Genetic-specific Effects of Fructose on Liver Lipogenesis

NCT03783195 | Completed Results

• 2 other identifiers: 17-3348P30DK056336-16S1
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief 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. 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. 2.to determine the impact of acute exposure of fructose on hepatic DNL, and
3. 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.

Conditions

NAFLD

Keywords

Glucose; Fructose; Fatty-liver; Polymorphisms; Imaging; Fibroscan

Outcome Measures

Primary Outcomes (4)

• Mean Change in Liver Fat Content Based on Elastography

  Elastography (Fibroscan) will be used to measure changes in liver fat.

  between week 0 (Baseline) and week 3

• Mean Percent Change in Liver Fat Content Based on MRI

  Magnetic resonance imaging (MRI) will be used to measure changes in liver fat (% change in fat fraction).

  between week 0 (Baseline) and week 3

• Mean Change in Serum Concentrations of Very Low Density Lipoprotein-triglycerides (VLDL-TG)

  VLDL-TG measurement in serum (mg/dl) at week 0 and Week 3.

  between week 0 (Baseline) and week 3

• Mean Change in AUC of Serum Very Low Density Lipoprotein-triglycerides (VLDL-TG)

  Area under curve (AUC) (mg\*hr/dl) of serum VLDL-TG for baseline and 3hr time points at week 0 and Week 3.

  between week 0 (Baseline) and week 3

Secondary Outcomes (18)

• Mean Change in Serum Concentrations of Triglycerides

  between week 0 (Baseline) and week 3

• Mean Change in AUC of Serum Triglycerides

  between week 0 (Baseline) and week 3

• Mean Change in Serum Concentrations of HDL Cholesterol

  between week 0 (Baseline) and week 3

• Mean Change in AUC of Serum HDL Cholesterol

  between week 0 (baseline) and week 3

• Mean Change in Serum Concentrations of LDL Cholesterol

  between week 0 (Baseline) and week 3

Study Arms (2)

High GRS group

EXPERIMENTAL

This group consists of individuals who are in the highest quartile of the genetic risk score (GRS) and will ingest one sugar drink (equal to 2 soft drinks) per day for 3 weeks. The GRS is computed by adding the number of alleles that increase the risk for liver lipogenesis or fatty liver.

Other: Sugar drink

Low GRS group

EXPERIMENTAL

This groups consists of individuals who are in the lowest quartile of the genetic risk score (GRS) and will ingest one sugar drink (equal to 2 soft drinks) per day for 3 weeks. The GRS is computed by adding the number of alleles that increase the risk for liver lipogenesis or fatty liver.

Other: Sugar drink

Interventions

Sugar drink OTHER

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

High GRS group; Low GRS group

Eligibility Criteria

• Age: 12 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Subjects 12 - 40 years
• No history of alcohol abuse (\> 7 drinks per week)
• History of fructose intake of \< 14 drinks per week
• Caucasian ethnicity
• BMI \> 25kg/m² - 32kg/m² or 85th -99th percentile but otherwise healthy

You may not qualify if:

• ages \< 12 and \> 40 years
• Pregnant/lactating
• known alcohol abuse or fructose intake \> 14 drinks per week
• not of Caucasian ethnicity
• glucose levels \> 100 mg/dL if fasting, \> 140mg/dL if within 2 hours post meal and \> 200 mg/dL if random sample
• taking anti-hypertensive, anti-diabetic, uric acid and/or lipid-lowering medications
• 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
• BMI \< 25kg/m² or \> 32 kg/m² or \< 85th or \> 99th percentile
• Liver fat fraction \>5% as per baseline MRI scan

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

UNC Nutrition Research Institute

Kannapolis, North Carolina, 28081, United States

Location

Related Publications (27)

• 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.

  PMID: 27543837 BACKGROUND

• 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.

  PMID: 18769702 BACKGROUND

• 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.

  PMID: 25514388 BACKGROUND

• 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.

  PMID: 15983189 BACKGROUND

• 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.

  PMID: 27995280 BACKGROUND

• 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.

  PMID: 19381015 BACKGROUND

• 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.

  PMID: 25904601 BACKGROUND

• 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.

  PMID: 28972537 BACKGROUND

• 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.

  PMID: 26005677 BACKGROUND

• 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.

  PMID: 24065788 BACKGROUND

• 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.

  PMID: 26738417 BACKGROUND

• 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.

  PMID: 22617559 BACKGROUND

• 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.

  PMID: 21423719 BACKGROUND

• 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.

  PMID: 20962157 BACKGROUND

• 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.

  PMID: 26043229 BACKGROUND

• 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.

  PMID: 27935520 BACKGROUND

• 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.

  PMID: 28579536 BACKGROUND

• 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.

  PMID: 21849529 BACKGROUND

• 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.

  PMID: 25825943 BACKGROUND

• 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.

  PMID: 20948525 BACKGROUND

• 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.

  PMID: 17991646 BACKGROUND

• 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.

  PMID: 8301227 BACKGROUND

• 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.

  PMID: 21252253 BACKGROUND

• 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.

  PMID: 24090729 BACKGROUND

• 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.

  PMID: 25659155 BACKGROUND

• 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.

  PMID: 24452634 BACKGROUND

• 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.

  PMID: 29109528 BACKGROUND

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Fatty Liver

Interventions

Sugar-Sweetened Beverages

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Beverages; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages

Results Point of Contact

• Title: Saroja Voruganti, PhD
• Organization: University of North Carolina at Chapel Hill

saroja@unc.edu

704-250-5009

Study Officials

• Saroja Voruganti

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants are assigned to high genetic risk score group in parallel to low genetic risk score group

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 20, 2018
• Study Start: January 25, 2019
• Primary Completion: April 25, 2023
• Study Completion: April 25, 2023
• Last Updated: October 23, 2024
• Results First Posted: October 23, 2024

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: 9- 36 months following article publication
• Access Criteria: Investigators whose proposed use of the data has been approved by the institutional review board, independent ethics committee or research ethics committee, as applicable and an executed data use agreement with UNC.

Locations

US (1)