Fructose Supplementation in Carriers for Hereditary Fructose Intolerance

Study Overview
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Brief Summary
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This study aimed to examine metabolic response to a short-term fructose enriched diet in carriers for hereditary fructose intolerance compared to controls. Effects of fructose coffees will be assessed in 7 healthy volunteers and 7 subjects with heterozygous mutation for ALDOB gene in a randomized, controlled, crossover trial.

Detailed Description
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A high fructose intake also increases blood lactate and uric acid concentrations. It has been proposed that uric acid may contribute to insulin resistance by impairing endothelium-dependent vasodilation, promoting pro-inflammatory effects and dyslipidemia by activating de novo lipogenesis. These consequences of fructose overconsumption may be even more marked in individuals with hereditary alterations in fructose metabolism. Indeed, individuals with hereditary fructose intolerance (HFI), due to biallelic mutations in the gene coding for aldolase B (ALDOB), may develop acute, life-threatening manifestations when exposed to fructose. Heterozygous carriers of ALDOB mutation are quite common in the general population, with a predicted frequency ranging between 1:55 and 1:120. Few studies have examined the effect of fructose ingestion in heterozygotes subject for HFI. Heterozygous carriers are generally considered to have normal fructose metabolism since a   50% level of aldolase B activity is presumed to be sufficient for adequate function. However, heterozygous carriers were reported to have enhanced uric acid responses to large intravenous and/or oral fructose loads. Investigators hypothesized that heterozygous carriers may also have mild defects of fructose metabolism and/or a larger increase in cardiometabolic risk factors than the normal population after ingestion of moderate amounts of fructose.

Official Title
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Metabolic Effects of Short-term Dietary Supplementation With Fructose in Carriers for Hereditary Fructose Intolerance

Conditions
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Hereditary Fructose Intolerance

Intervention / Treatment
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* Other: Experimental diet Fru rich diet
* Other: Experimental low Fru diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Case subjects: Heterozygous carriers for ALDOB mutation confirmed by molecular analysis Control subjects: healthy individuals matched for weight and age to subjects Exclusion Criteria: Fasting glucose > 7.0 mmol/L Fasting triglycerides > 4.0 mmol/L Chronic renal insufficiency (eGFR < 50 ml/min) Drugs Women who are pregnant or breast feeding For women: lack of safe contraception Alcool consumption > 30g/d Inability to discern

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Experimental diet Fru rich diet<br>Enriched fructose diet from day 1 to day 7. | Other: Experimental diet Fru rich diet<br>* 7 days (day 1 to day 7) with fructose enriched drinks 3x/d. Test meal at day 7 with fructose (0.7 g/body weight) and glucose (0.7 g/body weight)<br>|
| Other: Experimental low Fru diet<br>Low fructose diet from day 1 to day 7. | Other: Experimental low Fru diet<br>* 7 days (day 1 to day 7) with low-fructose diet (<10g/d). Test meal at day 7 with fructose (0.7 g/body weight) and glucose (0.7 g/body weight)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolite concentration | The primary endpoint is the change of metabolite concentration after ingestion of a test meal (oral glucose and fructose load) under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma glucose concentration | Change in glucose concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma insulin concentration | Change in insulin concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma fructose concentration | Change in fructose concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma uric acid concentration | Change in uric acid concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma lactate concentration | Change in lactate concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma urea concentration | Change in urea concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma creatinine concentration | Change in creatinine concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma phosphate concentration | Change in phosphate concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma triglycerides concentration | Change in triglycerides concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma metabolome concentration | Change in metabolome concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma ammonia concentration | Change in ammonia concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma amino acid concentration | Change in amino acid concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma alanine transaminase (ALAT) concentration | Change in alanine transminase (ALAT) concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Plasma aspartate transaminase (ASAT) concentration | Change in aspartate transaminase (ASAT) concentration after ingestion of a test meal under 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | Time Frame: -30 min before ingestion of a test meal to 120 min after ingestion of a test meal | 
| Urine metabolome concentration | Change in urine metabolome profile after low fructose diet and an enriched fructose diet according to a crossover design | Time Frame: 24 hour urine collection before ingestion of a test meal and after 7 days of 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | 
| Urine creatinine concentration | Change in urine creatinine profile after low fructose diet and an enriched fructose diet according to a crossover design | Time Frame: 24 hour urine collection before ingestion of a test meal and after 7 days of 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | 
| Urine urea concentration | Change in urine urea profile after low fructose diet and an enriched fructose diet according to a crossover design | Time Frame: 24 hour urine collection before ingestion of a test meal and after 7 days of 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | 
| Urine uric acid concentration | Change in urine uric acid profile after low fructose diet and an enriched fructose diet according to a crossover design | Time Frame: 24 hour urine collection before ingestion of a test meal and after 7 days of 2 conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | 
| Body weight | Change of body weight after low fructose diet and an enriched fructose diet according to a crossover design | Time Frame: at baseline before study intervention and at the end of each conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | 
| Blood pressure | Change of systolic and diastolic pressure after low fructose diet and an enriched fructose diet according to a crossover design | Time Frame: at baseline before study intervention and at the end of each conditions (enriched fructose diet vs poor fructose diet) according to a crossover design | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fructose, Uric acid, Glucose homeostasis