Cardiovascular Risk Factor, Insulin Sensitivity, Metabolic Syndrome, Type2 Diabetes Mellitus
Conditions
Keywords
orange juice, sugar-sweetened beverage, triglyceride, low density lipoprotein cholesterol, apolipoprotein B, uric acid, de novo lipogenesis, hepatic triglyceride, hepatic glucose production, whole body insulin sensitivity
Brief summary
The objectives of this proposal are to address the gaps in knowledge regarding the metabolic effects of consuming orange juice, the most frequently consumed fruit juice in this country, compared to sugar-sweetened beverage.
Detailed description
Specific Aims: There is considerable epidemiological evidence that demonstrates associations between added sugar/sugar-sweetened beverage consumption and increased risk for or prevalence of chronic diseases such as cardiovascular disease (CVD), type 2 diabetes (T2D), metabolic syndrome, and gout. Especially concerning is recent evidence from National Health and Nutrition Examination Survey III that demonstrates that there is increased risk of CVD mortality with increased intake of added sugar across quintiles (Yang, 2014). Even the US mean added sugar intake, 15% of daily calories, was associated with an 18% increase in risk of CVD mortality over 15 years. The results from the investigator's recently completed study (1R01 HL09133) corroborate these findings (Stanhope, 2015). They demonstrate that supplementing the ad libitum diets of young adults with beverages containing 0, 10, 17.5 or 25% of daily energy requirement (Ereq) as high fructose corn syrup (HFCS) affects lipid/lipoprotein risk factors for CVD in a dose response manner. Specifically, levels of nonHDL-cholesterol(C), LDL-C, apolipoprotein B (apoB), and postprandial triglycerides (TG) increased linearly over a 2-week period with increasing doses of HFCS. Furthermore, even the participants consuming the 10% Ereq dose exhibited increased levels of these risk factors compared to baseline. These and similar results have helped to lead to reductions in soda consumption in this country, and new dietary guidelines and FDA food labeling requirements to promote reductions in added sugar consumption. However, there are gaps in knowledge about other sugar-containing foods that lead to public confusion concerning healthier options for soda, and impede further progress in implementing public health policies that will promote further reductions in soda consumption. One such food is naturally-sweetened fruit juice. The amount of sugar in fruit juice is comparable to the amount in soda. Because of this, a consumer seeking answers on the internet will find many articles in which experts state or suggest that the effects of consuming fruit juice are as detrimental as or even worse than those of soda. However, in contrast to soda, fruit juice contains micronutrients and bioactives that may promote health. Therefore the consumer can also find numerous articles on the internet where the health benefits of fruit juice and these bioactives are extolled. There are a limited number of clinical dietary intervention studies that have directly compared the metabolic effects of consuming fruit juice and sugar-sweetened beverage, and their results are not conclusive. Thus we will pursue the following Specific Aims: 1. Specific Aim 1: To compare the weight-independent effects of consuming 25%Ereq as orange juice or sugar-sweetened beverages for 4 weeks on risk factors for CVD and other chronic disease in normal weight and overweight men and women. 2. Specific Aim 2: To mechanistically compare the weight-independent effects of consuming 25%Ereq as orange juice or sugar-sweetened beverages on metabolic processes associated with the development of CVD and T2D in normal weight and overweight men and women. 3. Specific Aim 3: To relate the changes assessed under Specific Aims 1 and 2 to the changes in the urinary levels of metabolites and catabolites of the main flavanones in orange juice, hesperetin and naringenin.
Interventions
OTHERNaturally-sweetened orange juice
Commercially-available ready-to-serve refrigerated orange juice
Sugar-sweetened water flavored with Kool-Aid (TM)
Sponsors
Touro University, California
National Heart, Lung, and Blood Institute (NHLBI)
University of California, Davis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Masking description
All outcomes will be analyzed/assessed by subject identity number, which are assigned prior to randomization to experimental arm.
Intervention model description
Randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
men and pre-menopausal women Body mass index: 20-35 kg/m2 Body weight \> than 50 kg Self-reported stable body weight during the prior six months
Exclusion criteria
Fasting glucose \>125 mg/dl Evidence of liver disorder (AST or ALT \>200% upper limit of normal range) Evidence of kidney disorder (\>2.0 mg/dl creatinine) Evidence of thyroid disorder (out of normal range) Systolic blood pressure consistently over 140 mmHg or diastolic blood pressure over 90 mmHg Triglycerides \> 400 mg/dl LDL-C \> 160 mg/dl in combination with Chol:HDL \> 4 Hemoglobin \< 10 g/dL Pregnant or lactating women 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, 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 Veins that are assessed by the 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 magnetic resonance imaging Any other condition that, in the opinion of the investigators, would put the subject at risk \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Matsuda Insulin Sensitivity Index (ISI) | 4 week | Absolute change of Matsuda ISI (4 week value - 0 week value). The Matsuda Index is a ratio of glucose and insulin levels during oral glucose tolerance test. It is calculated using fasting and mean glucose and insulin measurements, but the units of these measurements cancel out in the formula. A Matsuda value less than 2.5 may indicate insulin resistance, thus a lowering of the Matsuda index is a detrimental outcome. At baseline the Matsuda index in the participants for which it was assessed ranged from 1.4 to 7.8 (mean = 3.7, standard deviation = 1.6). |
| Hepatic Triglyceride | 4 weeks | Absolute change of % hepatic triglyceride (4 week value - 0 week value) |
| Postprandial Apolipoprotein CIII (apoCIII) | 4 weeks | Absolute change of plasma postprandial apoCIII concentration (4 week value - 0 week value) |
| Postprandial Triglyceride | 4 weeks | Absolute change of 4-h post-dinner AUC plasma triglyceride concentration (4 week value - 0 week value) |
| Fasting Low Density Lipoprotein Cholesterol (LDL-C) | 4 weeks | Absolute change of plasma LDL-C concentration (4 week value - 0 week value) |
| Postprandial Low Density Lipoprotein Cholesterol (LDL-C) | 4 weeks | Absolute change of plasma postprandial LDL-C concentration (4 week value - 0 week value) |
| Fasting Apolipoprotein B (apoB) | 4 weeks | Absolute change of plasma apoB concentration (4 week value - 0 week value) |
| Postprandial Apolipoprotein B (apoB) | 4 weeks | Absolute change of plasma postprandial apoB concentration (4 week value - 0 week value) |
| Fasting Uric Acid | 4 weeks | Absolute change of plasma uric acid concentration (4 week value - 0 week value) |
| Postprandial Uric Acid | 4 weeks | Absolute change of post-dinner 4-hour AUC plasma uric acid concentration (4 week value - 0 week value) |
| Fasting Apolipoprotein CIII (apoCIII) | 4 weeks | Absolute change of fasting plasma apoCIII concentration (4 week value - 0 week value) |
| M Value During Hyperinsulinemic Euglycemic Clamp | 4 weeks | Absolute change of M value (glucose infusion rate during final 30 minute steady state)/ fat free body mass (kg) (4 week value - 0 week value) |
| Postprandial de Novo Lipogenesis | 4 weeks | Absolute change of 8-hour area under the curve (AUC) percentage fractional rate postprandial de novo lipogenesis DNL (4 week value - 0 week value) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oral Glucose Tolerance Test (OGTT) Insulin 3-hour Area Under the Curve | 4 week | Absolute change in OGTT 3-hour AUC insulin concentration (4-week value - 0-week value) |
| Fasting Triglyceride | 4 weeks | Absolute change of plasma fasting triglyceride concentration (4 week value - 0 week value) |
| 3-(3'-Hydroxy-4'-Methoxyphenyl)Hydracrylic | 4 weeks | Absolute change of total 24-hour urinary 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic (4 week value - 0 week value) |
| Hesperetin-3'-O-glucuronide | 4 weeks | Absolute change of total 24-hour urinary hesperetin-3'-O-glucuronide (4 week value - 0 week value)Urine concentration hesperetin-3'-O-glucuronide |
| Hesperetin-3',7-0-diglucuronide | 4 weeks | Absolute change of total 24-hour urinary hesperetin-3',7-0-diglucuronide (4 week value - 0 week value) |
| p-Hydroxyhippuric Acid | 4 weeks | Absolute change of total 24-hour urinary p-Hydroxyhippuric acid (4 week value - 0 week value) |
| 3-(4'-Methoxyphenyl)Propionic Acid-3'-O-glucuronide | 4 weeks | Absolute change of total 24-hour urinary 3-(4'-methoxyphenyl)propionic acid-3'-O-glucuronide (4 week value - 0 week value) |
| Hesperetin-7-O-glucuronide | 4 weeks | Absolute change of total 24-hour urinary hesperetin-7-O-glucuronide (4 week value - 0 week value) |
| Naringin-7-O-glucuronide | 4 weeks | Absolute change of total 24-hour urinary naringen-7-O-glucuronide (4 week value - 0 week value) |
| Oral Glucose Tolerance Test (OGTT) Glucose 3-hour Area Under the Curve (AUC) | 4 week | Absolute change in OGTT 3-hour AUC glucose concentration (4-week value - 0-week value) |
| Fasting de Novo Lipogenesis | 4 weeks | Absolute change of fasting percentage fractional rate fasting de novo lipogenesis DNL (4 week value - 0 week value) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fasting Insulin | 4 week | Absolute change serum insulin concentration (4-week value - 0-week value) |
| Body Fat | 4 weeks | %body fat |
| Diastolic Blood Pressure | 4 weeks | Change in diastolic blood pressure (4-week value minus 0-week value) |
| Systolic Blood Pressure | 4 weeks | Change in systolic blood pressure (4-week value - 0-week value) |
| Body Weight | 4 weeks | Change in body weight (4-week value - 0-week value) |
| Fasting Glucose | glucose | Absolute change in fasting plasma glucose concentration (4-week value - 0-week value) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Naturally-sweetened orange juice Naturally-sweetened orange juice Form: Beverage Daily dosage: 25% of daily energy requirement Frequency: Divided into 3 servings/day Duration: 4 weeks
Naturally-sweetened orange juice: Commercially-available ready-to-serve refrigerated orange juice | 25 |
| Sugar-sweetened beverage Sugar-sweetened beverage Form: Beverage Daily dosage: 25% of daily energy requirement Frequency: Divided into 3 servings/day Duration: 4 weeks
Sugar-sweetened beverage: Sugar-sweetened water flavored with Kool-Aid (TM) | 24 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 5 | 0 |
| Overall Study | Withdrawn by PI due to dietary miscompliance | 1 | 0 |
| Overall Study | Withdrawn by PI due to veins not suitable for multiple blood draws | 0 | 1 |
Baseline characteristics
| Characteristic | Naturally-sweetened orange juice | Sugar-sweetened beverage | Total |
|---|---|---|---|
| Age, Continuous | 22.8 years STANDARD_DEVIATION 3.8 | 24.8 years STANDARD_DEVIATION 7.1 | 23.8 years STANDARD_DEVIATION 5.7 |
| Body Mass Index | 23.8 kg/meters^2 STANDARD_DEVIATION 3.6 | 24.0 kg/meters^2 STANDARD_DEVIATION 3.3 | 23.9 kg/meters^2 STANDARD_DEVIATION 3.4 |
| Diastolic Blood Pressure | 71.0 mmHg STANDARD_DEVIATION 7.5 | 69.7 mmHg STANDARD_DEVIATION 8.3 | 70.4 mmHg STANDARD_DEVIATION 7.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 20 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 16 Participants | 15 Participants | 31 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment United States | 25 participants | 24 participants | 49 participants |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
| Systolic blood pressure | 110.8 mmHg STANDARD_DEVIATION 11 | 111.0 mmHg STANDARD_DEVIATION 11.4 | 110.9 mmHg STANDARD_DEVIATION 11.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 24 |
| other Total, other adverse events | 3 / 25 | 0 / 24 |
| serious Total, serious adverse events | 0 / 25 | 0 / 24 |
Outcome results
Primary
Fasting Apolipoprotein B (apoB)
Absolute change of plasma apoB concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting Apolipoprotein B (apoB) | 2.9 mg/dl | Standard Deviation 4.6 |
| Sugar-sweetened beverage | Fasting Apolipoprotein B (apoB) | 3.4 mg/dl | Standard Deviation 7.5 |
p-value: 0.9295% CI: [-3.7, 3.4]ANCOVA
Primary
Fasting Apolipoprotein CIII (apoCIII)
Absolute change of fasting plasma apoCIII concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting Apolipoprotein CIII (apoCIII) | 0.40 mg/dl | Standard Deviation 1.03 |
| Sugar-sweetened beverage | Fasting Apolipoprotein CIII (apoCIII) | 0.60 mg/dl | Standard Deviation 0.92 |
p-value: 0.4295% CI: [-0.74, 0.31]ANCOVA
Primary
Fasting Low Density Lipoprotein Cholesterol (LDL-C)
Absolute change of plasma LDL-C concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting Low Density Lipoprotein Cholesterol (LDL-C) | 5.5 mg/dl | Standard Deviation 5.3 |
| Sugar-sweetened beverage | Fasting Low Density Lipoprotein Cholesterol (LDL-C) | 5.8 mg/dl | Standard Deviation 7.5 |
p-value: 0.8895% CI: [-4, 3.5]ANCOVA
Primary
Fasting Uric Acid
Absolute change of plasma uric acid concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting Uric Acid | -0.92 mg/dl | Standard Deviation 0.85 |
| Sugar-sweetened beverage | Fasting Uric Acid | 0.11 mg/dl | Standard Deviation 0.6 |
p-value: <0.000195% CI: [-1.34, -0.49]ANCOVA
Primary
Hepatic Triglyceride
Absolute change of % hepatic triglyceride (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. One participant in the Orange Juice Group was not able to attend the intervention MRI appointment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Hepatic Triglyceride | 0.05 % fat in liver | Standard Deviation 0.86 |
| Sugar-sweetened beverage | Hepatic Triglyceride | 0.26 % fat in liver | Standard Deviation 0.53 |
p-value: 0.3595% CI: [-0.21, 0.08]ANCOVA
Primary
Matsuda Insulin Sensitivity Index (ISI)
Absolute change of Matsuda ISI (4 week value - 0 week value). The Matsuda Index is a ratio of glucose and insulin levels during oral glucose tolerance test. It is calculated using fasting and mean glucose and insulin measurements, but the units of these measurements cancel out in the formula. A Matsuda value less than 2.5 may indicate insulin resistance, thus a lowering of the Matsuda index is a detrimental outcome. At baseline the Matsuda index in the participants for which it was assessed ranged from 1.4 to 7.8 (mean = 3.7, standard deviation = 1.6).
Time frame: 4 week
Population: This analysis includes participants enrolled after a coronavirus disease 2019 (COVID)-related protocol modification, who completed a 3-hour OGTT. These participants (n=39) did not undergo hyperinsulinemic euglycemic clamps. Final data collection and analysis for this population are complete. One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Matsuda Insulin Sensitivity Index (ISI) | -0.35 units on a scale | Standard Deviation 1 |
| Sugar-sweetened beverage | Matsuda Insulin Sensitivity Index (ISI) | -0.40 units on a scale | Standard Deviation 0.98 |
p-value: 0.9795% CI: [-0.61, 0.59]ANCOVA
Primary
M Value During Hyperinsulinemic Euglycemic Clamp
Absolute change of M value (glucose infusion rate during final 30 minute steady state)/ fat free body mass (kg) (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Unable to collect post-dinner blood samples from one participant in the sucrose group during the 4-week intervention trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | M Value During Hyperinsulinemic Euglycemic Clamp | -0.2 %fractional rate | Standard Deviation 1.9 |
| Sugar-sweetened beverage | M Value During Hyperinsulinemic Euglycemic Clamp | 0.2 %fractional rate | Standard Deviation 0.9 |
p-value: 0.5595% CI: [-2.1, 1.2]ANCOVA
Primary
Postprandial Apolipoprotein B (apoB)
Absolute change of plasma postprandial apoB concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Unable to collect post-dinner blood samples from one participant in the sucrose group during the 4-week intervention trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Postprandial Apolipoprotein B (apoB) | 3.7 mg/dl | Standard Deviation 4.5 |
| Sugar-sweetened beverage | Postprandial Apolipoprotein B (apoB) | 4.3 mg/dl | Standard Deviation 5.9 |
p-value: 0.8195% CI: [-3.3, 2.6]ANCOVA
Primary
Postprandial Apolipoprotein CIII (apoCIII)
Absolute change of plasma postprandial apoCIII concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Unable to collect post-dinner blood samples from one participant in the sucrose group during the 4-week intervention trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Postprandial Apolipoprotein CIII (apoCIII) | 0.64 mg/dl | Standard Deviation 0.93 |
| Sugar-sweetened beverage | Postprandial Apolipoprotein CIII (apoCIII) | 0.38 mg/dl | Standard Deviation 0.85 |
p-value: 0.2895% CI: [-0.23, 0.76]ANCOVA
Primary
Postprandial de Novo Lipogenesis
Absolute change of 8-hour area under the curve (AUC) percentage fractional rate postprandial de novo lipogenesis DNL (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Unable to collect post-dinner blood samples from one participant in the sucrose group during the 4-week intervention trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Postprandial de Novo Lipogenesis | 8.3 %fractional rate x 8 h | Standard Deviation 12.3 |
| Sugar-sweetened beverage | Postprandial de Novo Lipogenesis | 22.3 %fractional rate x 8 h | Standard Deviation 16.2 |
Comparison: Effect of group on change of outcome with adjustment for BMI, outcome at baseline and gender.p-value: 0.00295% CI: [-22.4, -5.4]ANCOVA
Primary
Postprandial Low Density Lipoprotein Cholesterol (LDL-C)
Absolute change of plasma postprandial LDL-C concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Unable to collect week 4 postprandial samples from one participant in the Sucrose Group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Postprandial Low Density Lipoprotein Cholesterol (LDL-C) | 5.9 mg/dl | Standard Deviation 4.8 |
| Sugar-sweetened beverage | Postprandial Low Density Lipoprotein Cholesterol (LDL-C) | 6.7 mg/dl | Standard Deviation 5.6 |
p-value: 0.6595% CI: [-3.7, 2.3]ANCOVA
Primary
Postprandial Triglyceride
Absolute change of 4-h post-dinner AUC plasma triglyceride concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Unable to collect post-dinner blood samples from one participant in the sucrose group during the 4-week intervention trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Postprandial Triglyceride | 41.8 mg/dl x 4 h | Standard Deviation 61.3 |
| Sugar-sweetened beverage | Postprandial Triglyceride | 53.5 mg/dl x 4 h | Standard Deviation 56.9 |
p-value: 0.5995% CI: [-42.9, 24.7]ANCOVA
Primary
Postprandial Uric Acid
Absolute change of post-dinner 4-hour AUC plasma uric acid concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Unable to collect post-dinner blood samples from one participant in the sucrose group during the 4-week intervention trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Postprandial Uric Acid | -3.3 mg/dl x 4 h | Standard Deviation 2.6 |
| Sugar-sweetened beverage | Postprandial Uric Acid | 0.40 mg/dl x 4 h | Standard Deviation 1.9 |
p-value: <0.000195% CI: [-4.7, -2.1]ANCOVA
Secondary
3-(3'-Hydroxy-4'-Methoxyphenyl)Hydracrylic
Absolute change of total 24-hour urinary 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | 3-(3'-Hydroxy-4'-Methoxyphenyl)Hydracrylic | 23322 ng | Standard Deviation 32654 |
| Sugar-sweetened beverage | 3-(3'-Hydroxy-4'-Methoxyphenyl)Hydracrylic | -336 ng | Standard Deviation 12414 |
p-value: 0.003295% CI: [8284, 38396]ANCOVA
Secondary
3-(4'-Methoxyphenyl)Propionic Acid-3'-O-glucuronide
Absolute change of total 24-hour urinary 3-(4'-methoxyphenyl)propionic acid-3'-O-glucuronide (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | 3-(4'-Methoxyphenyl)Propionic Acid-3'-O-glucuronide | 23124 ng | Standard Deviation 25954 |
| Sugar-sweetened beverage | 3-(4'-Methoxyphenyl)Propionic Acid-3'-O-glucuronide | -198 ng | Standard Deviation 876 |
p-value: 0.000195% CI: [11307, 32455]ANCOVA
Secondary
Fasting de Novo Lipogenesis
Absolute change of fasting percentage fractional rate fasting de novo lipogenesis DNL (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting de Novo Lipogenesis | 0.9 %fractional rate | Standard Deviation 1.8 |
| Sugar-sweetened beverage | Fasting de Novo Lipogenesis | 0.6 %fractional rate | Standard Deviation 1.7 |
Comparison: Effect of group on change in outcome with adjustment for BMI, Outcome at baseline and gender.p-value: 0.5695% CI: [-0.7, 1.3]ANCOVA
Secondary
Fasting Triglyceride
Absolute change of plasma fasting triglyceride concentration (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting Triglyceride | -3.5 mg/dl | Standard Deviation 21.2 |
| Sugar-sweetened beverage | Fasting Triglyceride | 6.4 mg/dl | Standard Deviation 14 |
p-value: 0.1195% CI: [-17.6, 1.8]ANCOVA
Secondary
Hesperetin-3',7-0-diglucuronide
Absolute change of total 24-hour urinary hesperetin-3',7-0-diglucuronide (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Invalid results obtained for this outcome in one participant in the sucrose group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Hesperetin-3',7-0-diglucuronide | 3797 ng | Standard Deviation 4955 |
| Sugar-sweetened beverage | Hesperetin-3',7-0-diglucuronide | -3 ng | Standard Deviation 10 |
p-value: 0.001295% CI: [1611, 6036]ANCOVA
Secondary
Hesperetin-3'-O-glucuronide
Absolute change of total 24-hour urinary hesperetin-3'-O-glucuronide (4 week value - 0 week value)Urine concentration hesperetin-3'-O-glucuronide
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Hesperetin-3'-O-glucuronide | 5550 ng | Standard Deviation 6502 |
| Sugar-sweetened beverage | Hesperetin-3'-O-glucuronide | 4 ng | Standard Deviation 95 |
p-value: 0.000395% CI: [2680, 8437]ANCOVA
Secondary
Hesperetin-7-O-glucuronide
Absolute change of total 24-hour urinary hesperetin-7-O-glucuronide (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Hesperetin-7-O-glucuronide | 9556 ng | Standard Deviation 11081 |
| Sugar-sweetened beverage | Hesperetin-7-O-glucuronide | -2 ng | Standard Deviation 18 |
p-value: 0.000295% CI: [4808, 14524]ANCOVA
Secondary
Naringin-7-O-glucuronide
Absolute change of total 24-hour urinary naringen-7-O-glucuronide (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. Invalid results obtained for this outcome in one participant in the sucrose group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Naringin-7-O-glucuronide | 3286 ng | Standard Deviation 4453 |
| Sugar-sweetened beverage | Naringin-7-O-glucuronide | -284 ng | Standard Deviation 851 |
p-value: 0.001195% CI: [1456, 5370]ANCOVA
Secondary
Oral Glucose Tolerance Test (OGTT) Glucose 3-hour Area Under the Curve (AUC)
Absolute change in OGTT 3-hour AUC glucose concentration (4-week value - 0-week value)
Time frame: 4 week
Population: This analysis includes participants enrolled after a COVID-related protocol modification, who completed a 3-hour OGTT. These participants (n=39) did not undergo hyperinsulinemic euglycemic clamps. Final data collection and analysis for this population are complete. One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Oral Glucose Tolerance Test (OGTT) Glucose 3-hour Area Under the Curve (AUC) | 46.8 mg/dl x 3 hours | Standard Deviation 56.2 |
| Sugar-sweetened beverage | Oral Glucose Tolerance Test (OGTT) Glucose 3-hour Area Under the Curve (AUC) | 25.6 mg/dl x 3 hours | Standard Deviation 80.1 |
p-value: 0.5995% CI: [-32, 55.1]ANCOVA
Secondary
Oral Glucose Tolerance Test (OGTT) Insulin 3-hour Area Under the Curve
Absolute change in OGTT 3-hour AUC insulin concentration (4-week value - 0-week value)
Time frame: 4 week
Population: This analysis includes participants enrolled after a COVID-related protocol modification, who completed a 3-hour OGTT. These participants (n=39) did not undergo hyperinsulinemic euglycemic clamps. Final data collection and analysis for this population are complete. One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Oral Glucose Tolerance Test (OGTT) Insulin 3-hour Area Under the Curve | 74.7 microUnit/ml x 3 hours | Standard Deviation 114.9 |
| Sugar-sweetened beverage | Oral Glucose Tolerance Test (OGTT) Insulin 3-hour Area Under the Curve | 0.1 microUnit/ml x 3 hours | Standard Deviation 105.4 |
p-value: 0.04695% CI: [1.3, 147.9]ANCOVA
Secondary
p-Hydroxyhippuric Acid
Absolute change of total 24-hour urinary p-Hydroxyhippuric acid (4 week value - 0 week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | p-Hydroxyhippuric Acid | 20347 ng | Standard Deviation 26775 |
| Sugar-sweetened beverage | p-Hydroxyhippuric Acid | -770 ng | Standard Deviation 9212 |
p-value: 0.002395% CI: [7353, 31691]ANCOVA
Other Pre-specified
Body Fat
%body fat
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria. DEXA analyzer not available to scan 2 participants in orange juice group and 1 participant in sucrose group during baseline trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Body Fat | -0.9 percentage of body fat | Standard Deviation 0.7 |
| Sugar-sweetened beverage | Body Fat | -0.5 percentage of body fat | Standard Deviation 1 |
p-value: 0.195% CI: [-1, 0.1]ANCOVA
Other Pre-specified
Body Weight
Change in body weight (4-week value - 0-week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Body Weight | -0.5 kg | Standard Deviation 1.2 |
| Sugar-sweetened beverage | Body Weight | -0.5 kg | Standard Deviation 0.7 |
p-value: 0.8895% CI: [-0.5, 0.6]ANCOVA
Other Pre-specified
Diastolic Blood Pressure
Change in diastolic blood pressure (4-week value minus 0-week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Diastolic Blood Pressure | -2.3 mmHg | Standard Deviation 7.2 |
| Sugar-sweetened beverage | Diastolic Blood Pressure | -1.0 mmHg | Standard Deviation 7.7 |
p-value: 0.6995% CI: [-4.4, 2.9]ANCOVA
Other Pre-specified
Fasting Glucose
Absolute change in fasting plasma glucose concentration (4-week value - 0-week value)
Time frame: glucose
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting Glucose | 1.5 mg/dl | Standard Deviation 3.8 |
| Sugar-sweetened beverage | Fasting Glucose | 0.3 mg/dl | Standard Deviation 4.7 |
p-value: 0.6595% CI: [-1.9, 3]ANCOVA
Other Pre-specified
Fasting Insulin
Absolute change serum insulin concentration (4-week value - 0-week value)
Time frame: 4 week
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Fasting Insulin | -0.31 microUnit/ml | Standard Deviation 1.8 |
| Sugar-sweetened beverage | Fasting Insulin | 0.38 microUnit/ml | Standard Deviation 2.32 |
p-value: 0.1795% CI: [-1.94, 0.35]ANCOVA
Other Pre-specified
Systolic Blood Pressure
Change in systolic blood pressure (4-week value - 0-week value)
Time frame: 4 weeks
Population: One participant was excluded due to extreme values that deviated from the mean by more than 2 standard deviations across multiple outcomes. The exclusion was based on protocol-defined criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naturally-sweetened orange juice | Systolic Blood Pressure | -2.9 mmHg | Standard Deviation 10.5 |
| Sugar-sweetened beverage | Systolic Blood Pressure | -4.2 mmHg | Standard Deviation 10.6 |
p-value: 0.8195% CI: [-4.4, 5.7]ANCOVA