Dr. Elif Oral, M.D. is a medical endocrinologist, whose main research interests lie in examining the mechanisms leading to obesity as well as nonalcoholic steatohepatitis, commonly known as fatty liver disease. Currently, she is leading two clinical studies, which investigate the role of the fat hormone leptin, in nonalcoholic steatohepatitis (or NASH). An additional study, which is underway, will evaluate the safety and efficacy of a novel, insulin-independent diabetes drug.

We are at an exciting time for obesity 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 during the practice of medicine. 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.

Approximately 20% of the patients with steatosis in the liver develop NASH. We estimate at least 5 million people in the United States today to have NASH. When one takes into consideration that about 20% of these patients will develop cirrhosis (roughly 1,000,000 people), it is easy to recognize the enormity of the resulting economic impact due to mortality and morbidity and the related health-care costs. Given all these data, it is quite clear that discovery of effective strategies to treat NASH will make a big impact on health-care costs in the United States. Furthermore, our studies will help us understand the link between fat deposition in liver and circulating leptin levels. Steatosis of organs such as liver appears to be responsible for the majority of morbidity associated with obesity (lipotoxicity). Thus, understanding the link between signals of adiposity (such as leptin) and NASH may help us improve our approaches to obesity, insulin resistance and ultimately Type 2 diabetes. Finally, our research has an important potential to expand the therapeutic benefits of exogenous leptin therapy.

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. This may mean that potentially one fourth of the obese population may get direct benefit from exogenous administration of leptin; translating into a hopeful therapy for approximately 20 million Americans. Thus, 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. If this approach is successful in NASH, we plan to target common obesity in future studies. 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 human obesity. Our ultimate goal is to develop effective therapeutic strategies against obesity.

While we are moving forward with our clinical studies, we also would like to develop novel collaborations and form the foundation to achieve three more broad goals:

1) To establish a constant inflow of obese patients so that we can continue to study the heterogeneity observed in them-this requires an effort to organize meaningful clinical service to these patients so that our research mission can be long-lived. I anticipate that our collaboration with the Department of Surgery and the development of the Bariatric Surgery Program will enable this.
2) To develop clinically relevant tools for assessing clinical heterogeneity in obesity. At this point, we are thinking broad. We are evaluating methods that will allow us to measure resting energy expenditure easily in clinic or to monitor voluntary small activity (such as fidgeting) in an outpatient setting. Further, we have started preliminary talks with the Department of Radiology to utilize imaging techniques such as functional MRI or positron emission tomography to understand the brain physiology in patients with obesity. Currently, we are making plans to employ these technologies in the context of our current proposal to assess effects of leptin therapy provided that we can obtain seed funding.
3) To establish a repository of cell lines and tissue bank for patients with obesity and other adiposity disorders so that molecular studies to understand the etiology of these disorders can be undertaken in collaboration with many U of M researchers.





Nonalcoholic steatohepatitis: is leptin deficiency an etiological factor? Phase I (IRBMED # 2003-0388) (HUM0042388)

Nonalcoholic steatohepatitis: is leptin deficiency an etiological factor? Phase 2 (IRBMED # 2005-0400) (HUM00038637)

Nonalcoholic steatohepatitis: is leptin deficiency an etiological factor? (Long-term follow-up) (HUM00019137)

Exenatide Observational Study in the U.S. ( HUM00020731)

Effect of macrocomposition on NAFLD in bariatric surgery condidates ( HUM00026382)

An Exploratory Phase 2 Study to Assess the Effect of Dapagliflozin on Glomerular Filtration Rate (GFR) in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic and Blood Pressure (BP) Control (HUM00035049)

Safety and efficacy of albiglutide administered in combination with insulin glargine, as compared with the combination of insulin glargine and preprandial lispro insulin, in subjects with type 2 diabetes mellitus (HUM00034756)

An Open-Label Treatment Protocol to Provide Metreleptin for the Treatment of Diabetes Mellitus and/or Hypertriglyceridemia Associated With Lipodystrophy (HUM00021139)