurosciences at the University of Calgary, said that “preserving cognitive function is one of the best ways to prevent dementia in old age. This study suggests that one of the ways that good nutrition and physical activity prevent dementia may be by maintaining healthy weight and body fat percentage.”

Smith is head of the brain core lab for the two population cohorts used for this new analysis– the Canadian Alliance for Healthy Hearts and Minds (CAHHM) and PURE Mind- a sub-study of the large, international Prospective Urban Rural Epidemiological (PURE) study.

The participants were in the age range of 30 to 75 with an average age of about 58. Just over 56% were women; they all lived in either Canada or Poland. The majority were White European origin, with about 16% other ethnic backgrounds. Individuals with known cardiovascular disease were excluded.

Posted on autoimmune conditions, Diabetes, Multiple Sclerosis

‘Boot camp’ enzyme prevents autoimmune conditions

Thymus cells making AIRE (green) that educate the surrounding developing T cells (red).


Thymus cells making AIRE (green) that educate the surrounding developing T cells (red).CREDIT WEHI

WEHI researchers have identified an enzyme in the thymus that is essential for immune T cells to correctly identify threats, safeguarding them from going rogue and attacking healthy tissue in the body.

The thymus is an important organ where immune T cells learn to fight infection. The new findings revealed that the enzyme KAT7 is necessary to activate thousands of genes required for ‘training’ immune T cells not to attack healthy tissue. Without proper training, immune T cells are at risk of sabotaging the immune system which could lead to autoimmune conditions such as Type 1 diabetes, or multiple sclerosis. 

Published in Science Immunology, the research paves the way for potential treatments to target KAT7, which could modify the training of immune T cells as needed. Such treatments could be used to either restrain immune T cells from drivingautoimmune conditions, or to supercharge immune T cells to better fight diseases such as cancer.

The research was led by former WEHI PhD student Dr Melanie Heinlein, along with Associate Professor Tim Thomas and Associate Professor Daniel Gray from WEHI, in collaboration with researchers at Monash University and the Weizmann Institute of Science in Israel.

At a glance

  • Researchers have discovered that the enzyme KAT7 is crucial for ‘training’ immune T cells to correctly identify and fight threats in the body.
  • They showed that blocking the function of KAT7 in pre-clinical models sent the immune system into overdrive, leading to a range of autoimmune conditions.
  • These findings show that KAT7 could be targeted therapeutically to either dampen or boost the immune system as required.

A ‘preview’ of threats

The thymus is like a ‘boot camp’ where immune T cells are trained to identify and fight pathogens, and taught not to attack healthy organs. As part of this preparation, immune T cells are shown a ‘preview’ of all the various components of healthy tissues they could encounter once they exit the thymus.

While it was previously known that the Autoimmune Regulator (AIRE) protein activated the thousands of genes needed for this preview, it was unclear how AIRE knew which genes it needed to ‘switch on’, until now. 

Dr Melanie Heinlein said the new findings revealed that the enzyme KAT7 was crucial for determining which genes AIRE needed to activate for immune T cells to be properly trained. 

“Like a training coordinator, KAT7 directs AIRE to the thousands of genes that must be activated for the ‘boot camp’ to run smoothly. KAT7 does this by tagging the genes that AIRE needs to ‘switch on’ for the preview of the body’s proteins to work. When all goes to plan, immune T cells are trained not to fight any normal tissues they could encounter in the body, ensuring they do not cause autoimmune disease,” she said.

Importance of KAT7

Associate Professor Tim Thomas said KAT7’s crucial role in keeping immune T cells to task was made clear when the researchers used a new drug to block its function. 

“We showed how a KAT7 inhibitor, developed in collaboration with Jonathan Baell at Monash University, was able to stop AIRE from switching on the genes needed to properly train immune T cells. Stopping this process sent the immune system into overdrive, leading to immune T cells going rogue and causing a range of autoimmune conditions in pre-clinical models. This shows a clear link between KAT7 and AIRE in maintaining immune tolerance,” he said.

“This has been a wonderful team effort. The highly collaborative study was made possible with expertise from across WEHI’s Flow Cytometry Laboratory, Genomics Facility, and the Centre for Dynamic Imaging, along with colleagues from Monash University and the Weizmann Institute of Science in Israel.”

Exciting treatment potential

Associate Professor Daniel Gray said the discovery could lead to new treatments for restraining immune T cells in order to prevent autoimmune conditions, or for supercharging immune T cells to fight disease.

“Our research shows KAT7 could be targeted to modify the training of immune T cells so they can either be stopped from causing autoimmunity, or boosted to fight disease.

“Potential applications of this knowledge include organ-specific autoimmune diseases such as Type 1 diabetes and multiple sclerosis, as well as cancer immunotherapy. In the latter scenario, the immune system could be supercharged to combat cancer by blocking KAT7 in the thymus,” he said.