Effects of Sucralose in Insulin Sensitivity
Condition: Insulin Sensitivity/Resistance
MeSH terms: Insulin Resistance; Hypersensitivity
Study type: Interventional

Summary: 
      Recently, it has been proposed that the consumption of non-nutritive sweeteners, including
      sucralose, it's not harmless and is related with metabolic effects. Some studies have
      reported that sucralose produces alterations in glucose homeostasis. In vitro studies
      indicate that sucralose is capable of interacting with sweet taste receptors (T1R2 and T1R3)
      in the intestine, thus increasing the expression of glucose transporters including the
      sodium-glucose cotransporter type 1 (SGLT1) and the glucose transporter 2 (GLUT2), increasing
      glucose absorption. This interaction with intestinal sweet taste receptors also generates an
      increase in the secretion of the incretins glucagon-like peptide type 1 (GLP-1) and the
      glucose-dependent insulinotropic polypeptide (GIP), which might enhance the postprandial
      insulin release. However, these results are preliminary and it's desirable to confirm if
      sucralose consumption is associated with glucose metabolism modifications using an
      appropriate methodological design and with gold standard methods. The aim of this
      triple-blind, placebo-controlled, parallel, randomized clinical trial is to confirm the
      changes in insulin sensitivity associated with sucralose consumption in humans, to identify
      whether these changes are in the liver or skeletal muscle and to investigate the
      pathophysiological mechanisms generating these changes. Specifically, we will investigate if
      sucralose generates a dysbiosis in the gut microbiota that could be related to insulin
      resistance by increasing concentrations of lipopolysaccharide, a toxin present in
      Gram-negative bacteria that triggers a low grade inflammation known as metabolic endotoxemia.
      In addition, the changes in postprandial concentrations of GLP-1, glucose, insulin and
      C-peptide due to the combination of sucralose with a mixed meal will be investigated. The
      results of this study will determine if sucralose consumption, frequently used as a
      non-nutritive sweetener, is associated to significant changes in glucose homeostasis in
      humans.
    

Detailed description: 
      Study design:

      This is a triple-blind, parallel, placebo-controlled, randomized clinical trial.

      Sample size:

      The sample size was calculated to observe a difference of 15% in insulin sensitivity based on
      two outcomes: glucose rate of appearance (Ra) and glucose rate of disappearance (Rd) obtained
      from the hyperinsulinemic-euglycemic glucose clamp to measure the liver and skeletal muscle
      insulin sensitivity.

      The calculation was done considering a probability of type I error (α) of 5%, with a power of
      90% and adding an extra 20% for potential losses at follow-up.

      The estimated sample size for the study is 24 subjects, 12 per group.

      Randomization:

      The participants will be randomly assigned to one of the two groups (sucralose or placebo)
      using the website Randomization.com (http://www.randomization.com) with a balanced block
      design of 4 blocks with 6 subjects each. The random allocation sequence will be done by an
      external researcher.

      Intervention:

      The intervention will consist of capsules filled with pure sucralose or placebo (cornstarch)
      accordingly to the group assignment. Each capsule will contain 90 mg of sucralose or placebo.
      Participants will be asked to consume one capsule in each meal (three per day) in order to
      achieve an ingestion of 270 mg of sucralose or placebo, this quantity corresponds
      approximately to the 30% of the acceptable daily intake (ADI) of sucralose for a lean person.
      This was calculated based on the ADI established by the joint Food and Agriculture
      Organization of the United Nations (FAO)/World Health Organization (WHO) expert committee on
      food additives (JECFA) of 15 mg per kg of body weight per day of sucralose.

      The use of identical capsules will allow the blinding, the capsules will be deposited in
      bottles numbered sequentially according to the enrollment process and neither the
      participants nor the researches will know the content of the capsules or the group assigned.

      Visit 1

      An oral glucose tolerance test (OGTT) will be performed in order to confirm that participants
      do not have diabetes or prediabetes. Fasting insulin, lipid profile and glycated hemoglobin
      will be measured. Also, anthropometry (weight, height, waist and hip circumference), blood
      pressure and heart rate will be documented. Body composition will be evaluated with dual
      X-ray absorptiometry (DXA) already available in the Research Unit and bioelectrical
      impedance. Physical activity will be registered with the questionnaire from the University of
      Laval that measure energy expenditure in Kcal per day. A format for three-day food intake
      record will be given to be prospectively registered by participants.

      Visit 2

      The first hyperinsulinemic-euglycemic glucose clamp (HEGC) will be done in this visit. The
      first phase of the HEGC will use an insulin infusion of 14 milliunits (mU)/m2 of BSA/min to
      evaluate hepatic insulin sensitivity. The second phase of the HEGC will use an insulin
      infusion of 50 mU/m2 of body surface area (BSA)/min to evaluate skeletal muscle insulin
      sensitivity. Each phase has an approximately duration of two to three hours.

      The researchers will proportionate the bottle with capsules that each participant will
      consume during the intervention period (30 ± 2 days) in this visit. Also, each participant
      will be asked to record on the adherence format if they consumed the capsule at breakfast,
      lunch and dinner each day of the intervention period and to record any symptom related to
      capsules ingestion. Another format to record three-day food consumption again will be given.

      Visit 3

      The second HEGC will be done in this visit following the same procedure as explained in visit
      2. Also, the physical activity questionnaire will be applied again and the second 3-day food
      record will be obtained to evaluate changes in physical activity and food habits,
      respectively. Participants will be asked to return the empty bottles to quantify adherence to
      the intervention. In addition adherence and symptoms formats will be collected.
    

Intervention name(s): Sucralose; Placebo
Intervention type(s): Other; Other
Intervention description(s): Food additive used to replace sugar providing a sweet taste without calories; Cornstarch without significant physiological effects
Other intervention name(s): non-nutritive sweetener
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Triple-blind, parallel, placebo-controlled, randomized clinical trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: sucralose; hyperinsulinemic-euglycemic clamp; insulin sensitivity