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There’s still more to learn about COVID-19 and diabetes

February 8, 2021

boy checking his blood glucose

Researchers have learned a lot about COVID-19 over the past year and are continuing to learn and study more about this infection caused by the SARS-CoV-2 virus. There have been many questions about whether COVID-19 affects people with diabetes differently than those without and why this might occur.

Diabetes experts, like Brynn Marks, M.D., M.S.H.P.Ed., endocrinologist at Children’s National Hospital, have been studying the relationship between COVID-19 and diabetes, especially in the pediatric population. Dr. Marks tells us more about what we know so far and further research that needs to be done when it comes to COVID-19 and diabetes.

1. What do we know about COVID-19 and its effect on people with known diabetes?

The Centers for Disease Control and Prevention (CDC) currently lists type 2 diabetes (T2D) as a high risk condition for severe illness related to COVID-19 infection, while stating that adults with type 1 diabetes (T1D) might be at increased risk. A recent study from Vanderbilt University found that people with T1D and T2D were at approximately equal risk for complications of COVID-19 infection. As compared to adults without diabetes, adults with T1D and T2D were 3-4 times more likely to be hospitalized and to have greater illness severity. Given these comparable risks, both the American Diabetes Association and the Juvenile Diabetes Research Foundation are lobbying for adults with T1D to be given the same level or priority for COVID-19 vaccines as adults with T2D.

However, as pediatricians, we all know to be wary of extrapolating adult data to pediatrics. Children are less likely to be infected with COVID-19 and if they are, the clinical course is typically mild. To date, there have not been any studies of the impact of COVID-19 on youth with known T2D. Our clinical experience at Children’s National Hospital and reports from international multicenter studies indicate that youth with T1D are not at increased risk for hospitalization from COVID-19 infection. However, paralleling ongoing disparities in T1D care, African Americans with known T1D and COVID-19 infection were more likely to be develop diabetic ketoacidosis (DKA) than their White counterparts.

With the increased use of diabetes technologies, including continuous glucose monitors, insulin pumps and automated insulin delivery systems, diabetes care lends itself well to telemedicine. Studies from Italy during the period of lockdown showed better glycemic control among youth with T1D. Further studies are needed to better understand the implications of telehealth on diabetes care, particularly among those in rural areas with limited access to care.

2. What do we know about the impact of the COVID-19 pandemic on children with newly diagnosed diabetes?

Nationwide studies from Italy and Germany over the first few months of the pandemic found no increase in the incidence of pediatric T1D during the COVID-19 pandemic as compared to the year before; in fact, the Italian study found that fewer children were diagnosed with T1D during the pandemic. However, many centers are seeing higher rates of DKA and more severe DKA at diagnosis during the pandemic, possibly due to decreased primary care visits and/or fears of contracting COVID-19 while seeking care.

To date, no studies have been published exploring the incidence of T2D in youth. A group from Children’s National, including myself, Myrto Flokas, M.D., Abby Meyers, M.D., and Elizabeth Estrada, M.D., from the Division of Endocrinology and Randi Streisand, Ph.D., C.D.C.E.S. and Maureen Monaghan, Ph.D., C.D.C.E.S., from the Department of Psychology and Behavioral Health, are gathering data to compare the incidence of T1D and T2D during the pandemic as compared to the year before.

3. Can COVID-19 cause diabetes to develop?

This has been area of great interest, but the jury is still out. The SARS-CoV-2 virus, which causes COVID-19 infection, binds the angiotensin-converting enzyme 2 (ACE2) receptor which is located in many tissues throughout the body, including the pancreas. SARS-CoV-2 has been shown to infect pancreatic tissue leading to impaired glucose stimulated insulin secretion. Although the SARS-CoV-2 virus could plausibly cause diabetes, assessment has been complicated by many confounders that could be contributing to hyperglycemia in addition to or rather than the virus itself. Stress-induced hyperglycemia from acute illness, the use of high dose steroids to treat COVID-19 infection, and the disproportionate rates of infection among those already at high risk for T2D, as well as weight gain due to changes in day-to-day life as a result of social distancing precautions are all likely contributing factors.

Kidney disease outcomes differ between severely obese kids vs. adults after bariatric surgery

November 8, 2019

“We know that bariatric surgery improves markers of kidney health in severely obese adults and adolescents,” says Marva Moxey-Mims, M.D. “This research helps to elucidate possible differences in kidney disease outcomes between children and adults post-surgery.”

Adolescents with Type 2 diabetes experienced more hyperfiltration and earlier attenuation of their elevated urine albumin-to-creatinine ratio (UACR) after gastric bypass surgery compared with adults. This finding contrasts with adolescents or adults who did not have diabetes prior to surgery, according to research presented Nov. 8, 2019, during the American Society of Nephrology’s Kidney Week 2019, the world’s largest gathering of kidney researchers.

“Findings from this work support a recent policy statement by the American Academy of Pediatrics (AAP) that advocates for increasing severely obese youths’ access to bariatric surgery,” says Marva Moxey-Mims, M.D., Chief of the Division of Nephrology at Children’s National Hospital and a study co-author. “We know that bariatric surgery improves markers of kidney health in severely obese adults and adolescents. This research helps to elucidate possible differences in kidney disease outcomes between children and adults post-surgery.”

According to the AAP, the prevalence of severe obesity in youth aged 12 to 19 has nearly doubled since 1999. Now, 4.5 million U.S. children are affected by severe obesity, defined as having a body mass index ≥35 or ≥120% of the 95th percentile for age and sex.

In a Roux-en-Y gastric bypass, the surgeon staples the stomach to make it smaller, so people eat less. Then, they attach the lower part of the small intestine in a way that bypasses most of the stomach so the body takes in fewer calories.

The multi-institutional study team examined the health effects of such gastric bypass surgeries by comparing 161 adolescents with 396 adults enrolled in related studies. They compared their estimated glomerular filtration rates by serum creatinine and cystatin C. UACR was also compared at various time periods, up till five years after surgery.

Across the board, adolescents had higher UACR – a key marker for chronic kidney disease – than adults. However, for kids who had Type 2 diabetes prior to surgery, the prevalence of elevated UACR levels dip from 29% pre-surgery to 6% one year post-surgery. By contrast, adults who had diabetes prior to surgery and elevated UACR did not see a significant reduction in UACR until five years post-surgery.

While hyperfiltration prevalence was similar in study participants who did not have Type 2 diabetes, adolescents who had Type 2 diabetes prior to surgery had an increased prevalence of hyperfiltration for the duration of the study period.

Financial support for research described in this post was provided by the National Institute of Diabetes and Digestive and Kidney Diseases.

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ASN Kidney Week 2019 presentation

“Five-year kidney outcomes of bariatric surgery in adolescents compared with adults”
Friday, Nov. 8, 2019, 10 a.m. to noon (EST)
Petter Bjornstad, University of Colorado School of Medicine; Todd Jenkins, Edward Nehus and Mark Mitsnefes, all of Cincinnati Children’s Hospital; Marva M. Moxey-Mims, Children’s National Hospital; and Thomas H. Inge, Children’s Hospital Colorado.

Two Children’s National spin-outs join Johnson & Johnson–JLABS

September 11, 2019

AlgometRx, which joins JPOD @ Philadelphia, was founded by Julia Finkel, M.D., pediatric anesthesiologist and director of Pain Medicine and Research at Children’s Sheikh Zayed Institute.

AlgometRx and Adipomics, two companies that spun out of innovations discovered at Children’s National Health System, have been selected by Johnson & Johnson Innovation – JLABS to join JPOD @ Philadelphia and JPOD @ Boston, respectively.

JLABS is a global network of no-strings-attached incubators for innovative companies from across the pharmaceutical, medical device, consumer and health technology sectors. Start-up companies are free to pursue their own research priorities independently, with access to state-of-the-art facilities to develop new drugs, medical devices, precision diagnostics and health technologies for people around the world.

Both companies got their start at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National. The Institute focuses on research and innovation that can improve health for children everywhere.

AlgometRx, which joins JPOD @ Philadelphia, was founded by Julia Finkel, M.D., pediatric anesthesiologist and director of Pain Medicine and Research at Children’s Sheikh Zayed Institute. The AlgometRx device is a first-of-its-kind platform technology that aims to objectively measure pain intensity, type and drug effects in real time by capturing a digital image of a patient’s pupillary light response and applying a series of proprietary algorithms to various characteristics.

AlgometRx is designed to provide an objective pain measurement that aims to help physicians select the correct analgesic class of drug and dosage. By optimizing pain assessment, drug selection and drug management, AlgometRx aims to impact the opioid epidemic and the monitoring and management of Opioid Use Disorder.

Adipomics, which joins JPOD @ Boston, was co-founded by Robert Freishtat, M.D., M.P.H., senior investigator in the Center for Genetic Medicine of the Children’s Research Institute and chief of the Division of Emergency Medicine at Children’s National, and pediatric surgeon Evan P. Nadler, M.D., co-director of the Obesity Program and director of the Bariatric Surgery Program at Children’s National.

Adipomics, which joins JPOD @ Boston, was co-founded by pediatric surgeon Evan P. Nadler, M.D., co-director of the Obesity Program and director of the Bariatric Surgery Program at Children’s National, and Robert Freishtat, M.D., M.P.H., senior investigator in the Center for Genetic Medicine of the Children’s Research Institute and chief of the Division of Emergency Medicine at Children’s National. Adipomics was founded with the aim to address the global epidemic of obesity-related diseases including Type 2 diabetes and cardiovascular diseases. World health experts predict that one billion people worldwide will be obese by 2030.

Drs. Nadler and Freishtat discovered that exosomes released from fat cells (adipocytes) carry genetic material that can mediate various diseases related to obesity. Through their research, they developed a proprietary method that aims to detect how obesity affects an individual patient’s metabolism before the onset of overt disease. Adipomics aims to create the first non-invasive, “anticipatory medicine” diagnostic that detects risk for obesity-related diseases prior to the onset of clinical signs or even biochemical abnormalities. If successful, this predictive methodology would enable treatment much earlier in the disease process, which is likely to improve effectiveness.

A recent news release from Children’s National provides more details on these innovations.

As organizations that share a commitment to improving the pace of healthcare innovation, Children’s National and Johnson & Johnson Innovation – JLABS also recently announced their collaboration to launch JLABS @ Washington, DC, a 32,000-square foot facility to be located at the new Children’s National Research & Innovation Campus in Washington, D.C. The JLABS @ Washington, DC will have the capacity to house up to 50 pharmaceutical, medical device, consumer and health technology companies that are aiming to advance the development of new drugs, medical devices, precision diagnostics and health technologies, including applications in pediatrics. The campus is located on a 12-acre portion of the former Walter Reed Army Medical Center campus in the nation’s capital and is slated to open in 2020, coinciding with the 150th Anniversary of Children’s National Health System.

Detecting early signs of type 2 diabetes through microRNA

June 9, 2019

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Now researchers understand the pathogenesis better among teens with mid-level obesity, thanks to clues released from circulating adipocyte-derived exosomes.

Researchers know that exosomes, tiny nanoparticles released from fat cells, travel through the bloodstream and body, regulating a variety of processes, from growth and development to metabolism. The exosomes are important in lean, healthy individuals in maintaining homeostasis, but when fat gets ‘sick’ – the most common reason for this is too much weight gain – it can change its phenotype, becoming inflammatory, and disrupts how our organs function, from how our skeletal muscle and liver metabolize sugar to how our blood vessels process cholesterol.

Robert J. Freishtat, M.D., M.P.H., the chief of emergency medicine at Children’s National Health System and a professor of precision medicine and genomics at the George Washington University School of Medicine and Health Sciences, and Sheela N. Magge M.D., M.S.C.E., who is now the director of pediatric endocrinology and an associate professor of medicine at the Johns Hopkins School of Medicine, were curious about what this process looked like in teens who fell in the mid-range of obesity.

Obesity is a major risk factor for insulin resistance and type 2 diabetes, but Dr. Freishtat and Dr. Magge wanted to know: Why do some teens with obesity develop type 2 diabetes over others? Why are some teens in this mid-range of obesity metabolically healthy while others have metabolic syndrome? Can fat in obese people become sick and drive disease?

To test this, Dr. Freishtat and Dr. Magge worked with 55 obese adolescents, ages 12 to 17, as part of a study at Children’s National. The participants – 32 obese normoglycemic youth and 23 obese hyperglycemic youth – were similar in age, sex, race, pubertal stage, body mass index and overall fat mass. The distinguishing factor: The hyperglycemic study participants, the teens with elevated blood sugar, differed in where they stored fat. They had extra visceral fat (or adipose tissue) storage, the type of fat that surrounds the liver, pancreas and intestines, a known risk factor for type 2 diabetes.

Dr. Magge and Dr. Freishtat predicted that circulating exosomes from the teens with elevated blood sugar are enriched for microRNAs targeting carbohydrate metabolism.

They used three tests to examine study participants’ metabolism, body composition and circulating exosomes. The first test, an oral glucose tolerance test, measures how efficiently the body metabolizes sugar; the second test is the whole body DXA, or dual-energy x-ray absorptiometry, which analyzes body composition, including lean tissue, fat mass and bone mineral density; and the third test, the serum adipocyte-derived exosomal microRNA assays, is an analysis of circulating fat signals in the bloodstream.

They found that teens with elevated blood sugar and increased visceral fat had different circulating adipocyte-derived exosomes. These study participants’ exosomes were enriched for 14 microRNAs, targeting 1,304 mRNAs and corresponding to 179 canonical pathways – many of which are directly associated with carbohydrate metabolism and visceral fat.

Dr. Magge will present this research, entitled “Changes in Adipocyte-Derived Exosomal MicroRNAs May Play a Role in the Progression from Obese Normoglycemia to Hyperglycemia/Diabetes,” as an oral abstract at the American Diabetes Association’s 79th Scientific Sessions on Saturday, June 8.

Dr. Freishtat envisions having this information will be especially helpful for a patient in a mid-range of obesity. Exosomes primarily consist of small non-coding RNAs. In the current study, the altered RNAs affect P13K/AKT and STAT3 signaling, vital pathways for metabolic and immune function.

“Instead of waiting until someone has the biochemical changes associated with type 2 diabetes, such as hyperglycemia, hyperlipidemia and insulin resistance, we’re hoping physicians will use this information to work with patients earlier,” says Dr. Freishtat. “Through earlier detection, clinicians can intervene when fat shows sign of illness, as opposed to when the overt disease has occurred. This could be intervening with diet and lifestyle for an obese individual or intervening with medication earlier. The goal is to work with children and teens when their system is more plastic and responds better to intervention.”

As this research evolves, Dr. Freishtat continues to look at the intergenerational effects of circulating adipocyte-derived exosomes. Through ongoing NIH-funded research in India, he finds these exosomes, similar in size to lipoproteins, can travel across the placenta, affecting development of the fetus in utero.

“What we’re finding in our initial work is that these exosomes, or ‘sick’ fat, cross the placenta and affect fetal development,” Dr. Freishtat says. “Some of the things that we’re seeing are a change in body composition of the fetus to a more adipose phenotype. Some of our work in cell cultures shows changes in stem cell function and differentiation, but what’s even more interesting to us is that if the fetus is a female sex that means her ovaries are developing while she’s in utero, which means a mother’s adipocyte-derived exosomes could theoretically be affecting her grandchild’s phenotype – influencing the health of three generations.”

While this research is underway, Dr. Freishtat is working with JPOD @ Boston, co-located with the Cambridge Innovation Center in Cambridge, Massachusetts, to develop a test to provide analyses of adipocyte-derived exosomal microRNAs.

“It’s important for families to know that these studies are designed to help researchers and doctors better understand the development of disease in its earliest stages, but there’s no need for patients to wait for the completion of our studies,” says Dr. Freishtat. “Reaching and maintaining a healthy body weight and exercising are important things teens and families can do today to reduce their risk for obesity and diabetes.”

ACC.19: A focus on pediatric cardiology

March 27, 2019

Dr. Gerard Martin, center, accepts an award before delivering the 2019 Dan G. McNamara Keynote lecture at ACC.19.

“Innovation meets tradition,” is how many attendees and journalists described the American College of Cardiology’s 68th Scientific Sessions (ACC.19), which took place March 16-18, 2019 in New Orleans, La.

Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., a pediatric cardiologist and the medical director of Global Services at Children’s National, supported this narrative by referencing both themes in his 2019 Dan G. McNamara keynote lecture, entitled “Improved Outcomes in Congenital Heart Disease through Advocacy and Collaboration.” Dr. Martin highlighted advancements in the field of pediatric cardiology that took place over the past 15 years, while touting modern advancements – such as pulse oximetry screenings for critical congenital heart disease – that were a result of physician-led advocacy and collaboration.

Dr. Martin’s message was to continue to invest in research and technology that leads to medical breakthroughs, but to remember the power of partnerships, such as those formed by the National Pediatric Cardiology Quality Improvement Collaborative. These alliances, which generated shared protocols and infrastructure among health systems, improved interstage mortality rates between surgeries for babies born with hypoplastic left heart syndrome.

A dozen cardiologists and clinicians from the Children’s National Heart Institute also participated in CME panel discussions or delivered poster presentations to support future versions of this template, touching on early-stage innovations and multi-institution research collaborations. The themes among Children’s National Heart Institute faculty, presented to a diverse crowd of 12,000-plus professional attendees representing 108 countries, included:

Personalized guidelines:

Sarah Clauss, M.D., F.A.C.C., a cardiologist, presented “Unique Pediatric Differences from Adult Cholesterol Guidelines: Lipids and Preventive Cardiology,” before Charles Berul, M.D., division chief of cardiology and co-director of the Children’s National Heart Institute, presented “Unique Pediatric Differences from Adult Guidelines: Arrhythmias in Adults with Congenital Heart Disease,” in a joint symposium with the American Heart Association and the American College of Cardiology.
Berul, who specializes in electrophysiology, co-chaired a congenital heart disease pathway session, entitled “Rhythm and Blues: Electrophysiology Progress and Controversies in Congenital Heart Disease,” featuring components of pediatric electrophysiology, including heart block, surgical treatment of arrhythmias and sudden death risk.

Early detection:

Anita Krishnan, M.D., associate director of the echocardiography lab, presented “Identifying Socioeconomic and Geographic Barriers to Prenatal Detection of Hypoplastic Left Heart Syndrome and Transposition of the Great Arteries” as a moderated poster in Fetal Cardiology: Quickening Discoveries.
Jennifer Romanowicz, M.D., a cardiology fellow, and Russell Cross, M.D., director of cardiac MRI, presented the “Neonatal Supraventricular Tachycardia as a Presentation of Critical Aortic Coarctation” poster in FIT Clinical Decision Making: Congenital Heart Disease 2.
Pranava Sinha, M.D., a cardiac surgeon, presented the poster “Neuroprotective Effects of Vitamin D Supplementation in Children with Cyanotic Heart Defects: Insights from a Rodent Hypoxia Model” in Congenital Heart Disease: Therapy 2.

Coordinated care:

Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P., a cardiologist with a focus on hyperlipidemia and preventive cardiology, co-presented an update about BMI quality improvement (Q1) activity from the American College of Cardiology’s Adult Congenital and Pediatric Quality Network – BMI Q1 leadership panel.
Niti Dham, M.D., director of the cardio-oncology program, and Deepa Mokshagundam, M.D., cardiology fellow, presented the poster “Cardiac Changes in Pediatric Cancer Survivors” in Heart Failure and Cardiomyopathies: Clinical 3.
Nancy Klein, B.S.N., R.N., C.P.N., clinical program coordinator of the Washington Adult Congenital Heart program at Children’s National, presented the poster “Improving Completion of Advanced Directives in Adults with Congenital Heart Disease” in Risks and Rewards in Adult Congenital Heart Disease.

Innovation:

Jai Nahar, M.D., a cardiologist, moderated “Future Hub: Augmented Cardiovascular Practitioner: Giving Doctors and Patients a New Voice.” The session focused on technical aspects of artificial intelligence, such as language processing and conversational artificial intelligence, as well as how applications are used in patient-physician interactions.

Nahar also participated in a key event on the Heart-to-Heart stage, entitled “Rise of Intelligent Machines: The Potential of Artificial Intelligence in Cardiovascular Care.”

“While I enjoyed the significant representation of Children’s National faculty at the meeting and all of the presentations this year, one research finding that I found particularly compelling was Dr. Krishnan’s poster about geographical disparities in detecting congenital heart disease,” says Dr. Berul. “Her research finds obstetricians providing care to women in the lowest quartile of socioeconomic areas were twice as likely to miss a diagnosis for a critical congenital heart defect during a fetal ultrasound, compared to obstetricians providing care for women in the highest quartiles.”

Dr. Krishnan’s study was the collaborative effort of 21 centers in the United States and Canada, and investigated how socioeconomic and geographic factors affect prenatal detection of hypoplastic left heart syndrome and transposition of the great arteries.

“We studied over 1,800 patients, and chose these diseases because they require early stabilization by a specialized team at a tertiary care center,” says Dr. Krishnan, who led the research in conjunction with the Fetal Heart Society Research Collaborative. “We hope that by understanding what the barriers are, we can reduce disparities in care through education and community-based outreach.”

A new type 2 diabetes program leader in a time of change

March 26, 2019

Elizabeth Estrada

Elizabeth Estrada, M.D., was struck by the increasing number of children with obesity and type 2 diabetes when she finished her fellowship in 1996. That fascination, along with increasingly alarming statistics about the rise in type 2 diabetes in youth over the past 20 years, steered her to a career focused on pediatric diabetes and metabolism that eventually led her to Children’s National Health System, where she will become the director of the type 2 diabetes program this spring.

Coming most recently from the University of North Carolina, where she served as Chief of the Division of Pediatric Endocrinology and Diabetes, Dr. Estrada will work closely with Children’s National Endocrinology Division Chief Andrew Dauber, M.D., and Diabetes Services Director Fran Cogen, M.D., to create a multidisciplinary type 2 diabetes care structure that she has seen success with throughout her career.

“Children with type 2 diabetes have very different needs than children with type 1,” Dr. Estrada explains. “They need more nutrition, more social work, and psychological support.”

Children’s National presents Dr. Estrada with a unique opportunity at a time when the field of care and treatment options for children with type 2 diabetes is expanding. She aims to develop a comprehensive, multidisciplinary program integrating the established Children’s National obesity program with the nationally-ranked endocrinology and diabetes team, which has a strong foundation in providing psychological support to families, which is part of a larger toolkit at Children’s National to help families manage a diabetes diagnosis.

The obesity program at Children’s National emphasizes personalized clinical care and education to prevent and reduce the prevalence of obesity, incorporating multiple aspects of medical and surgical care for obese children and adolescents through the Improving Diet, Energy and Activity for Life (IDEAL) clinic and the bariatric surgery program. The IDEAL clinic helps children with dietary counseling, health education classes, physical activity and weight-management techniques, as well as psychosocial support to help children reach and maintain a healthy weight.

One of the first children’s hospitals to be accredited by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP®) and the only hospital in the area to be accredited to perform bariatric surgery on adolescents, the bariatric surgery program at Children’s National is directed by Evan Nadler, M.D., who has been safely performing surgeries for nearly 15 years.

The American Diabetes Association (ADA) recently published updates to the “Standards of Medical Care in Diabetes,” which provides research-based practice recommendations for children and adolescents with type 2 diabetes, including metabolic surgery as a treatment recommendation, stating:

The results of weight-loss and lifestyle interventions for obesity in children and adolescents have been disappointing, and no effective and safe pharmacologic intervention is available or approved by the U.S. Food and Drug Administration in youth. Over the last decade, weight-loss surgery has been increasingly performed in adolescents with obesity. Small retrospective analyses and a recent prospective multicenter nonrandomized study suggest that bariatric or metabolic surgery may have benefits in obese adolescents with type 2 diabetes similar to those observed in adults.

The recommendations further stipulate that metabolic surgery should only be considered under certain circumstances, including for those adolescents with T2D who are markedly obsess (BMI > 35 kg/m2) and who have uncontrolled glycemia and/or serious comorbidities despite lifestyle and pharmacologic intervention, and it should only be performed by an experienced surgeon working as part of a well-organized and engaged multidisciplinary team.

Working closely with Dr. Nadler and the obesity team will be a hallmark of Dr. Estrada’s role.

Her goal is to organize a clinic that not only provides clinical care and surgical options, but also includes research and provides medical education and training to medical students, residents and fellows. Dr. Estrada’s own research has focused on insulin resistance, one of the underlying problems in type 2 diabetes.

“There are several clinical trials currently exploring the efficacy and safety of medications for type 2 diabetes in children, something that is incredibly important since Metformin and insulin are the only approved options at this point,” Estrada says. “It is imperative that we bring research to Children’s National as a complement to the existing programs and to continue providing the highest level of care for these patients.”

The Division of Diabetes and Endocrinology works with the National Institutes of Health, conducts independent research and received support from the Washington Nationals Dream Foundation for its diabetes program, the largest pediatric diabetes program in the region, which provides community education and counsels 1,800 pediatric patients each year.

Cellular signals may increase atherosclerosis risk

May 22, 2017

Fat cells from obese patients have the ability to send signals that can accelerate biological processes leading to atherosclerosis.

Obesity has been linked to a variety of adverse health conditions, including Type 2 diabetes, cancer, heart attack and stroke – conditions that may begin as early as childhood in patients whose obesity also begins early. While this much is known, it has been unclear how extra fat mass might lead to these chronic health conditions.

New research from Children’s National Health System scientists might help answer this question. In findings presented at the 2017 annual meeting of the Pediatric Academic Societies, the research team shows that exosomes – nanosized chemical messages that cells send to each other to regulate protein production – isolated from very obese teenage patients behave very differently from those derived from lean patients and could be key players in heightening the risk of developing atherosclerosis. This hardening of the arteries can, in turn, increase the risk of heart disease and stroke in adulthood.

A research team led by Robert J. Freishtat, M.D., M.P.H., chief of emergency medicine at Children’s National, is exploring possible links between extra belly fat and obesity-related diseases, such as atherosclerosis, a buildup of plaque in arteries that can harden and restrict blood flow. More precise knowledge of the mechanisms by which obesity ratchets up heart risks holds the promise of helping the next generation of kids avoid experiencing chronic disease.

The working theory is that exosomes derived from belly fat from obese patients have the distinct ability to accelerate biological processes leading to atherosclerosis.

The research team isolated exosomes from five obese teenagers and compared them to five sex-matched lean adolescents. It turns out that exosomes derived from fat pick up their marching orders from microRNA content likely to target cholesterol efflux genes, which help reduce cholesterol buildup in cells.

The research team looked at differences in cholesterol efflux gene expression in THP-1 macrophages. Uptake of low-density lipoprotein cholesterol, “bad” cholesterol, was 92 percent higher than in those exposed to exosomes from obese patients compared with their lean counterparts. Exposure to obese exosomes also reduced cholesterol efflux.

“Atherogenic properties of fat-cell derived exosomes from obese patients differ markedly from the non-atherogenic profile of exosomes from lean patients. It is especially concerning that we see biological clues of heightened risk in teenagers, and the finding underscores how the seeds for atherosclerosis can be planted very early in life,” Dr. Freishtat says.

The presentation is the latest finding from a research team that, over years of work, is unraveling the mechanisms of cellular signaling by fat cells. By closely examining very obese children – who have the most severe cardiometabolic disease – the team identified strong molecular signals of disease risk that they can search for in leaner patients who may be at risk for disease years from now.

“We know that morbidly obese patients have cardiovascular issues,” explains Dr. Freishtat. “An unanswered question is for patients with no clinical symptoms who are a little overweight. Can we look at them and say whether they are at risk for developing atherosclerosis, insulin resistance or Type 2 diabetes five or 10 years down the line? That’s the whole rationale for doing this work.”

The critical issue is what exosomes are up to. Dr. Freishtat says in lean people, they’re active and are very important in maintaining stable metabolism and homeostatic processes.

“When a person becomes obese, however, exosomes evolve,” he says. “They no longer support insulin signaling, which is helpful, and drive processes in the reverse direction, repressing insulin signaling – which can be harmful,” he adds.

Ultimately, the research team aims to revolutionize how chronic diseases like Type 2 diabetes are diagnosed. For far too long, clinicians have relied on symptoms like high glucose levels and excess urination to diagnose diabetes.

“By the time you have symptoms, it’s too late,” says Dr. Freishtat. “In many cases, damage has been done by relentless exposure to high sugar levels. The biological processes that underlie the Type 2 diabetes process began five, 10, 15 years earlier. If we can detect it earlier, before symptoms arise, intervention is going to have a more significant impact on improving and extending patients’ lives.”

Giving fat cell messages a positive spin

February 8, 2017

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.”