The past 30 years have seen a dramatic increase in the proportion of children with from obesity, diabetes, and metabolic syndrome, which drive up health care costs and contribute to premature mortality. The etiology(ies) of metabolic syndrome remain(s) unknown. The racial/ethnic presentations of metabolic syndrome differ, especially in children. Obese Latino children exhibit the highest prevalence of dyslipidemia, visceral adiposity, and non-alcoholic fatty liver disease (NAFLD);African American children present instead with hypertension, worsened insulin resistance, and glucose intolerance. Understanding these variations in presentation of metabolic syndrome holds the key to understanding its pathogenesis and, therefore, its prevention and treatment. Evidence for both genetic and environmental differences in symptom prevalence abound, and suggest a gene/race-diet interaction. One likely contributor to the etiology of metabolic syndrome is fructose. The secular trend in fructose consumption parallels the triple epidemics of obesity, type 2 diabetes, and metabolic syndrome in children. Fructose stimulates hepatic de novo lipogenesis, which we have demonstrated contributes to dyslipidemia and NAFLD;and hepatic uric acid synthesis, thought to be important in hypertension. We hypothesize that racial/ethnic differences in fructose metabolism contribute to the observed racial/ethnic differences in presentation of the metabolic syndrome: that in Latinos, fructose is primarily converted to TG by DNL, which leads to an increase in liver fat content, VLDL-TG output, and TG levels;but in African Americans, a greater proportion of fructose is converted to glucose, which leads to increased glycemia and insulin resistance. We further hypothesize that 10 days of isocaloric fructose restriction will decrease DNL and IHL and improve lipid profiles in Latinos;and improve glucose control, insulin sensitivity, and blood pressure in African Americans. We will examine insulin sensitivity and glucose disposal (by OGTT), de novo lipogenesis and triglyceride-rich lipoprotein kinetics (by stable isotope measurement), lipid partitioning within tissues (by magnetic resonance spectroscopy), and nitric oxide metabolites (by HLPC and ELISA) in children with metabolic syndrome, stratified by race and gender;and then again after 10 days fructose restriction. We anticipate that comorbidities will improve in a race/ethnic specific fashion. The results of this study will have immediate impact on: 1) reasons for racial/ethnic differences in insulin resistance and obesity;2) alterations of nutritional information and the Food Pyramid;3) public health efforts regarding prevention and treatment of obesity, diabetes, and metabolic syndrome around the world;and 4) the regulation of food industry claims and food advertising.

Public Health Relevance

The results of this study will have immediate impact on: 1) reasons for ethnic differences in insulin resistance and obesity;2) alterations of nutritional information and the Food Pyramid;3) public health efforts regarding prevention and treatment of obesity, diabetes, and metabolic syndrome around the world;and 4) the regulation of food industry claims and food advertising.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089216-04
Application #
8521268
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
2010-09-10
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$501,437
Indirect Cost
$67,547
Name
Touro University of California
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
023981082
City
Vallejo
State
CA
Country
United States
Zip Code
94592
Stanhope, Kimber L; Schwarz, Jean-Marc; Havel, Peter J (2013) Adverse metabolic effects of dietary fructose: results from the recent epidemiological, clinical, and mechanistic studies. Curr Opin Lipidol 24:198-206
Lustig, Robert H (2013) Fructose: it's "alcohol without the buzz". Adv Nutr 4:226-35