Clinical trial NCT02548767: Adverse Metabolic Effects of Dietary Sugar
Official title: Adverse Metabolic Effects of Dietary Sugar: Ad Libitum vs Energy-balanced Diets
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Disease of Cardiovascular System
Type 2 Diabetes
Obesity
Keywords: High fructose corn syrup
Sugar
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: Touro University, California
name: University of Southern California
name: USDA, Western Human Nutrition Research Center
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2015-09-14
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: BASIC_SCIENCE

Brief summary: It is not known whether consumption of excessive amounts of sugar can increase risk factors for cardiovascular disease or diabetes in the absence of increased food (caloric) intake and weight gain, nor whether the negative effects of sugar consumption are made worse when accompanied by weight gain. This study will investigate the effects of excess sugar when consumed with an energy-balanced diet that prevents weight gain, and the effects of excess sugar when consumed with a diet that can cause weight gain. The results will determine whether excess sugar consumption and excess caloric intake that lead to weight gain have independent and additive effects on risk factors for cardiovascular disease or diabetes, and will have the potential to influence dietary guidelines and public health policy.

Detailed description: Recent studies have demonstrated that consuming high fructose corn syrup (HFCS)- or sucrose-sweetened beverages increased lipid/lipoprotein risk factors for cardiovascular disease (CVD) in healthy adults compared with iso-caloric amounts of glucose or low-fat milk. The longest of these studies, which utilized a 6-month intervention, also showed increased liver and muscle TG and increased visceral adipose deposition. Neither of these studies found differences in weight gain between subjects consuming HFCS/sucrose beverages compared with control beverages. These results suggest that it is not just excess calories and weight gain that mediate the effects of dietary sugar/fructose on the development of metabolic disease; rather, dietary sugar per se is also a contributor. However, it is not known whether consumption of excessive amounts of sugar can increase risk factors for metabolic disease in the absence of positive energy balance and weight gain, nor whether the adverse effects of sugar consumption are exacerbated by weight gain. This study will compare the contribution of sugar with the contribution of energy level to the increases in risk factors for metabolic disease induced by consumption of HFCS-sweetened beverages under energy-balanced or ad libitum conditions. The investigators will measure risk factors and processes associated with metabolic disease in 4 groups of young, healthy adults who will consume 1) 0%, 2) or 25% of energy requirement as HFCS-sweetened beverages for 8 weeks with an energy-balanced diet for 6 weeks; 3) 0%, or 4) 25% of energy requirement as HFCS-sweetened beverages for 8 weeks with an ad libitum diet for 6 weeks. All diets, formulated to achieve a comparable macronutrient intake (55% energy as carbohydrate, 35% fat, 15% protein) among all 4 experimental groups, will be provided to the subjects throughout the entire study. The investigators hypothesize that under energy balanced (EB) condition that prevent body weight gain, consumption of HFCS-sweetened beverages will result in adverse metabolic effects compared with aspartame-sweetened beverages. Consumption of HFCS-sweetened beverages with the ad libitum (AL) diet will result in increased energy intake and body weight gain compared with aspartame-sweetened beverages, and will also result in adverse metabolic effects that are more marked than with consumption of HFCS-sweetened beverages with the energy-balanced diet. These results will demonstrate that consumption of HFCS-sweetened beverages increases risk for metabolic disease both directly, via the adverse effects of fructose on lipid and carbohydrate metabolism, and indirectly, via the effects of HFCS-sweetened beverages to promote excess energy intake and body weight gain. These findings will have the potential to influence dietary guidelines and public health policy.

Eligibility criteria: Inclusion Criteria:

* BMI 22-28 kg/m2
* Self-reported stable body weight during the prior six months

Exclusion criteria:

* Fasting glucose \>105 mg/dl
* Evidence of liver disorder \[AST (Aspartate Aminotransferase) or ALT (Alanine Aminotransferase)\] \>200% upper limit of normal range)
* Evidence of kidney disorder (\>2.0mg/dl creatinine)
* Evidence of thyroid disorder (out of normal range)
* Systolic blood pressure consistently over 140mm Hg (mercury) or diastolic blood pressure over 90mmHg
* Triglycerides \> 200mg/dl
* LDL-C \> 130mg/dl in combination with Chol:HDL \> 4
* Hemoglobin \< 8.5 g/dL
* Pregnant or lactating women
* Any other condition that, in the opinion of the investigators, would put the subject at risk
* Current, prior (within 12 months), or anticipated use of any hypolipidemic or anti-diabetic agents.
* Use of thyroid, anti-hypertensive, anti-depressant, weight loss medications or any other medication which, in the opinion of the investigator, may confound study results
* Use of tobacco
* Strenuous exerciser (\>3.5 hours/week at a level more vigorous than walking)
* Surgery for weight loss
* Diet exclusions: Food allergies, special dietary restrictions, food allergies, routine consumption of less than 3 meals/day, routine ingestion of more than 2 sugar-sweetened beverages or 1 alcoholic beverage/day, unwillingness to consume any food on study menu
* Hydrogen concentration in breath sample following consumption of HFCS-beverage during screening \>50ppm
* Veins that are assessed by the CCRC (Clinical Research Center) R.N.s as being unsuitable for long-term infusions and multiple blood draws from a catheter.
* Pre-existing claustrophobia or metal implants that preclude MRI

Primary outcomes:
measure: Change of de novo lipogenesis: palmitate tracer-to-tracee ratios by gas chromatography-mass spectrometry.
timeFrame: 22 hours at Baseline and 4-week Intervention
Secondary outcomes:
measure: Change of endogenous glucose production measured by standard dilution techniques
timeFrame: 7 hours at Baseline and 4-week Intervention
measure: Change of whole body insulin sensitivity
timeFrame: 3 hours at Baseline and 4-week Intervention
measure: Change of liver lipid
timeFrame: Baseline, 4-week Intervention and 8-week intervention
measure: Change of fat oxidation
timeFrame: 17 hours at Baseline and 4-week Intervention
measure: Change of Very low density lipoprotein (VLDL)-triglyceride (TG) kinetics
timeFrame: 22 hours at Baseline and 4-week Intervention
Other outcomes:
measure: Change of blood levels of LDL-cholesterol
timeFrame: Baseline and 4-week Intervention
measure: Change of blood levels of non-HDL-cholesterol
timeFrame: Baseline and 4-week Intervention
measure: Change of blood levels of apolipoprotein B
timeFrame: Baseline and 4-week Intervention
measure: Change of blood levels of triglyceride
timeFrame: Baseline and 4-week Intervention
measure: Change of blood levels of apolipoprotein C3
timeFrame: Baseline and 4-week Intervention
measure: Change of blood levels of uric acid
timeFrame: Baseline and 4-week Intervention
Locations:
city: Davis
country: United States
facility: University of California, Davis
state: California
city: Sacramento
country: United States
facility: Clinical Research Center
state: California
city: Vallejo
country: United States
facility: Touro University California Translational Research Clinic and Student Health Clinic
state: California
Study officials:
affiliation: University of California, Davis
name: Peter J Havel, DVM, Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Touro University
name: Jean-Marc Schwarz, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Kimber L Stanhope, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Stanhope KL, Schwarz JM, Havel PJ. Adverse metabolic effects of dietary fructose: results from the recent epidemiological, clinical, and mechanistic studies. Curr Opin Lipidol. 2013 Jun;24(3):198-206. doi: 10.1097/MOL.0b013e3283613bca.
citation: Cox CL, Stanhope KL, Schwarz JM, Graham JL, Hatcher B, Griffen SC, Bremer AA, Berglund L, McGahan JP, Keim NL, Havel PJ. Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans. Nutr Metab (Lond). 2012 Jul 24;9(1):68. doi: 10.1186/1743-7075-9-68.
citation: Cox CL, Stanhope KL, Schwarz JM, Graham JL, Hatcher B, Griffen SC, Bremer AA, Berglund L, McGahan JP, Havel PJ, Keim NL. Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women. Eur J Clin Nutr. 2012 Feb;66(2):201-8. doi: 10.1038/ejcn.2011.159. Epub 2011 Sep 28.
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.
citation: Stanhope KL. Role of fructose-containing sugars in the epidemics of obesity and metabolic syndrome. Annu Rev Med. 2012;63:329-43. doi: 10.1146/annurev-med-042010-113026. Epub 2011 Oct 27.
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.
citation: Maersk M, Belza A, Stodkilde-Jorgensen H, Ringgaard S, Chabanova E, Thomsen H, Pedersen SB, Astrup A, Richelsen B. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Am J Clin Nutr. 2012 Feb;95(2):283-9. doi: 10.3945/ajcn.111.022533. Epub 2011 Dec 28.
citation: Aeberli I, Hochuli M, Gerber PA, Sze L, Murer SB, Tappy L, Spinas GA, Berneis K. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care. 2013 Jan;36(1):150-6. doi: 10.2337/dc12-0540. Epub 2012 Aug 28.
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.
citation: Bergwall S, Johansson A, Sonestedt E, Acosta S. High versus low-added sugar consumption for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2022 Jan 5;1(1):CD013320. doi: 10.1002/14651858.CD013320.pub2.