This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Non-alcoholic fatty liver disease (NAFLD) is a major health problem in the United States, affecting approximately 20% of the adult population. NAFLD represents a spectrum of liver disease that can be characterized histologically as steatosis, steatohepatitis, fibrosis and cirrhosis. The prevalence of NAFLD is 4-5 times higher in obese than lean persons and is associated with insulin resistance and the metabolic syndrome. However, the mechanism(s) responsible for developing NAFLD in obese persons and the effects of NAFLD itself on metabolic function are not known. This gap in our basic understanding of this disease has made it difficult to identify effective treatments, and the appropriate therapeutic approach to NAFLD is not known. Although weight loss is generally recommended for obese patients with NAFLD, the available data suggest that rapid and marked weight loss increases inflammation, and even liver failure. Therefore, the primary goal of this proposal is to provide a better understanding of: 1) the pathogenesis and pahtophysiology of NAFLD in obese persons, adn 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. These studies will lay the groundwork for the development of new therapeutic interventions for obese patients with NAFLD.We will test the overall hypotheses that: 1) obesity causes hepatic fat accumulation, because of excessive fatty acid release from adipose tissue and increased FFA avaliability, 2) increased hepatic fat content increases lipid peroxidation and hepatic oxidative stress, which in conjunction with an obesity-related increase in cytokine production, leads to hepatic inflammation, necrosis and fibrosis, 3) increased hepatic fat content and liver inflammation causes insulin-resistant glucose metabolism in the liver and altered hepatic lipoprotein and protein synthesis, and 4) marked weight loss improves the histological and metabolic features of NAFLD, once patients are weight stable.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-CR-4 (02))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Kelsey, Megan M; Braffett, Barbara H; Geffner, Mitchell E et al. (2018) Menstrual Dysfunction in Girls From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. J Clin Endocrinol Metab 103:2309-2318
Kleinberger, Jeffrey W; Copeland, Kenneth C; Gandica, Rachelle G et al. (2018) Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med 20:583-590
Berkowitz, Robert I; Marcus, Marsha D; Anderson, Barbara J et al. (2018) Adherence to a lifestyle program for youth with type 2 diabetes and its association with treatment outcome in the TODAY clinical trial. Pediatr Diabetes 19:191-198
Arslanian, Silva; El Ghormli, Laure; Kim, Joon Young et al. (2018) The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test: Forerunner of Heightened Glycemic Failure Rates and Accelerated Decline in ?-Cell Function in TODAY. Diabetes Care :
Kriska, Andrea; El Ghormli, Laure; Copeland, Kenneth C et al. (2018) Impact of lifestyle behavior change on glycemic control in youth with type 2 diabetes. Pediatr Diabetes 19:36-44
Venditti, E M; Tan, K; Chang, N et al. (2018) Barriers and strategies for oral medication adherence among children and adolescents with Type 2 diabetes. Diabetes Res Clin Pract 139:24-31
Gidding, Samuel S; Bacha, Fida; Bjornstad, Petter et al. (2018) Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study. J Pediatr 192:86-92.e5
Bertozzi, Beatrice; Tosti, Valeria; Fontana, Luigi (2017) Beyond Calories: An Integrated Approach to Promote Health, Longevity, and Well-Being. Gerontology 63:13-19
Arslanian, Silva; El Ghormli, Laure; Bacha, Fida et al. (2017) Adiponectin, Insulin Sensitivity, ?-Cell Function, and Racial/Ethnic Disparity in Treatment Failure Rates in TODAY. Diabetes Care 40:85-93
Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78

Showing the most recent 10 out of 497 publications