A new approach to help treat type 2 diabetes
A research team that includes several FOEDRC faculty recently published an article describing a new approach to help treat type 2 diabetes. The research team included FOEDRC faculty members Robert Kerns PhD, Andrew Norris MD PhD, Eric Taylor PhD, Yumi Imai MD, and Jessica Smith MD. Also recognized in the publication was Wojciech Grzesik, PhD, who is a research scientist in the FOEDRC metabolic phenotyping core. The work was published in the prestigious journal “Nature Communications” and can be found at this link : https://pubmed.ncbi.nlm.nih.gov/35145074/
Type 2 diabetes affects over 35 million Americans and is a leading cause of disability, expense, and mortality. Type 2 diabetes rates are climbing, in part because there are not yet optimal therapies and preventative strategies. This newly published study reports the development of new prototype drugs that treat type 2 diabetes in mice. The target of these new prototype drugs is a protein named SWELL1. It is a chloride transport protein and is involved in beta-cell and adipose tissue functions. Interestingly, these new prototype drugs inhibit SWELL1 and simultaneously improve insulin sensitivity and increase beta-cell function. Because poor insulin sensitivity and poor beta-cell function are the two factors that cause type 2 diabetes, this new class of drugs represents a two-pronged approach to prevent and/or treat type 2 diabetes. As proof of concept, the investigators found that these prototype drugs potently improved blood sugar levels in mice with type 2 diabetes. The research was directed by Rajan Sah MD PhD, a former member of the FOEDRC who is currently faculty at Washington University in St Louis. The work was bolstered by ongoing collaborations between Dr. Sah and the FOEDRC. Furthermore, this line of research was initiated at the FOEDRC while Dr. Sah was faculty at the University of Iowa.
Finding ways to improve blood flow in peripheral arterial disease associated with type 2 diabetes
Recently the International Journal of Science featured important research by a member of the FOEDRC, Ayotunde Dokun, MD, PhD, Director of the Division of Endocrinology and Metabolism and his team.
Peripheral arterial disease is the narrowing or blockage of the vessels that supply blood to lower extremities. This disease affects millions of individuals with diabetes and is considered a major complication of diabetes which often lead to limb amputation. How diabetes contributes to the increased risk of limb amputation in individuals with peripheral arterial disease is poorly understood. We know that peripheral arterial disease complications are different in people with type 1 versus type 2 diabetes. Therefore, it is very likely that these two forms of diabetes affect worsening of peripheral arterial disease through different processes. We know that a protein called disintegrin and metalloproteinase gene 12 (ADAM12) is expressed at high levels in cells lining the blood vessels where there is poor blood flow. ADAM12 plays a key role in the ability to restore blood flow to limbs when there is blockage of blood vessels. Much less is known about how ADAM12 expression is increased or regulated in areas of poor blood flow. In our previous work, we showed that under normal conditions where there is no diabetes the levels of a small ribonucleic acid (RNA) called miR-29a must go down for ADAM12 expression to go up which then helps restore blood flow when there is blockage of blood vessel. In our most recent study, we found that following blockage of blood flow in type 2 diabetic limbs miR-29a levels does not go down which prevents increased expression of ADAM12 leading to poor blood flow recovery. We also found that treatment of mice with type 2 diabetes with an inhibitor of miR-29a improved ADAM12 expression and resulted in improved blood flow recovery, reduced skeletal muscle injury and improved muscle function. Importantly, we showed similar improvements if we augment ADAM12 expression directly by gene transfer. Therefore, our result has identified a way to possibly improve blood flow to limbs in type 2 diabetes by treating with inhibitors of miR-29a or by augmentation of ADAM12 expression.
The Impactful Diabetes Research Career of Eva Tsalikian, MD
On January 3rd, 2022, we celebrated the career of FOEDRC faculty member Dr. Eva Tsalikian on the occasion of her well-earned retirement. For over 4 decades, Dr. Tsalikian has been tireless in her pursuit of better treatments for children with diabetes. Her research work earned her the 2011 Mary Tyler Moore & S. Robert Levine Excellence in Clinical Diabetes Research award and she was the 2013 Honoree at the Eastern Iowa Juvenile Diabetes Research Foundation gala. She has published over 120 research articles, nearly all of which are focused on diabetes. Her early work focused on amino acid metabolism in diabetes. However, in the early 1990s she refocused her research efforts on improving clinical care for persons with diabetes. Here are some highlights of her many impactful contributions to diabetes research. (1) In the early 2000s, she published a series of articles that contributed to the advancement of continuous glucose monitors for use in diabetes treatment. (2) In another series of publications, she helped determine that out-of-control diabetes is associated with structural brain changes in children. Importantly, this finding helped spur major changes to the blood sugar goals of diabetes therapy in children. (3) In 2019, she was part of a study published in the New England Journal of Medicine showing that a medication called teplizumab can significantly delay the onset of type 1 diabetes. This work was a major step forward in the development of strategies to prevent type 1 diabetes. Impressively, during her productive research career, Dr. Tsalikian wore several other hats. She was a physician who provided clinical care to children and young adults with diabetes. She also built a thriving Pediatric Endocrinology and Diabetes clinical division at the University Hospital, starting essentially with only herself. It was for all of these reasons that we honored Dr. Tsalikian on January 3rd. However, we had another reason to celebrate. In retirement, as an emeritus faculty member, Dr. Tsalkilian will continue to be involved in diabetes research, helping advise the clinical group she founded as they move forward working to develop better treatments for diabetes.
Farewell and Thank You
It is with mixed emotions, but with a sense of great pride in our accomplishments that I write this my final Director’s report. When I came to the University of Iowa nearly 9-years ago, I was given a challenge to leverage the generous gift of the Fraternal Order of Eagles, to develop a world class diabetes research center. I reflected back on where things were at the University of Iowa in 2008, when the FOE began your campaign for the Diabetes Research Center and where they are now. In 2008, there were 5 faculty members identified as doing diabetes research with a total team of 20. We had 10 grants received and approximately $1M in funding from the National Institute of Health. Now, 13 years later the FOEDRC houses 110 faculty members, greater than1 000 researchers. Since that time we have received more than $375M in research funding from 780 grants and more than 1,600 published research articles. Many members of our team have received national and international recognition for their work. We have made important research breakthroughs ranging from the development of promising new approaches for treating diabetes, to increased understanding of how diabetes happens and what we can do to prevent it. As I move on, I hand the reins over to two distinguished and highly qualified colleagues, Dr. Andrew Norris and Kamal Rahmouni, who have agreed to serve as interim co-directors of the FOEDRC.
Andy Norris, MD PhD, is a physician scientist and Professor in the Department of Pediatrics and Biochemistry. He serves as the Director of the Division of Pediatric Endocrinology and Diabetes, and holds a Richard O. Jacobson Foundation Chair in Pediatrics. His research involves translational studies related to the integrated physiology of diabetes across the lifespan, with recent focus on cystic fibrosis related diabetes and early life determinants of diabetes risk. He has served as Associate Director of the FOEDRC since 2014. Andy has provided steady leadership within the FOEDRC since its inception. He was instrumental in setting up euglycemic clamps in our Mouse Metabolic Phenotyping Core, he has led our Chalk Talk series which has provided invaluable grant mentorship to entire FOEDRC Community. Andy served with me as Co-PI of our Diabetes Center Training grant, which will be renewed for funding for an additional 5 years.
Kamal Rahmouni is a professor in the Department of Neuroscience & Pharmacology and Internal Medicine. He also holds the Fraternal Order of Eagles Diabetes Center Research Endowed Chair and serves as Co-Director of the Obesity Research and Education Initiative. His research seeks to understand the fundamental processes involved in the control of energy homeostasis in health and disease. His work has led to the identification of novel mechanisms that underlie obesity and associated disorders including type 2 diabetes and hypertension. Kamal has been the recipient of the 2016 Paul Korner Award by the International Society of Hypertension (ISH) and the 2015 Mid-Career Award for Research Excellence from the Council of Hypertension from the American Heart Association. He is a co-PI on the Nephrology and Hypertension Training Grant and the Training Director of the American Heart Association Strategic Focused Research Network Award to the University of Iowa on cardiometabolic disease.
Kamal and Andy have mentored many trainees and faculty within the FOEDRC and are very qualified to continue the current trajectory of the Diabetes Center. I am confident that they will provide strong and steady leadership as long as needed, while a search for a new permanent director is conducted. The FOEDRC is strong and our current trajectory predicts a bright future. Thank you for the opportunity to serve you as Director of the FOEDRC and thank you for the generosity of the FOE to being us to this point. I look forward to serving as a senior advisor in the years ahead.
Celebrating the accomplishments of Matthew Potthoff, PhD
On September 23, the Carver College of Medicine hosted the Fall 2021 investiture to celebrate endowed faculty appointments. The receipt of endowed chairs recognizes faculty whom have established a track record of accomplishment and whose ongoing success will pave the way for the future of medicine. We are proud to announce that Matthew Potthoff, PhD, associate professor in the Department of Neuroscience and Pharmacology is the newest FOEDRC member appointed to an endowed chair. Specifically, Dr. Potthoff is the recipient of the Roy J. Carver Professorship in Neuroscience and Pharmacology. Dr. Potthoff’s research explores how peripheral hormonal cues signal the brain to control body weight and blood glucose levels. Potthoff and his research colleagues also study the role of epigenetics, which refers to the way in which the environment alters how DNA ultimately makes proteins, in regulating activity in brain cells and their impact on metabolism, neurodegeneration, and aging.
Endowed chairs are a valuable asset to the FOEDRC, as they confer prestige to the holder and University of Iowa; and contribute to our ability to recruit and retain the best diabetes and obesity scholars at the university and from institutions across the country. Kudos to Dr. Potthoff!
Regulation of Muscle Energy Production and Strength in Diabetes
In September 2021, Brian T. O’Neill, Assistant Professor in Internal Medicine and member of FOEDRC, published a paper in the Journal of Clinical Investigation that shows how insulin and the closely related insulin-like growth factor-1 (IGF-1) work in muscle to regulate energy production in mitochondria by suppressing the activation of FoxO transcription factors.
Decreased muscle strength and muscle atrophy are features of long-standing or uncontrolled diabetes that can worsen with aging or bedrest after surgery. Reduced muscle mass and decreased activity increases the risk for premature death. The mechanisms that lead to muscle weakness in diabetes are not well known. In collaboration with Dr. E. Dale Abel, Dr. Vitor Lira, and Dr. William Sivitz from the FOEDRC, Dr. O’Neill demonstrated that loss of insulin and IGF-1 signaling through insulin receptors (IR) and IGF-1 receptors (IGF1R) in muscle led to decreased mitochondrial function, decreased energy production in the form of ATP, and muscle weakness. Using mouse and cell models for loss of IR and/or IGF1R, they showed that these mitochondrial defects are mediated by FoxO transcription factors, in part by their ability to reduce the expression of important mitochondrial genes that govern mitochondrial oxygen consumption and ATP production. Indeed, when FoxOs were genetically absent, muscle ATP production was normal and muscle strength was restored. This work identifies FoxOs as important mediators of the detrimental effects of uncontrolled diabetes on muscle function, and may lead to strategies or therapies to improve rehabilitation and recovery from surgery or severe illness for patients with diabetes.
Early Pathogenesis of Cystic Fibrosis Related Diabetes
John Engelhardt, PhD, Professor and Chair, Department of Anatomy and Cell Biology, and Andrew Norris, MD, PhD, Professor of Pediatrics and Biochemistry and Associate Director of the FOE Diabetes Research Center (DRC), have just been awarded a three-year, $4.5M research grant from the NIH’s National Institutes of Diabetes, Digestive and Kidney Diseases. The project will investigate the changes that occur in insulin producing cells that are affected by cystic fibrosis (CF).
CF is a life-threatening genetic condition that affects roughly 30,000 Americans. Over half of persons with cystic fibrosis will develop diabetes. Drs. Engelhardt and Norris recently discovered that humans and ferrets with CF experience a loss of beta-cells early in life followed by a reappearance of beta-cells. These “reborn” beta-cells often function for decades before diabetes eventually occurs. What is not known is how the beta-cells are reborn. To address this knowledge gap, the group has created new genetic models that enable cells of the ferret to be tracked over time. Possibilities include that the “reborn” beta-cells come from prior beta-cells or alternatively come from other pancreatic structures. Answering this question could provide insight into how new beta-cells can be formed and might help identify new therapies for other forms of diabetes. The University of Iowa team includes pancreas expert Dr. Aliye Uc, Chief of Pediatric Gastroenterology, and Dr. Xingshen Sun, Research Assistant Professor. To further the research, the grant will support collaboration with Dr. Lori Sussel, beta-cell biology expert and Research Director at the Barbara Davis Center for Childhood Diabetes located in Denver, Colorado.