Diabetes and Endocrinology

Scientist with centrifuge

Giving fat cell messages a positive spin

Woman on a scale

Study findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that detrimental effects of carrying too much weight can recede. (Image source: Centers for Disease Control and Prevention)

Losing weight appears to reset the chemical messages that fat cells send to other parts of the body that otherwise would encourage the development of Type 2 diabetes, substantially reducing the risk of that disease, a team led by Children’s National Health System researchers report in a new study. The findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that many of the detrimental effects of carrying too much weight can recede, even on the molecular level, once they lose weight.

In 2015, Robert J. Freishtat, M.D., M.P.H., Chief of Emergency Medicine at Children’s National and Associate Professor of Pediatrics, Emergency Medicine and Integrative Systems Biology at The George Washington University School of Medicine & Health Sciences, and colleagues showed that fat cells (also known as adipocytes) from people who are obese send messages to other cells that worsen metabolic function. These messages are in the form of exosomes, nanosized blobs whose contents regulate which proteins are produced by genes. Exosomes are like “biological tweets,” Dr. Freishtat explains — short signals designed to travel long distances throughout the body.

Dr. Freishtat’s earlier research showed that the messages contained in exosomes from patients who are obese alter how the body processes insulin, setting the stage for Type 2 diabetes. However, says Dr. Freishtat, it has remained unclear since that publication whether these aberrant messages from adipocytes improve after weight loss.

“We’ve known for a long time that too much adipose tissue is bad for you, but it’s all moot if you lose the weight and it’s still bad for you,” he explains. “We wanted to know whether these negative changes are reversible. If you reduce fat, does the disease risk that goes along with excess fat also go away?”

Details of the study

To investigate this question, Dr. Freishtat and colleagues worked with six African American adults scheduled to receive gastric bypass surgery — a nearly surefire way to quickly lose a large amount of weight. The volunteers, whose average age was 38 years, started out with an average body mass index (BMI) of 51.2 kg/m2. (The Centers for Disease Control and Prevention considers a healthy BMI to range between 18.5 to 24.9.)

Two weeks before these volunteers underwent surgery, researchers collected blood samples and took a variety of measurements. The researchers then performed a repeat blood draw and measurements one year after the surgery took place, when the volunteers’ average BMI had dropped to 32.6.

Dr. Freishtat and colleagues drew out the adipocyte-derived exosomes from both sets of blood samples and analyzed their contents. The team reports in the January 2017 issue of Obesity that at least 168 microRNAs — the molecules responsible for sending specific messages — had changed before and after surgery. Further analyses showed that many of these microRNAs were involved in insulin signaling, the pathways that the body uses to regulate blood sugar. By changing these outgoing microRNAs for the better, Dr. Freishtat says, adipocytes actively were encouraging higher insulin sensitivity in other cells, warding off Type 2 diabetes.

Sure enough, each volunteer had better insulin sensitivity and other improved markers of metabolic health post-surgery, including lower branched chain amino acids and a two-fold reduction in their glutamate to glutamine ratio.

“These volunteers were essentially cured of their diabetes after surgery. The changes we saw in their surgery-responsive microRNAS correlated with the changes we saw in their metabolic health,” Dr. Freishtat says.

A glimpse into the future

Dr. Freishtat and colleagues plan to study this phenomenon in other types of weight loss, including the slower and steadier paths that most individuals take, such as improving diet and doing more exercise. The team expects to see similar changes in exosomes of patients who lose weight in non-surgical ways.

By further examining the aberrant messages in microRNAs being sent out from adipocytes, he says, researchers eventually might be able to develop treatments to reverse metabolic problems in overweight and obese patients before they lose the weight, improving their health even before the often challenging process of weight loss begins.

“Then, if you can disrupt this harmful signaling in combination with weight-loss strategies,” Dr. Freishtat says, “you’re really getting the best of both worlds.”

Eventually, he adds, tests might be available so that doctors can warn patients that their fat cells are sending out harmful messages before disease symptoms start. By giving patients an early heads up, Dr. Freishtat says, patients might be more likely to heed advice from physicians and make changes before it’s too late.

“If doctors could warn patients that their fat is telling their blood vessels to fill up with plaque and trigger a heart attack in 10 to 20 years,” he says, “patients might be more compliant with treatment regimens.”

Eric Vilain, M.D., Ph.D.

Eric Vilain to lead genetic medicine research

Eric Vilain

Eric Vilain, M.D., Ph.D., emphasizes the idea of health and disease as a compound process that will transform children’s health and impact a patient throughout life.

Eric Vilain, M.D., Ph.D., an internationally renowned geneticist well known for groundbreaking studies of gender based biology, will soon lead the Center for Genetic Medicine Research at Children’s National Health System.

Dr. Vilain joins Children’s National from the University of California, Los Angeles (UCLA) where he serves as Professor of Human Genetics, Pediatrics and Urology, Chief of Medical Genetics, and attending physician in the Department of Pediatrics.

As the Director of the Center for Genetic Medicine Research, Dr. Vilain will emphasize the idea of health and disease as a compound process, which he believes “can transform children’s health and help the treatment and prevention of illness, not only in childhood, but throughout a patient’s life.”

The Center for Genetic Medicine Research currently houses a highly interdisciplinary faculty of over 50 scientists and physician investigators and brings together a variety of clinical and scientific disciplines to coordinate scientific and clinical investigations simultaneously from multiple angles. The Center also provides access to the leading edge innovative technologies in genomics, microscopy, proteomics, bioinformatics, pre-clinical drug trials, and multi-site clinical trial networks for faculty within the Children’s Research Institute, the academic arm of Children’s National.

Dr. Vilain’s current laboratory focuses on the genetics of sexual development and sex differences – specifically the molecular mechanisms of gonad development and the genetic variants of brain sexual differentiation. His research also explores the biological bases of sex variations in predisposition to disease. His work crosses several disciplines (genetics, neuroscience, psychology) leading to findings with major societal implications. In addition to scientific investigation, Dr. Vilain created a clinic devoted to caring for patients with a wide array of genetic and endocrine issues, particularly those with variations of sexual development.

He brings nearly 30 years of expertise with him to Children’s National. He has authored seminal articles regarding the field of sexual development, and his research program has continuously been funded by the National Institutes of Health (NIH). Dr. Vilain is a Fellow of the American College of Medical Genetics and a member of numerous professional committees. The recipient of numerous awards, he has been recognized by organizations ranging from the NIH to the Doris Duke Charitable Foundation, March of Dimes, and the Society for Pediatric Research. He has served as an advisor to the International Olympic Committee Medical Commission since 2011 and has been a member of the Board of Scientific Counselors of the National Institute of Child Health and Human Development since 2015.

Mark Batshaw, M.D., Executive Vice President, Physician-in-Chief, and Chief Academic Officer at Children’s National says, “Dr. Vilain’s vision and expertise in the study and use of precision medicine approaches, and the development of novel treatments for diseases of childhood, will lead to drastically different and improved outcomes for some of the most devastating diseases, such as cancer.”

“I am honored to join the world-renowned team at Children’s National, and look forward to continuing to find new, innovative ways to research, diagnose and treat rare and common disorders,” Dr. Vilain adds.

Diabetes telemedicine program launches study survey and retrospective chart review

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Telemedicine isn’t new. And diabetes telemedicine isn’t new either. But the Diabetes Program at Children’s National Health System is doing more than just providing education and support groups via telemedicine. The largest pediatric diabetes program in the Mid-Atlantic region is evaluating just how successful its telemedicine program is with a six-month survey and retrospective chart review. “This is our opportunity to prove [the success] not anecdotally but with evidence,” says Colleen Meehan, M.D., M.P.H., a third-year resident at Children’s and one of the co-investigators for the project.

According to published literature, the Children’s National cohort is one of the largest of any other diabetes telemedicine program and extends the time period of care.

History of the program

Around the world, there isn’t enough endocrinology care, says Fran Cogen, M.D., C.D.E. Dr. Cogen and others at Children’s National have recognized the need right in their region—and worldwide—to deliver specialty care to patients who live too far from Washington, DC.

Many of the patients Dr. Cogen sees at Children’s National live on Maryland’s Eastern Shore, including the island of Tangiers, and in Delaware. That’s a two-and-a-half-hour drive over the Chesapeake Bay Bridge and an obstacle to scheduling follow-up appointments. To solve this issue, Children’s National partnered with Peninsula Regional Medical Center, in Salisbury, Md., three years ago to improve patients’ quality of life while getting them the care they needed.

How the program works

A nurse practitioner at Peninsula Regional sees patients for blood glucose checks and more frequently. Once a month, or depending on the severity of the diabetes, Dr. Cogen will observe—on a large TV screen from Children’s National—physical examinations, and then review insulin regimens and dosing, download the glucose meters in real time, discuss concerns, and develop treatment plans. There’s diabetes-specific software that patients can see at Peninsula Regional.

What the study can reveal

A 2014 pilot survey showed caregivers had great satisfaction with the program. Now, the team wants to formally study caregiver satisfaction and patient quality of life, as measured by a validated diabetes-specific Pediatric Quality of Life survey. With the largest cohort in diabetes telemedicine (75, type 1), it will also look at frequency of blood glucose monitoring, HbA1c, incidence of ER visits and hospitalizations for DKA or hypoglycemia, and percentage of missed clinic appointments. The team believes that this will show the diabetes telemedicine program is as effective as traditional face-to-face visits.

Other specialties at Children’s National are planning to provide telemedicine services, and some already do. The Diabetes Telemedicine Program is looking to expand coverage in Delaware, Maryland, and Virginia, to other rural areas that lack pediatric endocrinology or diabetes specialists.

“We can deliver quality care and develop a personal relationship without actually being physically present in the exam room,” Dr. Cogen says.

Robert J. Freishtat

A game changer for detecting complications from obesity

Robert J. Freishtat

The work that Children’s National Health System physician-scientist Robert J. Freishtat, M.D., M.P.H., and colleagues are doing could soon be a game changer when it comes to early intervention and prevention of obesity-related illnesses.

They already knew there’s a direct relationship between the amount of visceral adipose, or belly fat, a person has and development of some of the most common and life-threatening complications of obesity, including cardiovascular disease and the insulin resistance that leads to diabetes. What remained unclear, until recently, were the precise mechanisms for how the increase in belly fat triggers the onset of additional disease.

Dr. Freishtat, senior author of “Adipocyte-Derived Exosomal miRNAs: A Novel Mechanism for Obesity-Related Disease,” published by Pediatric Research, studies the adipocytes, or fat cells, of visceral adipose in both lean and obese patients to understand exactly how these fat cells can and do wreak havoc — not just locally but throughout the body. Cells leverage exosomes to communicate among themselves, but in overweight patients those cellular communications can go awry.

“As the body’s visceral fat grows, somewhere on the path to obesity the fat cells change and begin to release different exosomes than lean adipose cells do. These new messages disrupt some important processes that eventually prevent the body from effectively dealing with sugar and cholesterol,” says Dr. Freishtat, chief of Emergency Medicine at Children’s National, and associate professor of Pediatrics, Emergency Medicine, and Integrative Systems Biology at the George Washington University.

Dr. Freishtat describes exosomes as “biological tweets”— short messages shed by all cells that allow for intercellular communication and alter gene expression. In the case of the adipocytes that exist in large quantities of visceral fat, these “tweets” actually cause the downregulation of proteins impacting two key signaling pathways — TGF-β and Wnt/β-catenin — associated with controlling chronic inflammation and fibrotic disease throughout the body. These signaling changes make morbidly obese patients more vulnerable to systemwide issues, such as cholesterol accumulation and changes to how the liver processes fat.

Details of the study

The study authors surgically collected fat tissue from lean and obese female patients aged 11 to 19 and used modified bead-based flow cytometry to separate, identify, and compare the exosomal RNA shed by the fat cells in both lean and obese samples. To confirm the unique impact of the obese adipose exosomes on gene expression, the research team then exposed lung cells in vivo to the exosomes shed by both lean and obese adipose. They measured the impact of exposure and uptake on a single receptor type — activin receptor type-2B — known to have a major influence on the TGF-β pathway. The exosomes from obese adipose caused the receptor to slow down, leading to significant changes in the function of the TGF-β pathway.

The team continues to explore how the exosomes shed from excess amounts of visceral adipose spread throughout the body and how the function of organs such as the liver, the heart, and the brain are impacted by the migrating fat cells.

A Look into the future

Successfully identifying and isolating these exosomes also has opened the door to developing a test to detect them, an idea that may permit even earlier intervention to delay or prevent the onset of obesity-related illnesses.

“It is entirely plausible, and is on its way to happening very soon, that someone could walk into their physician’s office for a routine physical and, via a urine test, find out that they are on the road to some dangerous additional side effects of significant weight gain,” says Dr. Freishtat. “That type of early detection could really be a game changer for the millions of Americans who are on track to developing heart, liver, and other diseases resulting from morbid obesity.”