Fructose: Substrate, Stimulus, or Both?

Study Overview
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Brief Summary
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This objective of this study is to use sensitive methodology under controlled conditions to investigate the mechanisms by which fructose consumption contributes to excess fatty acid synthesis and elevations in blood glucose levels following consumption of meals containing fructose.

Official Title
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Fructose: Substrate, Stimulus, or Both?

Conditions
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Insulin Resistance, Insulin Sensitivity, Pre Diabetes

Intervention / Treatment
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* Other: High fructose, fructose labeled meal
* Other: High fructose, pyruvate labeled meal
* Other: Low fructose, fructose labeled meal
* Other: Low fructose, pyruvate labeled meal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index 22 to 35 kg/m2 Prediabetic (HbA1c 5.7% to 6.5%) or hyperinsulinemic (fasting insulin ≥12 µIU/mL) but non-diabetic (fasting glucose <126mg/dL and HbA1c < 6.5%) ; or normal control (fasting insulin <10 µIU/mL, fasting glucose <100 mg/dL, and HbA1c < 5.7%) Exclusion Criteria: Pregnancy or lactation within the past six months Type 1 or 2 diabetes mellitus History of liver disease or aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2x the upper limit of normal (ULN); Fasting triglyceride or total cholesterol levels above 95th percentile for age and sex; Hemoglobin or hematocrit below the lower limit of normal for sex; Report of hepatitis or HIV infection; History of cancer, use of any anti-diabetic medications or hypolipidemic agents in the past six months; History of surgical procedure for obesity; Self-reported change in body weight >5% in the past six months; History of other conditions known to affect insulin sensitivity and lipid metabolism; Known intolerance to acetaminophen or components of the liquid test meals.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 55 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High fructose meal, with fructose label<br>2-13C fructose incorporated into a meal with high fructose content | Other: High fructose, fructose labeled meal<br>* Liquid meal containing high fructose (16% of energy), labeled with 2-13C fructose<br>|
| Experimental: High fructose meal, with pyruvate label<br>2-13C pyruvate incorporated into a meal with high fructose content | Other: High fructose, pyruvate labeled meal<br>* Liquid meal containing high fructose (16% of energy), labeled with 2-13C pyruvate<br>|
| Experimental: Low fructose meal, with fructose label<br>2-13C fructose incorporated into a meal with low fructose content | Other: Low fructose, fructose labeled meal<br>* Liquid meals containing low fructose (6% of energy), labeled with 2-13C fructose<br>|
| Experimental: Low fructose meal, with pyruvate label<br>2-13C pyruvate incorporated into a meal with low fructose content | Other: Low fructose, pyruvate labeled meal<br>* Liquid meal containing low fructose (6% of energy), labeled with 2-13C pyruvate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic fractional de novo lipogenesis in triglyceride rich lipoprotein (TRL) | Measured by the detection of 13C carbons in TRL-palmitate from administered 13C labeled pyruvate or 13C labeled fructose. | 6 hours | 
| Rate of appearance of UDP-glucose | An estimate of hepatic glycogen flux measured by administration of D1 galactose and acetaminophen | 6 hours | 
| Rate of appearance of blood glucose from gluconeogenesis | Measured by the dilution method of labeled glucose | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum triglyceride concentration | Fasting and postprandial serum triglyceride levels | 6 hours | 
| Serum glucose concentration | Fasting and postprandial serum triglyceride levels | 6 hours | 
| Serum lactate concentration | Fasting and postprandial serum lactate levels | 6 hours | 
| Serum insulin concentration | Fasting and postprandial insulin levels | 6 hours | 
| Serum free fatty acid concentration | Fasting and postprandial fatty acid levels | 6 hours | 
| Enteral (chylomicron) fractional de novo lipogenesis (DNL) | Measured by the detection of 13C carbons in chylomicron-palmitate from administered 13C labeled pyruvate or 13C labeled fructose. | 6 hours | 
| Hepatic (VLDL) fractional de novo lipogenesis (DNL) | Measured by the detection of 13C carbons in VLDL-palmitate from administered 13C labeled pyruvate or 13C labeled fructose. | 6 hours | 
| Extrasplanchnic fructose | Calculated using total plasma fructose, plasma 2-13C fructose enrichment, and endogenous fructose production | 6 hours | 
| Whole body fructose oxidation | Measured by 13C atom % excess in exhaled breath, and VCO2 by indirect calorimetry | 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fructose, Glucose, Lipogenesis