The Fructose and Allulose Catalytic Effects (FACE) Trial

Type 2 Diabetes Clinical 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02459834
• Other study ID #: UT-FACE 2015
• Status: Completed
• Phase: N/A
• First received: May 21, 2015
• Last updated: August 4, 2017
• Start date: November 2015
• Est. completion date: August 2016

Study information

• Verified date: August 2017
• Source: University of Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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)

Related Conditions & MeSH terms

• Type 2 Diabetes

Intervention

Other:
• Allulose
A double-blind, randomized, multiple-crossover "equivalence" design. Each participant will act as their own control receiving the treatments in random order, each separated by a 1 week washout period. The treatment will be developed by Tate & Lyle.
• Fructose
A double-blind, randomized, multiple-crossover "equivalence" design. Each participant will act as their own control receiving the treatments in random order, each separated by a 1 week washout period. The treatment will be developed by Tate & Lyle.
• Control
A double-blind, randomized, multiple-crossover "equivalence" design. Each participant will act as their own control receiving the treatments in random order, each separated by a 1 week washout period. The treatment will be developed by Tate & Lyle.

Locations

Country	Name	City	State
Canada	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	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
University of Toronto	Tate & Lyle

Country where clinical trial is conducted

Canada, 

References & Publications (14)

Agius L, Peak M. Intracellular binding of glucokinase in hepatocytes and translocation by glucose, fructose and insulin. Biochem J. 1993 Dec 15;296 ( Pt 3):785-96. — View Citation

Cozma AI, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Wang DD, Mirrahimi A, Yu ME, Carleton AJ, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Beyene J, Kendall CW, Jenkins DJ. Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials. Diabetes Care. 2012 Jul;35(7):1611-20. doi: 10.2337/dc12-0073. Review. — View Citation

Hawkins M, Gabriely I, Wozniak R, Vilcu C, Shamoon H, Rossetti L. Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes. Diabetes. 2002 Mar;51(3):606-14. — View Citation

Hayashi N, Iida T, Yamada T, Okuma K, Takehara I, Yamamoto T, Yamada K, Tokuda M. Study on the postprandial blood glucose suppression effect of D-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjects. Biosci Biotechnol Biochem. 2010;74(3):510-9. Epub 2010 Mar 7. — View Citation

Heacock PM, Hertzler SR, Wolf BW. Fructose prefeeding reduces the glycemic response to a high-glycemic index, starchy food in humans. J Nutr. 2002 Sep;132(9):2601-4. — View Citation

Hossain MA, Kitagaki S, Nakano D, Nishiyama A, Funamoto Y, Matsunaga T, Tsukamoto I, Yamaguchi F, Kamitori K, Dong Y, Hirata Y, Murao K, Toyoda Y, Tokuda M. Rare sugar D-psicose improves insulin sensitivity and glucose tolerance in type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Biochem Biophys Res Commun. 2011 Feb 4;405(1):7-12. doi: 10.1016/j.bbrc.2010.12.091. Epub 2010 Dec 25. — View Citation

Iida T, Kishimoto Y, Yoshikawa Y, Hayashi N, Okuma K, Tohi M, Yagi K, Matsuo T, Izumori K. Acute D-psicose administration decreases the glycemic responses to an oral maltodextrin tolerance test in normal adults. J Nutr Sci Vitaminol (Tokyo). 2008 Dec;54(6):511-4. — View Citation

Moore MC, Cherrington AD, Mann SL, Davis SN. Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults. J Clin Endocrinol Metab. 2000 Dec;85(12):4515-9. — View Citation

Moore MC, Davis SN, Mann SL, Cherrington AD. Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes. Diabetes Care. 2001 Nov;24(11):1882-7. — View Citation

Petersen KF, Laurent D, Yu C, Cline GW, Shulman GI. Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans. Diabetes. 2001 Jun;50(6):1263-8. — View Citation

Shiota M, Moore MC, Galassetti P, Monohan M, Neal DW, Shulman GI, Cherrington AD. Inclusion of low amounts of fructose with an intraduodenal glucose load markedly reduces postprandial hyperglycemia and hyperinsulinemia in the conscious dog. Diabetes. 2002 Feb;51(2):469-78. — View Citation

Sievenpiper JL, Chiavaroli L, de Souza RJ, Mirrahimi A, Cozma AI, Ha V, Wang DD, Yu ME, Carleton AJ, Beyene J, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Kendall CW, Jenkins DJ. 'Catalytic' doses of fructose may benefit glycaemic control without harming cardiometabolic risk factors: a small meta-analysis of randomised controlled feeding trials. Br J Nutr. 2012 Aug;108(3):418-23. doi: 10.1017/S000711451200013X. Epub 2012 Feb 21. Review. — View Citation

Sievenpiper JL, de Souza RJ, Cozma AI, Chiavaroli L, Ha V, Mirrahimi A. Fructose vs. glucose and metabolism: do the metabolic differences matter? Curr Opin Lipidol. 2014 Feb;25(1):8-19. doi: 10.1097/MOL.0000000000000042. Review. — View Citation

Van Schaftingen E, Detheux M, Veiga da Cunha M. Short-term control of glucokinase activity: role of a regulatory protein. FASEB J. 1994 Apr 1;8(6):414-9. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma glucose iAUC		up to 12 weeks
Secondary	Plasma glucose total AUC		up to 12 weeks
Secondary	Plasma insulin iAUC		up to 12 weeks
Secondary	Plasma insulin total AUC		up to 12 weeks
Secondary	Maximum concentrations (Cmax) for plasma glucose and insulin		up to 12 weeks
Secondary	Time of maximum concentrations (Tmax) for plasma glucose and insulin		up to 12 weeks
Secondary	Matsuda whole body insulin sensitivity index (Matsuda ISI OGTT);		up to 12 weeks
Secondary	Early insulin secretion index (?PI30-0/?PG30-0);		up to 12 weeks
Secondary	Insulin secretion-sensitivity index-2 (ISSI-2)		up to 12 weeks
Secondary	Mean incremental plasma glucose and insulin responses		up to 12 weeks
Secondary	Mean plasma glucose and insulin responses		up to 12 weeks