We are at an exciting time for metabolic research. Significant mechanistic knowledge is gained in the laboratories using powerful, novel technologies. Most of the knowledge is obtained from laboratory animals and in artificial experimental settings that cannot accurately proximate human homeostasis. Thus, it is important to bring clinical expertise closer to the laboratory bench. It is also important to take concepts and mechanisms obtained at the bench closer to the patients' problems seen in clinic. We are committed to achieving this mission for disorders of human adiposity and related metabolic problems. We have a track record of being able to accomplish this in a rare human condition. We have learned valuable lessons from our unique experience in lipodystrophy syndromes and would like to see if these lessons can be applied to more common human conditions with related metabolic problems.
Elif A. Oral, MD, MS, who leads the research program, is a Professor in the Department of Internal Medicine in the Division of Metabolism, Endocrinology & Diabetes (MEND), Director of the Post Bariatric Clinic, and Director of the Obesity and Metabolic Disorders Program. She is an academic endocrinologist whose main research interests lie in examining the unifying consequences of having too much fat versus too little fat.
To define new metabolic diseases that would fall in the spectrum of Atypical Diabetes and Syndromic Metabolic Disease
We believe that patients with rare diseases are gifts of nature to clinical investigators. We made a commitment to honor these gifts by trying to uncover the mechanisms leading to these phenotypes and then work on solutions that may be unique for these patients. Ultimately, this is a form of personalized medicine that should bear fruit quickly with the rapidly advancing technology.
With colleagues at Michigan Medical Genetics Laboratories (MMGL), Drs. Innis and Tayeh, we have so far identified the molecular cause of disease in 35 unique cases, most of whom had abnormalities in previously discovered genes. We are working to find the solution now for 65 additional patients with some form of lipodystrophy.
With our industry partners and collaborators around the globe, we are looking to launch new clinical trials in distinctive forms of lipodystrophy (The BROADEN Study: A Study of Volanesorsen (Formerly ISIS-APOCIIIRx) in Patients With Familial Partial Lipodystrophy).
With our collaborators in the field of lipodystrophy, we hope to establish a global network that will facilitate understanding various forms of lipodystrophy, quickly filling gaps in knowledge. Goals of the network will be to:
- Increase global awareness of various lipodystrophy syndromes.
- Define the natural history of the disease states and develop standards of care in disease management.
- Rapidly perform clinical trials to prove efficacy of specific agents and expedite approval of the drugs to improve lives of patients afflicted with the diseases.
- Engage advocacy leaders, patients, families, and other stakeholders in the process of care delivery and new therapeutic development.
- Train the next generation of scientists in the field of human metabolic diseases.
- To establish a biorepository for blood, DNA, and human tissue for patients afflicted with lipodystrophy (potentially enriched with a body donation program).
To translate the personalization approach taken from rare human diseases to the broader populations
There is no doubt that leptin is very effective in states of leptin deficiency. However, little is known about the determinants of response in common obesity. If we can show that leptin response is dependent on baseline circulating levels in a disease accepted to be linked to obesity, this would be a significant contribution to the field of obesity. One of our goals is to see if the concept of Relative Leptin Deficiency is a meaningful concept in terms of predicting responsiveness to exogenous leptin therapy. We have utilized this approach in NASH, and treated a small number of men in whom the circulating leptin levels were less than 9 ng/mL. In this pilot study, we have seen clinically significant response in amelioration of NASH in histopathology (Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)).
We hope to collaborate with large epidemiological studies at the populational level to determine if individuals with metabolic disease can be identified with low leptin levels and potentially other biomarkers. We believe that approaching the diseases of human adiposity with the acceptance of clinical heterogeneity and developing methods of classification represents a viable strategy for understanding the multitudes of reasons leading to metabolic diseases with the ultimate goal to develop effective therapeutic strategies against metabolic disease using a personalized approach.
While designing our own investigator initiated trials with new therapeutic approaches for combatting metabolic disease (Amlexanox for Type 2 Diabetes and Obesity, Efficacy of Amlexanox vs. Placebo in Type 2 Diabetic Patients) or participating in large multi-center studies (Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL)), we have been seeking ways of understanding the heterogeneity of the populations enrolled in the studies.
To determine the outcomes of bariatric surgery procedures using the experience from our Post-Bariatric Endocrine Clinic
While Bariatric Surgery appears to target obesity with the broadest number of responders, there are still unique variations in the pattern, rate, and the degree of weight loss achieved.
- We have published the 2- and 5-year outcomes of our own program here at Michigan Medicine.
- We are working to determine if distinctive clusters can be observed among our cohort with respect to morphometric, genetic, epigenetic, and biochemical characteristics.
Elif A. Oral, MD, MS, is a Professor in the Division of Metabolism, Endocrinology & Diabetes (MEND) at the University of Michigan. She completed her medical education in her home country of Turkey at the University of Istanbul. In 1996, she completed her residency in Internal Medicine at Sinai Hospital of Detroit (Michigan). She then completed a Fellowship in Endocrinology, Metabolism and Diabetes at the National Institutes of Health, where she also chose to stay as a Senior Fellow under the mentorship of Drs. Simeon Taylor and Phillip Gorden in the Diabetes Branch of NIDDK.
Since joining the University of Michigan in 2002 as an Assistant Professor of Medicine, along with her regular faculty responsibilities, Dr. Oral also completed a Masters of Science Degree in Clinical Research Design and Biostatistics at the School of Public Health. Her clinical interests are in insulin resistance, obesity, lipid disorders, and diabetes. In 2019, she was elected as a member of the American Society for Clinical Investigation.
Dr. Oral's research focuses on the importance of adipocytes in human metabolism and adipocyte hormones such as leptin. She is best known for her work showing the remarkable efficacy of leptin in rare lipodystrophy syndromes. These studies provided the basis for her current studies investigating the effects of leptin in treatment of non-alcoholic fatty liver disease.
In addition to her roles as physician, educator, and researcher, Dr. Oral is also the Director of the Obesity and Metabolic Disorders Program and the Post-Bariatric Surgery Care Program.
Clinical Study Team
Nevin Ajluni, MD
Assistant Professor, Department of Internal Medicine
Nazanene Esfandiari, MD
Clinical Professor, Department of Internal Medicine
Rita Hench, BS, CCRC-Endocrine
Clinical Study Coordinator, Department of Internal Medicine
Andrew Kraftson, MD
Associate Professor, Department of Internal Medicine
Clinical Study Coordinator, Department of Internal Medicine
Please see below for recently completed NIH grants:
- NIH-NIDDK. 5-R01-DK-088114-A1. Effects of Recombinant Human Leptin in Nonalcoholic Fatty Liver Disease (NAFLD). This proposal will investigate the efficacy of recombinant leptin therapy in NASH and relative leptin deficiency against placebo for a period of one year. It will also evaluate long-term effects in patients who have been treated with recombinant leptin therapy in our pilot studies. February 5, 2011 to December 31, 2015 with NCX till February 28, 2017. Oral EA (PI), $1,250,000 total direct costs
- NIH R21-DK-098776. Probing the Relevance of the “Counter-Inflammatory” Noncanonical IkB Kinases in Regulation of Human Metabolism: An Early Proof-of-Concept Study. This proposal focuses on a clinical proof of concept study to evaluate a novel hypothesis. We hypothesize that the noncanonical IkB kinases IKKe and TBK1 are “counterinflammatory” kinases that keep inflammatory pathways in check while helping to support a positive energy balance. The overarching goal of this proposal is to develop a novel therapy for treatment of Type 2 diabetes. September 18, 2013 to July 31, 2015 with NCX until July 31, 2016. Oral EA (PI), $415,334 total direct costs.
- NIH-NIDDK. RO3- DK092542-01A1 Role of Lipid Intermediates in the Limited Human Adipose Tissue Expandability Associated with Obesity Induced Insulin Resistance. This project evaluates the profiles and functions of lipid intermediates in clinical phenotypes associated with insulin resistance and obesity. September 15, 2012 to September 20, 2013. Oral EA (Sub-contract PI from U Mississippi), $566,000 total direct costs.
Click here to view Dr. Oral's publications.