Genetic-specific Effects of Fructose on Liver Lipogenesis

NAFLD Clinical Trial

Official title:

Genetic-specific Effects of Fructose on Liver Lipogenesis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03783195
• Other study ID #: 17-3348
• Secondary ID: P30DK056336-16S1
• Status: Completed
• Phase: N/A
• Start date: January 25, 2019
• Est. completion date: April 25, 2023

Study information

• Verified date: May 2023
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary goal of this study is to identify a set of genotypes that increase the risk for nonalcoholic fatty liver disease (NAFLD) and predispose individuals to increased de novo lipogenesis (DNL) and liver fat accumulation when exposed to fructose intake. The proposed goal will be achieved through the completion of following aims:

1. To determine the impact of prolonged exposure of fructose on hepatic lipid accumulation in Caucasian individuals with high and low genetic risk for NAFLD,

2. to determine the impact of acute exposure of fructose on hepatic DNL, and

3. to determine the relationship between markers of DNL, liver fat accumulation and serum concentrations of lipids, uric acid and liver function markers before and after the fructose challenge.

Description:

BACKGROUND AND RATIONALE Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in liver cells not caused by alcohol. A leading cause of chronic liver disease in the US, NAFLD represents a group of disorders including steatosis, nonalcoholic steatohepatitis with fibrosis. It has substantially risen in prevalence over the last two decades with the estimated prevalence being 20% among US adults and 25% in young adults (18-39 years). Over 64 million individuals are believed to have NAFLD with annual medical costs rising to more $100 billion. More common in individuals who are obese or diabetic and/or have metabolic syndrome, NAFLD has been associated with increased cirrhosis, liver-related mortality and hepatocellular carcinoma.

Both genetic and environmental, including nutritional, factors contribute to the onset and progression of NAFLD. Increased consumption of sugar-sweetened, fructose-rich beverages has been linked to NAFLD. Fructose, commonly found in soft drinks, fruit juices and energy drinks, affects many metabolic processes, foremost being an increase in fat accumulation in the liver and hence, NAFLD. Genome-wide and candidate gene studies have identified several genes associated with NAFLD. However, none of these studies have shown the cumulative effects of single nucleotide polymorphisms (SNPs) on changes in liver fat when exposed to fructose. The results from this study can be extrapolated to larger cohorts and other ethnicities and are therefore, expected to lay the foundation for developing personalized nutritional plans.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: April 25, 2023
• Est. primary completion date: April 25, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 12 Years to 40 Years

Eligibility

Inclusion Criteria:

1. Subjects 12 - 40 years

2. No history of alcohol abuse (> 7 drinks per week)

3. History of fructose intake of < 14 drinks per week

4. Caucasian ethnicity

5. BMI > 25kg/m² - 32kg/m² or 85th -99th percentile but otherwise healthy

Exclusion Criteria:

1. ages < 12 and > 40 years

2. Pregnant/lactating

3. known alcohol abuse or fructose intake > 14 drinks per week

4. not of Caucasian ethnicity

5. glucose levels > 100 mg/dL if fasting, > 140mg/dL if within 2 hours post meal and > 200 mg/dL if random sample

6. taking anti-hypertensive, anti-diabetic, uric acid and/or lipid-lowering medications

7. known diagnosis of diabetes, fructose intolerance, chronic kidney disease, NAFLD or any liver-related disease, hypertriglyceridemia, polycystic ovary syndrome, hypothyroidism, obstructive sleep apnea, hypopituitarism and hypogonadism

8. BMI < 25kg/m² or > 32 kg/m² or < 85th or > 99th percentile

9. Liver fat fraction >5% as per baseline MRI scan

Related Conditions & MeSH terms

• NAFLD

Intervention

Other:
• Sugar drink
A sugar drink made with 1.2 g/kg body weight of added sugar( 0.75g/kg body weight of fructose + 0.45g/kg body weight of glucose) and 24oz water

Locations

Country	Name	City	State
United States	UNC Nutrition Research Institute	Kannapolis	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (27)

Akhavan T, Anderson GH. Effects of glucose-to-fructose ratios in solutions on subjective satiety, food intake, and satiety hormones in young men. Am J Clin Nutr. 2007 Nov;86(5):1354-63. doi: 10.1093/ajcn/86.5.1354. — View Citation

Alwahsh SM, Gebhardt R. Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD). Arch Toxicol. 2017 Apr;91(4):1545-1563. doi: 10.1007/s00204-016-1892-7. Epub 2016 Dec 19. — View Citation

Awai HI, Newton KP, Sirlin CB, Behling C, Schwimmer JB. Evidence and recommendations for imaging liver fat in children, based on systematic review. Clin Gastroenterol Hepatol. 2014 May;12(5):765-73. doi: 10.1016/j.cgh.2013.09.050. Epub 2013 Sep 30. — View Citation

Basaranoglu M, Basaranoglu G, Bugianesi E. Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction. Hepatobiliary Surg Nutr. 2015 Apr;4(2):109-16. doi: 10.3978/j.issn.2304-3881.2014.11.05. — View Citation

Bonder A, Afdhal N. Utilization of FibroScan in clinical practice. Curr Gastroenterol Rep. 2014 Feb;16(2):372. doi: 10.1007/s11894-014-0372-6. — View Citation

Davis JN, Le KA, Walker RW, Vikman S, Spruijt-Metz D, Weigensberg MJ, Allayee H, Goran MI. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr. 2010 Dec;92(6):1522-7. doi: 10.3945/ajcn.2010.30185. Epub 2010 Oct 20. — View Citation

Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L. Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes. 2005 Jul;54(7):1907-13. doi: 10.2337/diabetes.54.7.1907. Erratum In: Diabetes. 2006 Feb;55(2):563. Periasami, Raj [corrected to Periasamy, Raj]; Seongsu, Park [corrected to Park, Seongsu]. — View Citation

Faix D, Neese R, Kletke C, Wolden S, Cesar D, Coutlangus M, Shackleton CH, Hellerstein MK. Quantification of menstrual and diurnal periodicities in rates of cholesterol and fat synthesis in humans. J Lipid Res. 1993 Dec;34(12):2063-75. — View Citation

Goran MI, Walker R, Allayee H. Genetic-related and carbohydrate-related factors affecting liver fat accumulation. Curr Opin Clin Nutr Metab Care. 2012 Jul;15(4):392-6. doi: 10.1097/MCO.0b013e3283544477. — View Citation

Hudgins LC, Parker TS, Levine DM, Hellerstein MK. A dual sugar challenge test for lipogenic sensitivity to dietary fructose. J Clin Endocrinol Metab. 2011 Mar;96(3):861-8. doi: 10.1210/jc.2010-2007. Epub 2011 Jan 20. — View Citation

Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, Ishimoto T, Sautin YY, Lanaspa MA. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013 Oct;62(10):3307-15. doi: 10.2337/db12-1814. — View Citation

Lallukka S, Sadevirta S, Kallio MT, Luukkonen PK, Zhou Y, Hakkarainen A, Lundbom N, Orho-Melander M, Yki-Jarvinen H. Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) - an 11-Year Prospective Study. Sci Rep. 2017 Nov 6;7(1):14561. doi: 10.1038/s41598-017-14706-0. — View Citation

Moore JB, Gunn PJ, Fielding BA. The role of dietary sugars and de novo lipogenesis in non-alcoholic fatty liver disease. Nutrients. 2014 Dec 10;6(12):5679-703. doi: 10.3390/nu6125679. — View Citation

Santoro N, Caprio S, Pierpont B, Van Name M, Savoye M, Parks EJ. Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene. J Clin Endocrinol Metab. 2015 Aug;100(8):E1125-32. doi: 10.1210/jc.2015-1587. Epub 2015 Jun 4. Erratum In: J Clin Endocrinol Metab. 2020 Jan 2;105(2): — View Citation

Schwarz JM, Noworolski SM, Erkin-Cakmak A, Korn NJ, Wen MJ, Tai VW, Jones GM, Palii SP, Velasco-Alin M, Pan K, Patterson BW, Gugliucci A, Lustig RH, Mulligan K. Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity. Gastroenterology. 2017 Sep;153(3):743-752. doi: 10.1053/j.gastro.2017.05.043. Epub 2017 Jun 1. — View Citation

Schwarz JM, Noworolski SM, Wen MJ, Dyachenko A, Prior JL, Weinberg ME, Herraiz LA, Tai VW, Bergeron N, Bersot TP, Rao MN, Schambelan M, Mulligan K. Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat. J Clin Endocrinol Metab. 2015 Jun;100(6):2434-42. doi: 10.1210/jc.2014-3678. Epub 2015 Mar 31. — View Citation

Shin HJ, Kim HG, Kim MJ, Koh H, Kim HY, Roh YH, Lee MJ. Normal range of hepatic fat fraction on dual- and triple-echo fat quantification MR in children. PLoS One. 2015 Feb 6;10(2):e0117480. doi: 10.1371/journal.pone.0117480. eCollection 2015. — View Citation

Softic S, Gupta MK, Wang GX, Fujisaka S, O'Neill BT, Rao TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest. 2017 Nov 1;127(11):4059-4074. doi: 10.1172/JCI94585. Epub 2017 Oct 3. Erratum In: J Clin Invest. 2018 Mar 1;128(3):1199. — View Citation

Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O'Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS; NASH CRN; GIANT Consortium; MAGIC Investigators; Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WH, Hirschhorn JN, Borecki IB; GOLD Consortium. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011 Mar;7(3):e1001324. doi: 10.1371/journal.pgen.1001324. Epub 2011 Mar 10. — View Citation

Stanhope KL, Bremer AA, Medici V, Nakajima K, Ito Y, Nakano T, Chen G, Fong TH, Lee V, Menorca RI, Keim NL, Havel PJ. Consumption of fructose and high fructose corn syrup increase postprandial triglycerides, LDL-cholesterol, and apolipoprotein-B in young men and women. J Clin Endocrinol Metab. 2011 Oct;96(10):E1596-605. doi: 10.1210/jc.2011-1251. Epub 2011 Aug 17. — View Citation

Stanhope KL, Medici V, Bremer AA, Lee V, Lam HD, Nunez MV, Chen GX, Keim NL, Havel PJ. A dose-response study of consuming high-fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults. Am J Clin Nutr. 2015 Jun;101(6):1144-54. doi: 10.3945/ajcn.114.100461. Epub 2015 Apr 22. — View Citation

Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T, Beysen C, Hellerstein MK, Berglund L, Havel PJ. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009 May;119(5):1322-34. doi: 10.1172/JCI37385. Epub 2009 Apr 20. — View Citation

Ter Horst KW, Schene MR, Holman R, Romijn JA, Serlie MJ. Effect of fructose consumption on insulin sensitivity in nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials. Am J Clin Nutr. 2016 Dec;104(6):1562-1576. doi: 10.3945/ajcn.116.137786. Epub 2016 Nov 9. — View Citation

Ventura EE, Davis JN, Goran MI. Sugar content of popular sweetened beverages based on objective laboratory analysis: focus on fructose content. Obesity (Silver Spring). 2011 Apr;19(4):868-74. doi: 10.1038/oby.2010.255. Epub 2010 Oct 14. — View Citation

Vos MB, Kimmons JE, Gillespie C, Welsh J, Blanck HM. Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey. Medscape J Med. 2008 Jul 9;10(7):160. — View Citation

Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, Racila A, Hunt S, Beckerman R. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016 Nov;64(5):1577-1586. doi: 10.1002/hep.28785. Epub 2016 Sep 26. — View Citation

Zhou Y, Wei F, Fan Y. High serum uric acid and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis. Clin Biochem. 2016 May;49(7-8):636-42. doi: 10.1016/j.clinbiochem.2015.12.010. Epub 2015 Dec 29. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Liver fat content (%)	Magnetic resonance imaging (MRI) and transient elastography (Fibroscan) will be used to measure changes in liver fat.	at week 0 and 3
Primary	Serum concentrations of low density lipoprotein-triglycerides (VLDL-TG)	VLDL-TG measurement in serum (mg/dl)	0, 1 and 3 hours at week 0 and week 3
Secondary	Serum concentrations of triglycerides	Fasting concentrations of serum triglycerides (mg/dl) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of HDL cholesterol	Fasting concentrations of serum HDL cholesterol (mg/dl) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of LDL cholesterol	Fasting concentrations of serum LDL cholesterol (mg/dl) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of total cholesterol	Fasting serum concentrations of total cholesterol (mg/dl) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of uric acid	Fasting concentrations of serum uric acid (ng/ml) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of liver function marker (Alanine transaminase- ALT).	Fasting concentrations of serum ALT (IU/L) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of liver function marker (Aspartate transaminase-AST).	Fasting concentrations of serum AST (IU/L) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of liver function marker (Alkaline phosphatase-ALP)	Fasting concentrations of serum ALP (IU/L) will be measured.	at week 0 and week 3
Secondary	Serum concentrations of liver function marker (Gamma glutamyl transpeptidase-GGT)	Fasting concentrations of serum GGT will be measured.	at week 0 and week 3