Fred Levine

How antipsychotics cause side effects such as obesity and diabetes

Originally published January 31, 2012

In 2008, roughly 14.3 million Americans were taking antipsychotics—typically prescribed for bipolar disorder, schizophrenia, or a number of other behavioral disorders—making them among the most prescribed drugs in the U.S. Almost all of these medications are known to cause metabolic side effects such as obesity and diabetes, leaving patients with a difficult choice between improving their mental health and damaging their physical health. In a paper published January 31 in the journal Molecular Psychiatry, researchers reveal how antipsychotic drugs interfere with normal metabolism by activating a protein called SMAD3, an important part of the transforming growth factor beta (TGFβ) pathway.

The TGFβ pathway is a cellular mechanism that regulates many biological processes, including cell growth, inflammation, and insulin signaling. In this study, all antipsychotics that cause metabolic side effects activated SMAD3, while antipsychotics free from these side effects did not. What’s more, SMAD3 activation by antipsychotics was completely independent from their neurological effects, raising the possibility that antipsychotics could be designed that retain beneficial therapeutic effects in the brain, but lack the negative metabolic side effects.

Long-term investments in research pay off

by Kristina Meek on September 26, 2012 at 10:43 am | 0 Comments

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Dr. Fred Levine worked tirelessly to discover a potential therapeutic for diabetes.

Dr. Fred Levine, director of our Sanford Children’s Health Research Center, started searching for potential diabetes drugs in 2005. Back then, Sanford-Burnham didn’t have a high-throughput drug screening center. It didn’t even have a children’s health research center.

One day, Dr. Levine was conferring with his colleague Dr. Mark Mercola, a heart researcher. Dr. Mercola was using some modest drug screening equipment set up in a converted office down the hall from his laboratory. He was screening chemical compounds with the hope of finding a few they could further explore as potential drugs for treating heart disease. Dr. Levine thought the same technique might lead to potential treatments for type 1 (juvenile) diabetes.

Diabetes finding could also mean good news for cancer

by Heather Buschman, Ph.D. on July 26, 2012 at 9:01 am | 0 Comments

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Dr. Fred Levine and colleagues discovered BIM5078 (center), a chemical compound that binds the nuclear receptor HNF4α (Image by Dr. Sumeet Salaniwal, Sanford-Burnham)

If someone were to design a protein to be perfectly shaped for pairing up with therapeutic drugs, they’d probably come up with something that looks like a nuclear receptor. These proteins normally sense nutrients or hormones and react by binding DNA, turning their target genes on or off, and ultimately altering cellular function in some way. But what makes nuclear receptors perfect for drug targeting are their pockets—the spots normally bound by a hormone or nutrient also make the perfect docking point for drugs aimed at boosting or blocking the receptor’s effect.

Take pancreatic beta cells, for example, where nuclear receptors sense dietary changes and respond by kicking up the cells’ production of insulin. One particular nuclear receptor at work in that case is called hepatocyte nuclear factor (HNF) 4α. Because of its role in insulin production and other aspects of beta cell function, HNF4α mutations have been linked to certain types of diabetes.

Given that it’s a nuclear receptor, scientists also think HNF4α might make a good therapeutic target for diabetes and other diseases. But the search for molecules that actually bind and influence HNF4α—the precursors to new medicines—has been a long one.

How antipsychotics cause side effects such as obesity and diabetes

by Heather Buschman, Ph.D. on January 31, 2012 at 3:15 pm | 4 Comments

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Fred Levine, M.D., Ph.D., director of the Sanford Children’s Health Research Center at Sanford-Burnham

How a few extra mice prompted a diabetes collaboration

by Heather Buschman, Ph.D. on December 5, 2011 at 8:59 am | 1 comment

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insulin-producing beta-cells in a mouse pancreas (Image courtesy of Edward Monosov)

Dr. Barbara Ranscht and her lab are working to better understand how T-cadherin—a protein found on the surface of neurons, muscle, and other cells—regulates communication between cells during development and disease. The best way to go about this is to see what happens when the protein is missing. To do this, her lab developed a mouse model that lacks the protein altogether. Using these animals, Dr. Ranscht’s group has revealed that T-cadherin protects the stressed heart and is necessary for new blood vessel growth in injury models.

One day, Dr. Ranscht found herself discussing possible roles for T-cadherin in metabolism with Sanford-Burnham colleagues Dr. Björn Tyrberg and Dr. Fred Levine. The researchers especially wondered about T-cadherin’s role in the pancreas (Drs. Tyrberg’s and Levine’s organ of expertise).

Sisters in science

by Heather Buschman, Ph.D. on November 4, 2011 at 9:41 am | 0 Comments

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Dr. David Pearce, Vice President of Research at Sanford Health and Director of Sanford Children’s Health Research Center in Sioux Falls

On October 27-28, researchers from both research centers gathered at Sanford-Burnham’s La Jolla campus to share new research directions and stimulate further collaboration at the fourth annual Sanford Children’s Health Research Center Scientific Symposium. Attendees heard overviews from the leaders of both Sanford-Burnham and Sanford Health and learned about Sanford Health’s new BioBank, a repository for patient samples that will help drive personalized medicine and provide fodder for population genomics studies. More than a dozen scientists presented their ongoing studies of embryonic development, type 1 diabetes, brain tumors, lung injury in newborns, and rare inherited conditions such as Batten disease. Hot topics also included stem cells and RNA biology.

Innovation for IBD

by Heather Buschman, Ph.D. on August 29, 2011 at 2:28 pm | 0 Comments

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Dr. Fred Levine, director of the Sanford Children's Health Research Center

The Kenneth Rainin Foundation announced that Sanford-Burnham’s Dr. Fred Levine and Dr. Hudson Freeze will receive a 2011 Innovator Award for Inflammatory Bowel Disease (IBD) Research. The team will receive a $100,000, one-year grant for their idea to develop new IBD treatments by targeting a protein called HNF-4a.

HNF-4a is a nuclear receptor, meaning that it directly binds DNA and turns genes on or off in response to outside signals. HNF4a is found throughout the intestine, where it helps maintain structural integrity of the intestinal lining. Previous studies suggest that HNF4a might play a role in IBD. In a mouse model of IBD, lack of HNF4a increased disease severity. HNF4a levels are also low in intestinal biopsy samples from IBD patients. Given this information, it makes sense that enhancing HNF4a function might have the opposite effect, diminishing the disease. However, there hasn’t been a practical way to do that—until now.

Seeing is believing

by Heather Buschman, Ph.D. on April 6, 2011 at 10:01 am | 1 comment

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Left: traditional electron microscopy view of actin filaments. Right: Dr. Dorit Hanein's 3-D view of actin.

Left: electron microscopy view of actin. Right: Dr. Dorit Hanein's 3-D view.

Life is complicated. Even one tiny cell has a lot going on at any given time, even when things are running smoothly. Normal cellular functions and their emergency responses (like to injury or infection) are mostly carried out by proteins. Proteins tell other proteins what to do by carrying signals, tagging one another with chemical groups, chewing up other proteins or helping assemble new ones, and so on. They also help orchestrate which genes are turned on or off and when.

The cell itself is constantly sensing and reacting to constant environmental fluctuations, as are the individual proteins and other molecules. So how do you connect these two things?

“You can see a cell by eye, using a standard microscope. But you can’t see individual molecules that way,” explains Sanford-Burnham’s Dr. Dorit Hanein. “A cell is on the micrometer scale (one-thousandth of a millimeter), while an individual molecule is on the nanometer scale (one-millionth of a millimeter). That’s like the difference between walking the 500 miles from here [San Diego] to San Francisco, versus walking from here to the moon.”

What Dr. Hanein and other scientists need are techniques that allow them to look not just at the moon, but at the earth, the moon and everything in between.

Firing on all cylinders

by Josh Baxt on January 21, 2011 at 11:25 am | 0 Comments

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January is a good time to reflect on the previous year and plan for the new one. Recently, Sanford-Burnham CEO Dr. John Reed delivered his annual State of the Institute address at both our Orlando and San Diego campuses.

As Dr. Reed noted, 2010 was quite a productive year. On January 26, we announced T. Denny Sanford’s$50 million gift and our new name: Sanford-Burnham Medical Research Institute. In addition to Mr. Sanford’s gift, significant contributions were made by Pauline Foster, Arthur Brody and Gary and Jeanne Herberger. Also, the Sanford-Burnham Gala had a record year.

Dr. Reed welcomed new faculty, including Drs. Carl Ware, Robert Wechsler-Reya, Sheila Collins Fraydoon Rastinejad, Sepideh Khorasanizadeh, Xianlin Han, Salvatore Albani, and Alessandra Sacco. He also noted that, despite stagnant research funding, Sanford-Burnham had an excellent year bringing in grant funding to advance important research.

“According to government data, last year, our main source for support, the NIH, funded fewer grants than it has for any year in the last nine years,” said Dr. Reed. “When adjusted for inflation, and excluding the one-time stimulus funding, NIH budgets have been in net decline. Despite those challenging circumstances, last year we posted a nine percent increase in grant revenue institute-wide, surpassing the $100 million mark for the first time.”

But of course, the highlight was the research. Sanford-Burnham scientists helped produce more than 300 peer-reviewed papers last year. That’s a lot of ground to cover, so Dr. Reed could only give a few highlights:

Spotlight on disease: type 2 diabetes

by Heather Buschman, Ph.D. on January 14, 2011 at 2:29 pm | 4 Comments

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Diabetes results from a lack of insulin, a hormone that stimulates cells to take up glucose (a type of sugar) from the bloodstream. Cells need glucose as fuel to produce energy. Type 1 diabeticslack insulin because their immune systems destroy the pancreatic cells that produce it. Type 2 diabetics progress through two stages of the disease. In the first stage, called “insulin resistance”, cells no longer respond to insulin. The pancreas compensates for this resistance by producing more insulin. As insulin resistance persists, the pancreas cannot make enough insulin to keep up with the increased demand. The pancreas eventually shuts down insulin production altogether, resulting in type 2 diabetes.Without sugar that can be converted to energy, cells starve and glucose levels build up in the blood, which can lead to life-threatening complications such as cardiovascular disease. Since fat interferes with the body’s ability to process insulin and overweight people are at increased risk for the disease, type 2 diabetes is sometimes called “obesity-related” diabetes. Type 2 diabetics are encouraged to carefully monitor their diet and exercise in order to prevent dangerous fluctuations in blood sugar levels.

Spotlight on disease: type 1 diabetes

by Heather Buschman, Ph.D. on December 22, 2010 at 9:44 am | 3 Comments

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Type 1 diabetes is an autoimmune disorder – a person’s own immune system attacks beta cells found in the pancreas. Beta cells normally respond to high levels of sugar in the blood by releasing insulin, a protein hormone that acts like a key binding to a lock (or receptor) that is present on every cell in the body. When insulin binds to its receptor, it unlocks a door in cells that allows this sugar—known as glucose– to enter and be used for energy.Since type 1 diabetics lack insulin-producing beta cells, glucose remains in the blood and cells starve. Even with insulin therapy, the level of blood glucose in type 1 diabetics is not normal. Glucose is a highly reactive molecule that damages the cells and tissues that it contacts, particularly the cells that line blood vessels. As a result, diabetes is a leading cause of blindness, kidney disease, limb amputation and heart disease. Because type 1 diabetes commonly manifests in childhood, it has traditionally been called “juvenile” diabetes. Type 1 diabetes treatment is life-long; diabetics must carefully monitor their blood sugar and receive daily insulin injections or wear an insulin-delivering pump.

Presenting new science

by Josh Baxt on December 8, 2010 at 1:42 pm | 1 comment

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Open today’s paper (or your favorite news site) and, chances are, you will read about a significant scientific breakthrough. However, you probably won’t get the back story. A team of researchers spent long days and nights in the lab. They tested many hypotheses for years — some accurate, some not. Slowly, they gathered data, submitted their findings to a journal and, after revisions, published the article.But the back story goes deeper than that. The scientists who collaborate on these discoveries have varying degrees of education and experience. In addition to the principal investigators who lead the projects, there are postdoctoral fellows and Ph.D. candidates who conduct the majority of the hands-on science.

Chance encounter saves a child’s life

by Josh Baxt on November 10, 2010 at 3:28 pm | 2 Comments

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In 2008, a young child, known simply as Baby Amy, was flown from her home in Ireland to Winnipeg, Canada to be treated for Infantile Hypophosphatasia (HPP) a horrible – often fatal – disease that makes bones dangerously fragile. The results were striking. On the way to Canada, Baby Amy was transported in an insulated box to prevent her bones from breaking. On the way home, after receiving an enzyme replacement therapy (a drug called ENB-0040), she was healthy enough to be held by her mother. Dr. José Luis Millán, a professor in the Sanford Children’s Health Research Center at Sanford-Burnham had worked closely with ENOBIA Pharma and Dr. Michael P. Whyte of Shriner’s Hospital for Children in St. Louis to create this first-ever treatment for HPP. He was understandably thrilled.

Collaboration helps a young Iranian girl

by Heather Buschman, Ph.D. on July 16, 2010 at 12:34 pm | 1 comment

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Sanford-Burnham researchers don’t often get the opportunity to meet patients who benefit from their research. But last month, a four-and-a-half year old girl named Alma came to La Jolla to visit Dr. Hudson Freeze’s laboratory. Alma and her family live in Iran, but were in the United States for six months while she received treatments at the Mayo Clinic. Alma has an inherited genetic disorder that causes her to suffer from developmental problems and a severe skin ailment. For most of her life, the cause of Alma’s health issues was unknown. But that has now changed, thanks to a new study led by Dr. Joseph Gleeson at the University of California, San Diego (UCSD). In the study, which appeared July 15 in the journal Cell, Dr. Gleeson, Dr. Freeze and their colleagues helped identify the gene mutation responsible for Alma’s condition. In doing so, they also uncovered a new inherited disease that will be classified within a family of similar conditions known as Congenital Disorders of Glycosylation (CDG).

A fruitful collaboration

by Josh Baxt on June 18, 2010 at 3:43 pm | 0 Comments

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In late 2007, the Sanford Children’s Health Research Center was established at Sanford-Burnham’s La Jolla campus with a $20 million gift from South Dakota philanthropist T. Denny Sanford through Sanford Health. The gift was the foundation for a long-term partnership between Sanford Health of Sioux Falls, South Dakota, and Sanford-Burnham. The collaboration combines world-class scientific talent with state-of-the art technology to conquer childhood diseases like type 1 diabetes, muscular dystrophy and many others. In addition to the center in La Jolla, Sanford Health has created a Children’s Health Research Center in Sioux Falls. Together, Sanford-Burnham and Sanford Health are establishing an integrated, academic/pediatric research network.

Top 10 most-read blog posts of 2012: #5

How antipsychotics cause side effects such as obesity and diabetes

Long-term investments in research pay off

Diabetes finding could also mean good news for cancer

How antipsychotics cause side effects such as obesity and diabetes

How a few extra mice prompted a diabetes collaboration

Sisters in science

Innovation for IBD

Seeing is believing

Firing on all cylinders

Spotlight on disease: type 2 diabetes

Spotlight on disease: type 1 diabetes

Presenting new science

Chance encounter saves a child’s life

Collaboration helps a young Iranian girl

A fruitful collaboration

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