MSCs: what’s in a name?

Whether they are "stem" or "stromal", from adult tissues or from umbilical cord blood, MSCs are being used for a lot of clinical trials. Read more

Mopping up immune troublemakers after transplant

Memory CD8+ T cells play an important role in kidney transplant rejection, and they resist drugs that would otherwise improve Read more

Tracking a frameshift through the ribosome

Ribosomal frameshifting, visualized through X-ray Read more

diabetes

Unlocking a liver receptor puzzle

Imagine a key that opens a pin tumbler lock.  A very similar key can also fit into the lock, but upside down in comparison to the first key.

Biochemist Eric Ortlund and colleagues have obtained analogous results in their study of how potential diabetes drugs interact with their target, the protein LRH-1. Their research, published in Journal of Biological Chemistry, shows that making small changes to LRH-1-targeted compounds makes a huge difference in how they fit into the protein’s binding pocket.

First author Suzanne Mays, a graduate student in Emory's MSP program

First author Suzanne Mays, a graduate student in Emory’s MSP program

This research was selected as “Paper of the Week” by JBC and is featured on the cover of the December 2 issue.

LRH-1 (liver receptor homolog-1) is a nuclear receptor, a type of protein that turns on genes in response to small molecules like hormones or vitamins.  LRH-1 acts in the liver to regulate metabolism of fat and sugar.

Previous research has shown that activating LRH-1 decreases liver fat and improves insulin sensitivity in mice. Because of this, many research teams have been trying to design synthetic compounds that activate this protein, which could have potential to treat diabetes and nonalcoholic fatty liver disease. This has been a difficult task, because not much is known about how synthetic compounds interact with LRH-1 and switch it into the active state. Read more

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The unsweetened option

Pediatric hepatologist Miriam Vos is starting a new study testing the effects of a low-sugar diet in children with NAFLD (non-alcoholic fatty liver disease). The study is supported by the Nutrition Science Initiative and conducted in a partnership with UCSD/Rady Children’s Hospital, San Diego. See below for more on NUSI.

While there are no medications approved for NAFLD – a healthy diet and exercise are the standard of care – plenty of drugs are under development, as a recent article from Mitch Leslie in Science illustrates. As a reality check and benchmark, the NUSI study will address whether the low-tech intervention of altering diet can be effective.

Lab Land has delved into NAFLD and its increasing prevalence in previous posts. Plenty of correlational data shows that sugar intake is linked to NAFLD (a recent paper from the Framingham Heart Study), but Vos points out that there are no studies showing that reducing sugar is sufficient to drive improvement in the disease.

Diet is a challenge to examine in humans rigorously. In observational studies, investigators are always bumping up against the limits of memory and accurate reporting. In an interventional study with adults, it’s possible to provide them a completely defined menu for a short time in a closed environment, but that’s less practical for longer periods or with children.

The press release announcing the NUSI study says: half of the families will eat and drink what they normally do while the rest will be put on sugar-free meals and snacks, all of which will be provided for the participants and their families for eight weeks.

Miriam Vos, MD

I was curious about how this would work, especially for boys aged 11 to 16 (the participants in her study), so I asked Vos more about it for Lab Land.

“We try to provide them a diet that is otherwise similar to what the family is used to,” she says. “For example, if they’re accustomed to home-cooked meals, our team of nutritionists will work with them to find different recipes.” Read more

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Hunting for potential diabetes drugs

Pathologist Keqiang Ye and his colleagues have been prolific in finding small molecules able to mimic the action of the brain growth factor BDNF. Aiming to export that success to similar molecules (that is, other receptor tyrosine kinases), they have been searching for potential drugs able to substitute for insulin.

Diabetes drugs Januvia (sitagliptin) and Lantus (insulin analog) are top 20 drugs, both in terms of dollars and monthly prescriptions, and the inconvenience of insulin injection is well known, so the business potential is clear.

A paper published in the journal Diabetes in April describes Ye’s team’s identification of a compound called chaetochromin A, which was originally isolated by Japanese researchers studying toxins found in moldy rice. Chaetochromin A can drive down blood sugar in normal, type 1 diabetes and type 2 diabetes mouse models, the authors show.

See here for another compound identified in Ye’s lab with similar properties.

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Why humans develop gout

Thanks to prolific UK science writer Ed Yong for picking up on a recent paper in PNAS from Eric Gaucher’s lab at Georgia Tech and Eric Ortlund’s at Emory.

Gaucher and Ortlund teamed up to “resurrect” ancient versions of the enzyme uricase, in search of an explanation for why humans develop gout. Yong explains:

The substance responsible for the condition [gout] is uric acid, which is normally expelled by our kidneys, via urine. But if there’s too much uric acid in our blood, it doesn’t dissolve properly and forms large insoluble crystals that build up in our joints. That explains the http://www.raybani.com/ painful swellings. High levels of uric acid have also been linked to obesity, diabetes, and diseases of the heart, liver and kidneys. Most other mammals don’t have this problem. In their bodies, an enzyme called uricase converts uric acid into other substances that can be more easily excreted.

Uricase is an ancient invention, one that’s shared by bacteria and animals alike. But for some reason, apes have abandoned it. Our uricase gene has mutations that stop us from making the enzyme at all. It’s a “pseudogene”—the biological version of a corrupted computer file. And it’s the reason that our blood contains 3 to 10 times more uric acid than that of other mammals, predisposing us to gout.

“Our role* on the project was to solve the three dimensional structure of this enzyme using X-ray crystallography to figure out how these ancient mutations led to a decline in uricase activity in humans and apes,” Ortlund says. “We were interested in how this enzyme lost function, and for the future, how we can restore function to this enzyme to create a more “human-like” (and thus less immunogenic) protein than the current available bacterial or baboon-pig uricase chimeras.”

(There’s even a patent on this ancient uricase as a potential treatment for gout, and a start-up company named General Genomics)

Their paper also explores what advantage humans might have gained from losing functional uricase. The proposal is: by disabling uricase, ancient primates became more efficient at Ray Ban outlet turning fructose, the sugar found in fruit, into fat. Their results provide some support for the “thrifty gene hypothesis:” the idea that humans are evolutionarily adapted to being able to survive an erratic food supply, which is not so great now that people in developed countries have access to lots of food. The authors write:

The loss of uricase may have provided a survival advantage by amplifying the effects of fructose to enhance fat stores, and by the ability of uric acid to stimulate foraging, while also increasing blood pressure in response to salt. Thus, the loss of uricase may represent the first example of a “thrifty gene” to explain the current epidemic of obesity and diabetes, except that it is the loss of a gene, and not the acquisition of a new gene, that has ray ban da sole outlet increased our susceptibility to these conditions. 

*Ortlund’s former postdoc Michael Murphy was involved in this part.

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Eyes on dopamine

Dopamine-restoring drugs already used to treat Parkinson’s disease may also be beneficial for the treatment of diabetic retinopathy, a leading cause of blindness in adults, researchers have discovered. The results were published recently in Journal of Neuroscience.

Diabetic retinopathy affects more than a quarter of adults with diabetes and threatens the vision of more than 600,000 people in the United States. Doctors had previously thought most of the impairment of vision in diabetic retinopathy came from damage to the blood vessels induced by high blood sugar, but had known that dopamine, a vital neurotransmitter in the brain, was also important in the retina.

“There was some evidence already that dopamine levels were reduced in diabetic retinopathy, but what’s new here is: we can restore dopamine levels and improve visual Ray Ban outlet function in an animal model of diabetes,” says Machelle Pardue, PhD, associate professor of ophthalmology at Emory University School of Medicine and research career scientist at the Atlanta VA Medical Center. Read more

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Possible diabetes drug/stent interaction

Diabetes and heart disease often intersect. Emory cardiologist Aloke Finn and his colleagues recently had two papers in the Journal of the American College of Cardiology and in Atherosclerosis describing a possible interaction between the widely used diabetes drug metformin and drug-eluting stents, which are used to to treat coronary artery disease. Anwer Habib, MD is the first author of both papers.

The stent props the once-blocked artery open while the drugs in the stents are supposed to prevent the artery from becoming blocked again. The drugs — usually mTOR inhibitors such as http://www.magliettedacalcioit.com everolimus or the newer zotarolimus — slow down cell growth, but this cuts both ways. The drugs slow down the recovery of the lining of the blood vessel and this may contribute to blood clot formation after stent placement.

In cultured human cells and in rabbits with implanted stents, Finn and colleagues showed that metformin augmented the effect of mTOR inhibitors on regrowth of the blood vessel lining. (However — the authors acknowledge that their animal model was not diabetic or atherosclerotic.)

The findings could mean that people taking metformin would need to take medications to prevent blood clotting medications for a longer time after stent placement. The authors say that clinical studies following patients who receive drug-eluting stents should look at metformin’s effects on blood clotting events. A study examining drug eluting stents in diabetic patients is in the works at Emory.

 

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Editorial on bilateral vs single coronary bypass surgery

John Puskas, chief of cardiac surgery at Emory University Hospital Midtown, recently had an editorial in the journal Circulation on the topic of coronary bypass surgery.

John Puskas, MD

Specifically, he says that many cardiac surgeons are reluctant to employ bilateral internal thoracic artery grafts (as opposed to a single graft), even though there is a long-term benefit, because of perceived risk of infection and suboptimal financial incentives.

Puskas’ key message paragraph was so clear that it demands reposting here:

Why are American surgeons doing so few BITA [bilateral internal thoracic artery] grafts? Fundamentally, U.S. surgeons are responding to their practice environment, especially to a fear of deep sternal wound infection in an increasingly obese, diabetic population of patients. The surgeon pays a large and immediate political price for a deep sternal wound infection and receives relatively little credit for the extra years that BITA grafting adds to a patient’s life in the future. There is also a relative Ray Ban outlet financial disincentive to perform BITA grafting: incremental payment for the second internal thoracic artery graft is small considering the extra time required in the operating room. Moreover, the Centers for Medicare and Medicaid Services no longer reimburse for extra care necessary for treatment of mediastinitis [internal chest inflammation/infection] after cardiac surgery, because this is now deemed a never event. Thus, surgeons, who are increasingly employed by hospitals and hospital systems, are under intense pressure to perform CABG surgery that is safe and cost-effective according to short-term metrics.

Puskas and his colleagues have published an analysis of bilateral vs single grafting at Emory, as well as a proposed metric for when single grafting should be used in the context of patients with diabetes:

Our present practice is generally to use BITA grafting in patients who are <75 years, have suitable coronary artery targets, are not morbidly obese, and whose glycosylated hemoglobin level is <7.0% to 7.5%.

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Drug discovery: shifting from brain growth factors to insulin

Earlier this year, the FDA put limitations on some anti-diabetic drugs because of their cardiovascular risks. The prevalence of diabetes in the United States continues to increase and is now above 8 percent of the population, so the need for effective therapies remains strong.

Keqiang Ye, PhD

Pathologist Keqiang Ye and colleagues have a paper in the Journal of Biological Chemistry describing their identification of a compound that mimics the action of insulin. This could be the starting point for developing new anti-diabetes drugs.

The new research is an extension of the Ye laboratory’s work on TrkA and TrkB, which are important for the response of neurons to growth factors. Ye and Sung-Wuk Jang, a remarkably productive postdoc who is now an assistant professor at Korea University, developed an assay that allowed them to screen drug libraries for compounds that directly activate TrkA and TrkB. This led them to find a family of growth-factor-mimicking compounds that could treat conditions such as Parkinson’s disease, depression and stroke.

Since TrkA/B and the insulin receptor are basically the same kind of molecule — receptor tyrosine kinases– and use some of the same cellular circuitry, Ye and Jang’s assay could also be used with the insulin receptor. Kunyan He and Chi-Bun Chan are the first two authors on the new paper. They report that the compound DDN can make cells more sensitive to insulin and improve their ability to take up glucose. They show that DDN (5,8-diacetyloxy-2,3-dichloro-1,4- naphthoquinone) can lower blood sugar, both in standard laboratory mice and in obese mice that serve as a model for type II diabetes.

Ye reports that he and his colleagues are working with medicinal chemists to identify related compounds that may have improved efficacy and potency.

“I hope in the near future we may have something that could replace insulin for treating diabetes orally,” he says.

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Exercise, changes in diet alter course for pre-diabetics

The D-CLIP Study staff in Chennai, India

A type 2 diabetes intervention program developed by researchers from Emory and the Madras Diabetes Research Foundation (MDRF) in India is showing promising results in improving risk factors, such as lowering weight and decreasing blood pressure and glucose levels.

The ongoing study, called the Diabetes Community Life Improvement Program, (D-CLIP) was designed to test the benefits of a low-cost community program for people at increased risk for type 2 diabetes, most commonly associated with obesity. The curriculum integrates exercise, nutrition education and dietary changes. The study is being conducted in Chennai, India with hopes of expanding the program into other parts of South Asia.

Six-hundred participants with prediabetes were randomly assigned to either a standard of care control treatment or weekly D-CLIP classes for six months, where they learned about making healthy choices in real life situations such as restaurants and grocery stores. They also learned how to incorporate exercise into their daily routines with the goal of completing 150 minutes of physical activity a week.

Of the 200 participants who have completed the course to date, 83 percent have lost between five and 13 pounds. There also was improvement in blood glucose, serum cholesterol and blood pressure levels in participants.

“This initial research is quite encouraging because it shows we can turn the tide of type 2 diabetes onset by promoting simple lifestyle changes through well-structured community programming,” says Venkat Narayan, MD, Hubert Professor in Emory’s Rollins School of Public Health and a professor in Emory School of Medicine. “Attendance at the lifestyle classes is 85 to 90 percent, with lifestyle changes strongly evident. More than anything, we have formed strong partnerships with the local community that will ultimately lead to the implementation of more successful programs like this.”

The study is conducted by the Global Diabetes Research Center, a collaboration between Emory University and MDRF in Chennai, India. The center received its initial support from the Emory Global Health Institute, with funding from BRiDGES (Bringing Research in Diabetes to Global Environments and Systems), an International Diabetes Federation program supported by an educational grant from Eli Lily. Currently, the 17th session of D-CLIP classes is in progress, with the study set to close in early 2013.

Participants in the D-CLIP study learned to incorporate exercise into their lives to stave off type 2 diabetes.

“We have always known that the right diet and exercise can improve health,” says V. Mohan, MD, president of the Madras Diabetes Research Foundation. “But there has been no scientific community-based program to quantify this until now. We hope this is just the beginning of efforts to reduce the incidence of the type 2 diabetes epidemic worldwide.”

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Challenges in islet transplantation

Two recent research papers from the Emory Transplant Center describe research on pancreatic islet transplantation, an experimental procedure that could help people with type I diabetes live without daily insulin injections.

Islet transplantation may offer people with type I diabetes the ability to produce their own insulin again

As with other types of transplantation, the challenge with islet transplantation is to avoid rejection of the donated organ and to balance that goal against side effects from the drugs needed to control the immune system. These papers illustrate how that balancing act is especially complex.

In the last decade, transplant specialists developed a method for islet transplantation named the “Edmonton protocol” after pioneers at the University of Alberta. While the emergence of this method was a major step forward, there are limitations:

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