Diabetes Research Growing

David Sparling, M.D., Ph.D., Section Chief for Diabetes and Endocrinology in the Department of Pediatrics, is active as a researcher and a clinician.

Diabetes Research Expands to Meet Needs Driven by Aggressive Conditions

With both Type 1 and Type 2 diabetes continuing to increase, researchers are fueled by a sense of urgency to drive innovations that slow growth of the disease and the toll it is taking on people of all ages.

According to the Centers for Disease Control, more than 554,400 Oklahoma adults have a diabetes diagnosis, which equates to 14.3% of the population. One in 10 infants and toddlers are already obese, and one in five youth are both obese and at risk for childhood diabetes. Every year, diabetes and pre-diabetes costs $3.2 billion in Oklahoma, including $873 million in indirect costs for lost productivity. If trends continue, the American Medical Association estimates that one-third of all children born in the United States, as well as one-half of Native American children, will develop Type 2 diabetes in their lifetimes.

“The face of diabetes has undergone striking changes over several decades,” said Jed Friedman, Ph.D., director of Harold Hamm Diabetes Center. “The number of Americans diagnosed with diabetes has increased from 5.5 million in 1980 to 34 million in 2020. Currently, one in eight Oklahomans has Type 2 diabetes, and one-third of the state’s adult population have pre-diabetes and are completely unaware of their precarious

During the tenure of Jed Friedman, Ph.D., director of Harold Hamm Diabetes Center, federal research dollars have increased from $2 million to more than $20 million.

condition. Native Americans have over twice the risk of developing diabetes and are almost twice as likely as non-Hispanic whites to die from diabetes or suffer from its complications, including cardiovascular disease, fatty liver disease and cancer. While these statistics are grim, we know that research holds the key to make progress against this disease.”

The statistics are alarming, and a changing dynamic is especially concerning: Type 2 diabetes, which formerly was only seen in adults, is dramatically increasing in children, driven by the obesity epidemic. Related conditions like non-alcoholic fatty liver disease are taking the same course, leading to a lifetime burden of care. Additionally worrisome is that both conditions seem to progress faster in youth than they do in adults.

The research enterprise in the OU College of Medicine and OU Health Harold Hamm Diabetes Center continues expanding to meet the demand for new insight into the causes of and treatments for both Type 1 and Type 2 diabetes. In the past three years, seven new investigators, with established federal funding, have been recruited, which brings the diabetes research base to approximately 130 faculty and trainees across five colleges, the OU Norman campus, and the Oklahoma Medical Research Foundation. Federal research grants have increased from $2 million to $20 million, and philanthropic support is strong and growing.

Friedman, who arrived on campus in 2019, established three research pathways toward a cure for diabetes. The first focuses on the first 1,000 days — from conception to a child’s second year of life — when there are critical windows of development where metabolic conditions are established that affect a person’s health across the life span. The second pathway, protecting the pancreas, involves identifying proteins that could play a role in interrupting the destruction of the pancreas. The third pathway, the intersection of diabetes and cancer, addresses common risk factors and explores connected solutions for the two diseases.

The first 1,000 days is a major focus in the Section of Diabetes and Endocrinology in the Department of Pediatrics. The section has expanded dramatically, led in its early growth by former Section Chief Kenneth Copeland, M.D., and continued today under the leadership of newly appointed Section Chief David Sparling, M.D., Ph.D. The section’s research enterprise broadly focuses on the outcomes of obesity in youth, maternal determinants of disease, the long-term metabolic effects of breast milk, the importance of microRNAs to metabolism, alternations in the gut microbiome, and many other areas.

The section also maintains respectful partnerships with many tribal nations in Oklahoma. These partnerships began as a clinical partnership; later, mutually beneficial research collaborations were added. Among the most notable of those research partnerships are the National Institutes of Health-funded TODAY studies, whose cumulative findings were published in July 2021 in the prestigious New England Journal of Medicine. The OU Health Sciences Center was the largest of 15 national clinical sites in the trial and partnered with tribal nations and communities including the Absentee Shawnee Tribe, the Cherokee Nation, the Choctaw Nation of Oklahoma, and the Oklahoma City Area Office of the Indian Health Service. About 40% of study participants in Oklahoma were youth from tribal nations.

The TODAY studies (Treatment Options for Type 2 Diabetes in Adolescents and Youth) found that people with Type 2 diabetes diagnosed during youth — as young as 10 years old — have a high risk of developing complications at early ages and have a greater chance of multiple complications within 15 years after diagnosis.

“The TODAY studies demonstrated that youth-onset Type 2 diabetes is much more aggressive than Type 2 diabetes in adults. Youth experience multiple complications very early in their disease process. This demonstrates the need to aggressively treat youth-onset Type 2 diabetes as well as continue to strive for better treatment to prevent the disease progression,” said pediatric endocrinologist Jeanie Tryggestad, M.D., an associate professor in the section. Tryggestad continues to analyze data from the TODAY studies.

The pediatric version of non-alcoholic fatty liver disease (NAFLD) is also a major research focus. Like Type 2 diabetes, NAFLD was historically only diagnosed in adults but is now observed frequently in young people and appears to develop quicker. NAFLD, a buildup of excess fat in the liver not related to alcohol use, leads to inflammation and fibrosis. It is the

Both the pediatric research team, pictured here, and the adult team, shown below, have grown in size and number of grants.

most common liver disease worldwide, affecting nearly 40% of youth with obesity and 10% of the general pediatric population. NAFLD usually develops silently and is often diagnosed in its advanced form along with diabetes.

Kevin Short, Ph.D., an associate professor in the section, is co-leading a new $2.3 million federal grant that aims to better understand the characteristics that drive the development of NAFLD in children, and to identify biomarkers that could one day be used to monitor treatments.

“NAFLD in children is paralleling what we see with Type 2 diabetes — they are diseases formerly observed almost exclusively in adults,” Short said. “It is concerning that children are developing these diseases because they’ll have a lifetime burden of care. With NAFLD in children, the condition not only worsens at a faster pace than it does in adults, but an increasing number of young people are requiring liver transplants by the time they reach young adulthood. In order to develop new treatments, we need to distinguish how kids may be different than adults who have the same disease.”

Friedman is spearheading two major studies, funded by a combined $10 million in NIH grants, that focus on the first 1,000 days. One investigates how the diabetes drug metformin, used by millions of pregnant women, affects developing babies and their future risk for obesity. Because women with diabetes often give birth to newborns with excessive birth weight, metformin is frequently prescribed to lower the expectant mother’s blood sugar and slow the growth of the fetus. While metformin is beneficial in that regard, researchers lack understanding about the long-term safety of the drug in pregnancy.

“Our concern is that metformin on the maternal side crosses the placenta and creates an adult dose of the drug in a developing fetus,” Friedman said. “The fetus is not accustomed to experiencing this drug at a high level, and it doesn’t have a way to clear it. Even though these babies are not overgrown when they are born, we have epidemiological evidence that, as teenagers, they start to develop obesity. We think that whatever sets that in motion probably occurs with their exposure to metformin. We just don’t know how or under what conditions that happens. Team science involving nutrition, neonatology, endocrinology and OB-GYN make these studies possible.”

With the second grant, Friedman is investigating how a mother’s obesity and high-fat diet may change the way her offspring’s genes, including the gut microbiome, work. Studies in animals and neonates suggest that development of the immune system is profoundly altered by disruption of pioneering gut bacteria in early life, which can promote chronic inflammatory disease development in later life. Even a brief disruptive period can induce immunological changes that persist into adulthood.

“Our recent publications showed that a gut microbial imbalance in human infants is associated with changes in immunity with direct connections to both Type 1 and Type 2 diabetes and obesity,” he said.

Friedman’s experiments center on the bone marrow, which is where the immune system originates in a stem cell and sets the stage for inflammatory cells going forward. His hypothesis is that a mother’s obesity and high-fat diet are changing the gut microbiome and the genes that control immunity and, therefore, inflammation in the future can be changed by improving the maternal diet.

Clinical research is also a strong focus for both pediatric and adult versions of diabetes. In the Section of Diabetes and Endocrinology, researchers take part in several national consortiums, including the Pediatric Diabetes Consortium, the Type 1 Diabetes Exchange, and TrialNet. Wavelengths, a research program and clinical registry operated in partnership with OU Health adult providers, allows researchers to follow the outcomes of older adolescents and young adults with Type 1 diabetes.

OU Health’s Type 2 Diabetes Comprehensive Clinic in Youth is a vehicle for enrolling patients in clinical trials studying new drugs for Type 2 diabetes, which pale in comparison to the number of medications for adults with Type 2 diabetes, Sparling said.

A dramatic increase in Type 2 diabetes in children is among the drivers of research in the OU College of Medicine.

Michael Rudolph, Ph.D., is a researcher at Harold Hamm Diabetes Center and an assistant professor in the Department of Physiology.

Tiangang Li,, Ph.D., is a researcher at Harold Hamm Diabetes Center and an associate professor in the Department of Physiology. Harold Hamm Diabetes Center researcher Archana Unnikrishnan, Ph.D., is an assistant professor in the Department of Biochemistry and Molecular Biology.

“Classically, children were not involved in large research studies that established whether a medication was safe and effective,” Sparling said. “While there are many medications for adults with Type 2 diabetes, there are very few for children. Until just a few years ago, the only medication first indicated for a child with diabetes was metformin. If their diabetes could not be controlled with metformin, the only other medication we had was insulin. And the TODAY study demonstrated that more than 50% of kids who go on metformin will fail that treatment in less than four years and progress to needing insulin. We currently have only two other medications approved for treating Type 2 diabetes in youth, and they must be injected. Our hope is that with expansion of medications for children we can slow the disease process. Because Type 2 diabetes is so aggressive in children, we need to be aggressive in treating it.”

In the cancer-diabetes research focus, a recent drug-related finding by an adult diabetes researcher holds promise for the treatment of Type 2 diabetes in adults. Tiangang Li, Ph.D., discovered that a drug developed to suppress cancerous tumors also has the ability to lower blood sugar levels that were elevated due to obesity and Type 2 diabetes. In addition, the drug appears to be effective at lowering blood sugar without requiring a reduction in body weight. “This project illustrates a new pathway whereby a cancer drug can be repurposed for possible diabetes therapy,” Friedman said.

With a $1.6 million federal grant, Li is also studying the progression of NAFLD in adults, which affects approximately one-quarter of the global adult population and often occurs with obesity and Type 2 diabetes. Some people have NAFLD for years with little to no harmful effects, but a small percentage slowly develop NASH, or non-alcoholic steatohepatitis, an advanced form of fatty liver disease that can lead to cirrhosis and liver cancer. Why some people develop NASH and others don’t is not well understood.

“Researchers have begun to realize that people with fatty liver disease may develop NASH for different reasons, or a combination of different reasons,” Li said. “It is important to better understand how the disease develops because we don’t currently have a drug to treat NASH.”

In addition to the leap in federal research dollars for diabetes research, philanthropic support is on the rise as well. The Chickasaw Nation made a major gift, and the Harold Hamm Foundation donated $34 million to accelerate faculty recruitment and to establish a pilot grant program with matching grants. This year, with matching funds from the Presbyterian Health Foundation, Stephenson Cancer Center, Oklahoma Medical Research Foundation, Meinders Foundation and the OU Health Sciences Center, the Harold Hamm Diabetes Center awarded $1.83 million to 17 researchers.

“We like to say that research is at the root of our enterprise,” Friedman said. “The expansion of our research programs is critical for helping children, adults and their families live healthier lives without diabetes and its consequences. With our increased federal dollars, generous philanthropic support and extensive collaborations, we are poised to make discoveries that will achieve our mission.”

Alexandra Ikeguchi, M.D.

Oncologist Helps Lead Clinical Trial Showing Best Treatment Sequence for Metastatic Melanoma

An OU Health physician served as an investigator for a National Cancer Institute-sponsored clinical trial that yielded important answers concerning the treatment of patients with advanced melanoma skin cancer.

Alexandra Ikeguchi, M.D., an assistant professor of medicine, led OU Health’s participation in the trial, which examined two treatment sequences for advanced melanoma to determine which one increased the survival rate for patients. The treatments involved four drugs given in two combinations — two immunotherapy drugs and two targeted therapy drugs. The trial produced a clear answer: Patients who received the two immunotherapy drugs first, followed by the targeted therapy drugs, had a 20% increase in survival over two years. “These two treatments have been considered the standard of care for metastatic melanoma, and they were both developed in the same time period, but they had never been compared head to head,” Ikeguchi said. “This trial is important because it demonstrates that our patients with advanced melanoma will likely live longer if they receive the immunotherapy drugs first, followed by the targeted therapy drugs.”

The two immunotherapy drugs are nivolumab and ipilimumab (N/I), and the two targeted therapy drugs are dabrafenib and trametinib (D/T). As immunotherapy drugs, the N/I combination works by prompting the body’s natural defenses to fight cancer. In this case, it keeps the body’s T cells from “turning off” so that they can actively attack cancer cells. The D/T combination directly targets cancers with a BRAF V600 mutation, which drives cancer cell growth. The mutation is present in about half of patients with metastatic melanoma skin cancer, Ikeguchi said.

Treatment at Stephenson Cancer Center has aligned with the findings. The trial is also important news for community oncologists who are not affiliated with a research-driven academic center like OU Health. Community oncologists treat fewer patients with advanced melanoma, and because the N/I immunotherapy combination can cause significant side effects, those oncologists tend to shy away from prescribing it, Ikeguchi said.

“The toxicity associated with the N/I combination is manageable, but you have to be experienced in managing it. If oncologists only see half a dozen patients a year with advanced melanoma, they may not have the comfort level in doing that,” she said. “Most oncologists in the community have been prescribing targeted therapy, so this clinical trial is saying that practice should be re-examined.”

The trial, called the DREAMseq phase 3 clinical trial, was carried out by researchers from the ECOG-ACRIN Cancer Research Group (Eastern Cooperative Oncology Group and American College of Radiology Imaging Network). It consists of 1,300 member institutions in the United States and around the world and is primarily supported through research funding from the National Cancer Institute. As a National Cancer Institute-Designated Cancer Center, Stephenson Cancer Center participates in ECOG-ACRIN clinical trials and those of many other oncology groups.

“Because we are a National Cancer Institute-Designated Center, we don’t have to confine ourselves to one cooperative group. We can pick out trials that are important and beneficial to our patient population no matter where they are headquartered,” Ikeguchi said.

“Our patients at Stephenson Cancer Center are very eager to go on clinical trials, as was the case with this trial,” she added. “They want to help themselves, but they are also altruistic in giving their time and effort to a trial that will ultimately help many people.”

Rajagopal Ramesh, Ph.D.

Researcher Earns Federal Grant to Study New Drug Delivery Concept for Lung Cancer

Lung cancer, especially when diagnosed at stage 3 or 4, is notoriously difficult to treat. Only a fraction of patients respond to existing treatments, and the five-year survival rate is less than 18%. In an effort to improve those odds, an OU College of Medicine researcher is studying an innovative new approach to treatment — using tiny particles naturally produced by the body, loading them with chemotherapy and an imaging agent, then giving them directions to the cancerous cells.

Rajagopal Ramesh, Ph.D., professor of pathology, recently earned a $2.8 million grant from the National Cancer Institute to conduct the promising study, one of only a few such projects funded in the United States. He is focusing on exosomes — nanometer-sized particles produced in the billions by the body’s cells. Exosomes are attractive as a drug delivery vehicle because of their nanoparticle size, which allows them to pass through tiny blood vessels to reach areas that conventional drugs cannot. And because exosomes are naturally produced, they are likely less toxic than particles that are synthesized using chemicals.

For this study, Ramesh’s use of exosomes is three-fold. First, he loads the exosomes with chemotherapy drugs. Then he adds iron oxide particles, the same agent that is used in MRIs to capture an image inside the body. Finally, he coats the entire exosome with a tumor-targeted peptide that essentially provides directions so that the exosomes travel to the cancerous cells instead of normal cells.

“Our preliminary data show that more than 90% of the exosome specifically goes to the tumor cells instead of harming normal cells with chemotherapy and causing side effects,” Ramesh said. “Once it reaches the tumor, we can monitor the killing of cancer cells in real time because of the imaging agent we loaded into the exosome. After treatment, we can again image the reduction of cancer cells. That’s why we call it a targeted multi-functional exosome.”

Lung cancer often metastasizes to the brain, liver and bone, which makes it especially difficult to treat with conventional therapies. Because exosomes are only 30 to 160 nanometers wide (for comparison, a human hair is approximately 100,000 nanometers wide), Ramesh hypothesizes that they will be able to reach those different areas efficiently and deliver the chemotherapy.

Decades ago, researchers considered exosomes “cellular garbage,” but over the past 10 to 15 years, the scientific community has reconsidered their role, Ramesh said. Both normal cells and cancer cells produce exosomes. Cancer cells produce a higher number of exosomes, and they seem to carry a message to normal cells telling them to transform into cancer cells, he said. Researchers then began thinking about using exosomes from normal cells to deliver drugs to cancer cells.

If Ramesh’s laboratory study is successful, his next steps would be to scale up the production of exosomes to be tested in humans as drug delivery vehicles. The concept is encouraging for its potential to “outsmart” clever tumor cells.

“The challenge we have with cancer, in particular lung cancer, is that tumor cells have the ability to modify themselves in a way that the drugs cannot recognize them anymore. It’s like a cop constantly chasing a thief,” he said. “That’s why we are trying this new option to see if we can prove the concept.”

Research reported in this story is supported by the National Cancer Institute, a component of the National Institutes of Health, under the award number 1R01CA254192-01A1. The project also has been supported by the Presbyterian Health Foundation in Oklahoma City and the Jim and Christy Everest Endowed Chair in Cancer Developmental Therapeutics Research, which Ramesh holds.

During his 45 years on campus, Danny Cavett supported patients and healthcare providers alike.

After 45 Years, Danny Cavett Retires as Director of Pastoral Care at OU Health

For 45 years, Danny Cavett has been a compassionate and supportive presence for hospital patients and their families, helping them navigate difficult circumstances and create meaning from situations that seemed to have none. This spring, Cavett officially retired as Director of Pastoral Care for OU Health, where his work as a chaplain has touched an untold number of people.

“I’m going to miss being there every day, but I will stay connected,” Cavett said. “It’s been my life and has helped me feel fulfilled. I love having relationships with families.”

Cavett is retiring from a program that he has significantly strengthened. The pastoral care department now has a staff of eight chaplains and two administrative assistants, along with several other chaplains who fill in as needed. They cover OU Health University of Oklahoma Medical Center, Oklahoma Children’s Hospital OU Health, and OU Health Edmond Medical Center. Cavett also directed OU Health’s nationally certified Clinical Pastoral Education Program, which has four full-time chaplain residents in training.

Their work is often demanding. Last year, there were 6,500 trauma cases at OU Health’s Level 1 Trauma Center; someone from Cavett’s team was present for each one, keeping families updated and comforted. They also respond to all heart attacks and strokes that occur within the hospital, as well as every death. They help families find funeral homes, facilitate autopsies with pathologists, obtain signatures for death certificates, and more. In addition, they aim to visit every new patient within 24 hours of admission.

“We do that to the tune of about 95%. I’m proud of that,” Cavett said. “We know that if a person receives a visit from pastoral care, even if it’s to say, ‘We’re here if you need us,’ then studies show that patient satisfaction goes up quite a bit.”

Although patients may receive visits from their own clergy, the work of a chaplain is a bit different, Cavett said. Chaplains talk about the patient’s medical problems, ask what kind of help they may need, and work with the patient to move toward goals or find meaning in what they’re experiencing. They do so by honoring the patient’s own ideas about spirituality. “Our calling is to work with the patient’s own background instead of me placing my spirituality on them,” Cavett said. “We want to take their story and help them grow with it.”

“It’s been my life and has helped me feel fulfilled. I love having relationships with families.”

Cavett and his fellow chaplains have faced additional challenges during the time of COVID-19. When the surge of cases has been at its highest, no family members could come into the hospital; instead, Cavett and his team would go find the patient’s family in their car to deliver news. If a patient was near death, one or two family members could go to the bedside.

“Danny’s dedication to our health system and the patients we serve has been invaluable,” said Jon Hayes, President of Oklahoma Children’s Hospital OU Health. “He has been a kind and comforting presence for our patients as well as our healthcare providers and staff. As we have faced tremendous challenges during the COVID-19 pandemic, Danny’s wisdom and compassion have never been more important. It is hard to imagine OU Health without Danny, but he has made us all better at what we do because of the example he has set.”

Since he began his career, Cavett has experienced substantial change in the medical profession and the evolution of hospital facilities. He began working as a chaplain in 1977 at Oklahoma Children’s Memorial Hospital, which was then located in Bielstein Center near the intersection of 13th Street and Stonewall Avenue. Soon, the hospital expanded with the construction of Garrison Tower, which now connects to the original Bielstein building.

When he started, the hospital had room for about 50 children who were in wards instead of private rooms. Cavett saw each patient or family three times a day, and quickly became known at the hospital. Unfortunately, he also conducted many funerals for children who could not be cured by medical treatments available at the time. As medicine advanced, life expectancy lengthened, and Cavett noticed a related phenomenon among young patients.

“It was wonderful that children began living longer, but we were still treating kids like they were going to die,” he said. “Everything was centered around them, and that gave some kids a victim mentality. I decided that we needed to start a camp to teach kids how to cope with their illnesses — to be a thriver and embrace their story.”

That was the genesis of Cavett Kids, a calling that has run in parallel to Cavett’s career as a chaplain. The first camp he organized was for children with kidney disease; it’s still going strong 44 years later. In 1997, Cavett Kids Foundation became a nonprofit organization, and today it offers seven camps and numerous other programs free of charge for children with chronic and life-threatening illness.

“I remember that first year, we connected all the kids because they didn’t know each other,” he said. “I still do all the teaching at the camps about not being a victim. Our motto is that the illness does not define the child. They get to have fun with other kids who have the same medical condition, and they learn what it means to be a thriver.”

Cavett’s career also has been shaped by communal tragedies. In 1995, when a bomb exploded at the Alfred P. Murrah Building in downtown Oklahoma City, he had just walked into Children’s Hospital. He never went to the bombing site because the need was so great at the hospital.

“We set up a place for the parents who were waiting to hear about their kids (who were in a daycare in the building), and we went into the ER and tried to match kids with their parents,” Cavett said. “By noon that day, it was pretty clear that there would not be many more children who survived. The parents kept coming back to me asking if there was any news. And there wasn’t. That still really haunts me. It’s a memory I have to deal with.”

In the aftermath of the bombing, Cavett helped start a support group for families who lost children. He also helped colleagues in psychiatry conduct research on the prevalence of post-traumatic stress disorder among survivors. Because of his experience with that tragedy, he was called upon to help after planes hit the World Trade Center towers on Sept. 11, 2001. He was assigned to the New York City Fire Department’s medical clinic, where he talked with each firefighter who came in, listened to their experiences, and recommended mental health services if needed. He also traveled to individual fire departments to further visit with firefighters who were working at the site.

Throughout his career, Cavett has given his expertise to two other important entities in the healthcare profession: the Medical Ethics Committee at OU Health and the Institutional Review Board (IRB) of the OU Health Sciences Center. Medical Ethics Committee members are on call to provide consultations anytime a healthcare provider, patient or family member has a concern about a treatment regimen. They thoroughly look at each case and make recommendations to physicians overseeing care. As an IRB member, Cavett is part of the group that reviews and monitors research involving human participants. He plans to continue serving on the oncology IRB in his retirement.

Although he is ready to step back from many of his duties, Cavett said he will stay connected to OU Health through committee work and filling in as a chaplain when needed. His decades of experience will no doubt continue influencing others as well.

“I try to teach people about how to handle the stories we see and hear because compassion fatigue, burnout and moral distress are very real,” he said. “Some stories are very dear, so I keep them in my emotional bag around my shoulders. But if I keep every story in that bag, it becomes too heavy to carry. Some stories I have learned to put on a shelf where I can retrieve them if I need to.

“During my career, I’ve seen a progression of myself becoming less stoic and more willing to show my feelings. I still remember a young girl at one of my early camps who loved to play golf. She got to play golf during the camp, and the next week she died. That’s very dear to my heart. The tears come a lot quicker now. I used to hide them, but now I don’t.”