Adverse Metabolic Effects of Dietary Sugar

Obesity Clinical Trial

Official title:

Adverse Metabolic Effects of Dietary Sugar: Ad Libitum vs Energy-balanced Diets

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02548767
• Other study ID #: 499106
• Secondary ID: 1R01HL121324
• Status: Completed
• Phase: N/A
• Start date: February 2016
• Est. completion date: March 13, 2020

Study information

• Verified date: September 2021
• Source: University of California, Davis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: March 13, 2020
• Est. primary completion date: March 13, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Disease
• Chronic Disease of Cardiovascular System
• Obesity
• Type 2 Diabetes

Intervention

Other:
• high fructose corn syrup
High fructose corn syrup provided as 15% HFCS/85% water (weight/weight) fruit-flavored beverage
• aspartame
Aspartame provided as 0.04% aspartame/99.96% water (weight/weight), fruit-flavored beverage
• Energy-balanced diet
Provided in quantities that equal energy requirement. Formulated such that the overall macronutrient intake; including beverage; equal 45%/5% energy requirement at complex/simple carbohydrate, 35% energy requirement as fat, 15% energy requirement as protein.
• Ad libitum diet
Provided in quantities that exceed energy requirement by approximately 25%. Formulated such that the overall macronutrient intake; including beverage; equals approximately 45%/5% energy requirement at complex/simple carbohydrate, 35% energy requirement as fat, 15% energy requirement as protein.

Locations

Country	Name	City	State
United States	University of California, Davis	Davis	California
United States	Clinical Research Center	Sacramento	California
United States	Touro University California Translational Research Clinic and Student Health Clinic	Vallejo	California

Sponsors (5)

Lead Sponsor	Collaborator
University of California, Davis	National Heart, Lung, and Blood Institute (NHLBI), Touro University, California, University of Southern California, USDA, Western Human Nutrition Research Center

Country where clinical trial is conducted

United States, 

References & Publications (9)

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. — View 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. — View 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. — View Citation

Maersk M, Belza A, Stødkilde-Jørgensen 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. — 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

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, 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. Review. — 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

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change of blood levels of LDL-cholesterol	fasting and postprandial plasma concentrations of TG, cholesterol, low density lipoprotein cholesterol, apolipoprotein B, apolipoprotein C3 are measured	Baseline and 4-week Intervention
Other	Change of blood levels of non-HDL-cholesterol	fasting and postprandial plasma concentrations of TG, cholesterol, low density lipoprotein cholesterol, apolipoprotein B, apolipoprotein C3 are measured	Baseline and 4-week Intervention
Other	Change of blood levels of apolipoprotein B	fasting and postprandial plasma concentrations of TG, cholesterol, low density lipoprotein cholesterol, apolipoprotein B, apolipoprotein C3 are measured	Baseline and 4-week Intervention
Other	Change of blood levels of triglyceride	fasting and postprandial plasma concentrations of TG, cholesterol, low density lipoprotein cholesterol, apolipoprotein B, apolipoprotein C3 are measured	Baseline and 4-week Intervention
Other	Change of blood levels of apolipoprotein C3	fasting and postprandial plasma concentrations of TG, cholesterol, low density lipoprotein cholesterol, apolipoprotein B, apolipoprotein C3 are measured	Baseline and 4-week Intervention
Other	Change of blood levels of uric acid	fasting and postprandial plasma concentrations of uric acid are measured	Baseline and 4-week Intervention
Primary	Change of de novo lipogenesis: palmitate tracer-to-tracee ratios by gas chromatography-mass spectrometry.	Blood samples are collected during 26-h isotopic acetate infusion. Blood samples are processed for determination of palmitate tracer-to-tracee ratios by gas chromatography-mass spectrometry.	22 hours at Baseline and 4-week Intervention
Secondary	Change of endogenous glucose production measured by standard dilution techniques	Blood samples are collected during isotopic glucose infusion, and endogenous glucose production (glucose appearance) is measured by standard dilution techniques.	7 hours at Baseline and 4-week Intervention
Secondary	Change of whole body insulin sensitivity	A variable 20% glucose infusion is adjusted to maintain euglycemia during insulin infusion in order to determine insulin-mediated glucose uptake.	3 hours at Baseline and 4-week Intervention
Secondary	Change of liver lipid	Quantified from magnetic resonance imaging	Baseline, 4-week Intervention and 8-week intervention
Secondary	Change of fat oxidation	Fat oxidation is calculated from measures of oxygen consumption and carbon dioxide production by indirect calorimetry.	17 hours at Baseline and 4-week Intervention
Secondary	Change of Very low density lipoprotein (VLDL)-triglyceride (TG) kinetics	During overnight fasting VLDL-TG kinetics will be determined using a prime constant infusion of isotopic glycerol. During the meal-feeding protocol, the washout kinetic enrichment of isotopic glycerol in the TG will be used to estimate VLDL-TG with a non-steady modeling approach.	22 hours at Baseline and 4-week Intervention