Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition which may progress to cirrhosis. Its pathogenesis is obscure and no effective therapy exists. Insulin resistance (IR) may play a central role in the pathogenesis of NAFLD but the underlying mechanism for this association is unclear. One potential mechanism linking IR to NAFLD is hypertriglyceridemia and increased hepatic influx of free fatty acids (FFAs). Data suggest that the prevalence of NAFLD is increasing in parallel with the rising prevalence of obesity and diabetes. Consequently, a cost-effective treatment is needed to prevent an epidemic of chronic liver disease related to IR. My preliminary data reveal that nearly 90%of patients with NAFLD have hyperinsulinemia, irrespective of the presence of obesity or overt diabetes. NAFLD may also represent an early clinical feature of IR that precedes the development of diabetes and/or obesity. I hypothesize that IR is characteristic of NAFLD and that improving insulin sensitivity (IS) will improve the metabolic and histologic features of this condition. I will test this hypothesis by accomplishing the following specific aims:
Specific Aim #1 : Conduct a case-control study to determine if IR is characteristic of NAFLD. To do this we will: ? Measure IS and insulin clearance using intravenous glucose tolerance testing and Bergman Minimal Modeling in patients with NAFLD, healthy control subjects, and patients with non-steatotic liver disease. ? Determine if IR is associated with increased circulating levels of triglycerides and FFAs compared to matched control groups.
Specific Aim #2 : Conduct a prospective randomized, double-blind, placebo-controlled trial using an insulin-sensitizing agent to treat patients with NAFLD. Study endpoints will include: ? Measurements of IS, hepatic insulin clearance, triglycerides, and FFAs. ? Change in the histologic features that define NAFLD and quantitative measures of visceral and peripheral fat. This project will determine whether IR and/or impaired insulin clearance is characteristic of NAFLD as compared to those with or without chronic non-steatotic liver disease, and whether improving IS will improve the clinical-pathologic features that define NAFLD. I will obtain an MPH degree with an emphasis in epidemiology for the purpose of studying NAFLD and the associated deregulation of insulin and lipid metabolism. The epidemic of obesity and diabetes requires skilled patient-oriented researchers knowledgeable in public health and epidemiology to establish health programs and treatment initiatives to decrease the anticipated morbidity and mortality of chronic liver disease related to IR.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK062116-01A2
Application #
6871563
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2005-06-15
Project End
2006-03-31
Budget Start
2005-06-15
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$123,390
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Yang, Ju Dong; Abdelmalek, Manal F; Pang, Herbert et al. (2014) Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 59:1406-14
Corbin, Karen D; Abdelmalek, Manal F; Spencer, Melanie D et al. (2013) Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis. FASEB J 27:1674-89
Guy, Cynthia D; Suzuki, Ayako; Zdanowicz, Marzena et al. (2012) Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 55:1711-21
Guy, Cynthia D; Suzuki, Ayako; Burchette, James L et al. (2012) Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Hum Pathol 43:790-800
Abdelmalek, Manal F; Lazo, Mariana; Horska, Alena et al. (2012) Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology 56:952-60
Suzuki, Ayako; Abdelmalek, Manal F; Schwimmer, Jeffrey B et al. (2012) Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 10:786-94
Palmeri, Mark L; Wang, Michael H; Rouze, Ned C et al. (2011) Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease. J Hepatol 55:666-672
Abdelmalek, Manal F; Suzuki, Ayako; Guy, Cynthia et al. (2010) Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 51:1961-71
Abdelmalek, Manal F; Sanderson, Schuyler O; Angulo, Paul et al. (2009) Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 50:1818-26

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