Adverse Metabolic Effects of Dietary Sugar

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Chronic Disease of Cardiovascular System, Type 2 Diabetes, Obesity

Intervention / Treatment
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* Other: high fructose corn syrup
* Other: aspartame
* Other: Energy-balanced diet
* Other: Ad libitum diet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HFCS-EB<br>Consume 3 servings/day of high fructose corn syrup (HFCS)-sweetened beverage along with the provided energy-balanced diet. The 3 HFCS-sweetened beverages will contain 25% of energy requirement and the remainder of the provided diet will contain 75% of energy requirement. All and only the provided beverage and diet will be consumed for eight weeks. | Other: high fructose corn syrup<br>* High fructose corn syrup provided as 15% HFCS/85% water (weight/weight) fruit-flavored beverage<br>* Other names: sugar, HFCS, high fructose corn syrup-55, HFCS-55;Other: Energy-balanced diet<br>* 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.<br>* Other names: Weight-maintaining diet;|
| Placebo Comparator: Asp-EB<br>Consume 3 servings/day of aspartame-sweetened beverage along with the provided energy-balanced diet. The 3 aspartame-sweetened beverages will contain 0% of energy requirement and the remainder of the provided diet will contain 100% of energy requirement. All and only the provided beverage and diet will be consumed for eight weeks. | Other: aspartame<br>* Aspartame provided as 0.04% aspartame/99.96% water (weight/weight), fruit-flavored beverage<br>* Other names: non-caloric sweetener;Other: Energy-balanced diet<br>* 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.<br>* Other names: Weight-maintaining diet;|
| Experimental: HFCS-AL<br>Consume 3 servings/day of high fructose corn syrup (HFCS)-sweetened beverage along with the provided ad libitum diet. The 3 HFCS-sweetened beverages will contain 25% of energy requirement and the remainder of the provided diet will contain approximately 125% of energy requirement. All the provided beverage will be consumed for eight weeks. Only the provided beverage and diet will be consumed for eight weeks. The provided diet will be consumed ad libitum and the uneaten portions will be returned to study staff. | Other: high fructose corn syrup<br>* High fructose corn syrup provided as 15% HFCS/85% water (weight/weight) fruit-flavored beverage<br>* Other names: sugar, HFCS, high fructose corn syrup-55, HFCS-55;Other: Ad libitum diet<br>* 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.<br>* Other names: Positive-energy diet;|
| Placebo Comparator: Asp-AL<br>Consume 3 servings/day of aspartame-sweetened beverage along with the provided ad libitum diet. The 3 aspartame-sweetened beverages will contain 0% of energy requirement and the remainder of the provided diet will contain approximately 125% of energy requirement. All the provided beverage will be consumed for eight weeks. Only the provided beverage and diet will be consumed for eight weeks. The provided diet will be consumed ad libitum and the uneaten portions will be returned to study staff. | Other: aspartame<br>* Aspartame provided as 0.04% aspartame/99.96% water (weight/weight), fruit-flavored beverage<br>* Other names: non-caloric sweetener;Other: Ad libitum diet<br>* 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.<br>* Other names: Positive-energy diet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Change of liver lipid | Quantified from magnetic resonance imaging | Baseline, 4-week Intervention and 8-week intervention | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High fructose corn syrup, Sugar