Clinical trial NCT02459834: The Fructose and Allulose Catalytic Effects (FACE) Trial
Official title: An Acute Randomized Dose-finding Equivalence Trial of Small, Catalytic Doses of Fructose and Allulose on Postprandial Carbohydrate Metabolism: The Fructose and Allulose Catalytic Effects (FACE) Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes
Keywords: Allulose
Fructose
Dose Response
Catalytic Dose
Carbohydrate metabolism
Randomized clinical trials
Lead sponsor: University of Toronto
Sponsor class: OTHER
Collaborators: name: Tate & Lyle
First posted: 2015-06-02
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: Diabetes remains one of the most important unmet prevention and treatment challenges, and the prevalence of diabetes continues to grow. Some functional food ingredients may hold promise as potential therapies for diabetes. One such functional food is allulose, which is a c-3 epimer of fructose. Allulose is a non-caloric sugar found naturally in small amounts in foods such as dried fruits, brown sugar and maple syrup. Previous research has found that catalytic doses of fructose and allulose have been shown to decrease the postprandial glycemic responses to high glycemic index meals. Fructose, in exchange for other carbohydrates, has also been found to decrease HbA1c levels. Whether the effects of fructose and allulose are equivalent is of particular interest, as allulose represents a non-caloric alternative to fructose. The minimum 'catalytic' dose at which improvements in carbohydrate metabolism are observed also remains to be determined for each of the sugars in people with and without diabetes. This study is an acute randomized controlled dose-finding equivalence trial to assess the effect of fructose and allulose at 2 dose levels (5g and 10g) compared with control (0g) on the glucose and insulin responses to a 75g oral glucose tolerance test (OGTT) in healthy and type 2 diabetes participants.

Detailed description: Diabetes remains one of the most important unmet prevention and treatment challenges. Despite the growing armamentarium of medications, which include six new classes of drugs since metformin was first approved in 1995 in the US, the combined prevalence of impaired glucose tolerance (IGT) and diabetes continues to grow. Although oral antihyperglycaemic agents have been shown to prevent the development of diabetes in high-risk individuals and to reduce the risk of microvascular complications in individuals with type 2 diabetes, they have failed to deliver the anticipated macrovascular benefits.

Some functional food ingredients may hold promise as potential therapies for diabetes. An emerging literature has shown that low-dose fructose and its c-3 epimer, allulose (a non-caloric sugar found naturally in small amounts in foods such as dried fruits, brown sugar, and maple syrup which is generally recognized as safe \[GRAS\] by the FDA under GRN 400 since 2012 and GRN 498 since 2014) may benefit glycemic control.

Clinical translation of these findings has proven promising. Catalytic doses of fructose at 7.5g and 10g and allulose at 5g, 7.5g, and 10g (but not 2.5g) have been shown to decrease the postprandial glycemic responses to high glycemic index meals (oral glucose, maltodextrins, or mashed potatoes) from \~15-30% in healthy participants and those with prediabetes or diabetes. These acute effects have been shown to be sustainable over the longer term in the case of fructose. In separate systematic reviews and meta-analyses of controlled feeding trials, the investigators showed that both small doses (defined as ≤36g/day based on 3 meals at ≤10g/meal and 2 snacks at ≤3g/snack) and higher doses (median, 60g/day) of fructose in exchange for other carbohydrates decreased HbA1c by 0.4% and 0.53%, respectively, a level of reduction which exceed the clinically meaningful threshold of 0.3% proposed by the Federal Drug Administration (FDA) for the development of new oral anti-hyperglycemic agents.

Although these findings provide a compelling proof of concept, there is an urgent need for replication studies. Whether the effects of fructose and allulose are equivalent is of particular interest, as allulose represents a non-caloric alternative to fructose. The minimum 'catalytic' dose at which improvements in carbohydrate metabolism are observed also remains to be determined for each of the sugars in people with and without diabetes.

OBJECTIVES

* To assess the acute catalytic effects of fructose and allulose at 2 dose levels (5g, 10g) compared with control (0g) on glucose and insulin responses to a 75g oral glucose tolerance test (75g-OGTT) in healthy participants and participants with type 2 diabetes.
* To assess whether there is a dose response or threshold over the proposed dose range (0g, 5g, 10g) for the effects of fructose and allulose on glucose and insulin responses to a 75g-OGTT in healthy participants and participants with type 2 diabetes.
* To assess whether the effects of allulose and fructose are equivalent on the primary endpoint of incremental area under the curve (iAUC) for plasma glucose across the 2 dose levels (5g and 10g) compared with control (0g) in healthy participants and participants with type 2 diabetes.

Eligibility criteria: Inclusion Criteria:

* Healthy participants:

  * Adult males and non-pregnant females
  * Normal weight
  * Non-smokers
  * Free of any disease or illness
  * Do not regular take any medications
  * Have a primary care physician
* Diabetes participants:

  * Well-controlled diabetes on diet and/or oral antihyperglycemic agents
  * Not taking insulin
  * Free of any major illness
  * Have a primary care physician

Exclusion Criteria:

* Healthy participants:

  * Age \<18 or \>75y, Pregnant female
  * Regular medication use
  * Complementary or alternative medicine (CAM) use
  * BMI\<18.5kg/m2, \>30kg/m2
  * Prediabetes or diabetes (HbA1c≥6%, FBG≥6.1mmol/L)
  * Hypertension (BP≥140/90), Dyslipidemia (Canadian Cardiovascular Society guidelines)
  * Metabolic syndrome (harmonized definition)
  * Polycystic ovarian syndrome
  * Cardiovascular disease
  * Gastrointestinal disease
  * Previous bariatric surgery
  * Liver disease (abnormal liver enzymes)
  * Hyperthyroidism (abnormal TSH)
  * Hypothyroidism (abnormal TSH)
  * Nephropathy (albumin-to-creatinine ratio \[ACR\] \>20)
  * Chronic kidney disease (eGFR \>60ml/min/1.73m2)
  * Inflammatory conditions (CRP\>3g/L)
  * Acute or chronic infection (abnormal white blood cell count (WBC), CRP\>3g/L)
  * Anemia (abnormal Hb)
  * Lung disease
  * Cancer/malignancy
  * Psychiatric illness
  * Major surgery in the last 6 months
  * Other major illness
  * Smoker
  * Heavy alcohol use (\>3 drinks/day)
* Diabetes participants:

  * Age \<18 or \>75y
  * Pregnant female
  * Poorly controlled diabetes (HbA1c\>7.5%)
  * Recent diabetes medication change (\< 3 months)
  * Insulin use
  * Complementary or alternative medicine (CAM) use
  * BMI\<18.5kg/m2, ≥35kg/m2
  * Cardiovascular disease
  * Retinopathy
  * Neuropathy
  * Diabetic foot
  * Gastrointestinal disease
  * Previous bariatric surgery
  * Liver disease (abnormal liver enzymes)
  * Hyperthyroidism (abnormal TSH)
  * Hypothyroidism (abnormal TSH)
  * Anemia (abnormal Hb)
  * Nephropathy (albumin-to-creatinine ratio \[ACR\] \>20)
  * Chronic kidney disease (eGFR \>60ml/min/1.73m2)
  * Inflammatory conditions (CRP\>3g/L)
  * Acute or chronic infection (abnormal WBC, CRP\>3g/L)
  * Lung disease
  * Cancer/malignancy
  * Psychiatric illness
  * Major surgery in the last 6 months
  * Other major illness
  * Smoker
  * Heavy alcohol use (\>3 drinks/day)

Primary outcomes:
measure: Plasma glucose iAUC
timeFrame: up to 12 weeks
Secondary outcomes:
measure: Plasma glucose total AUC
timeFrame: up to 12 weeks
measure: Plasma insulin iAUC
timeFrame: up to 12 weeks
measure: Plasma insulin total AUC
timeFrame: up to 12 weeks
measure: Maximum concentrations (Cmax) for plasma glucose and insulin
timeFrame: up to 12 weeks
measure: Time of maximum concentrations (Tmax) for plasma glucose and insulin
timeFrame: up to 12 weeks
measure: Matsuda whole body insulin sensitivity index (Matsuda ISI OGTT);
timeFrame: up to 12 weeks
measure: Early insulin secretion index (∆PI30-0/∆PG30-0);
timeFrame: up to 12 weeks
measure: Insulin secretion-sensitivity index-2 (ISSI-2)
timeFrame: up to 12 weeks
measure: Mean incremental plasma glucose and insulin responses
timeFrame: up to 12 weeks
measure: Mean plasma glucose and insulin responses
timeFrame: up to 12 weeks
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: The Toronto 3D (Diet, Digestive tract and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital
state: Ontario
Study officials:
affiliation: University of Toronto
name: John L Sievenpiper, MD PhD FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
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