Clinical trial NCT04182464: Effects of Sucralose in Insulin Sensitivity
Official title: Changes in Insulin Sensitivity in Liver and Esqueletal Muscle Due to Sucralose Consumption
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Insulin Sensitivity/Resistance
Keywords: sucralose
hyperinsulinemic-euglycemic clamp
insulin sensitivity
Lead sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Sponsor class: OTHER
First posted: 2019-12-02
Enrollment: 24
Sex: ALL
Minimum age (years): 20
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Triple-blind, parallel, placebo-controlled, randomized clinical trial.
Primary purpose: OTHER

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Normal BMI (18.5-24.9 kg/m2)
* Low habitual consumption of non-nutritive sweeteners (NNS
* Fasting plasma insulin concentration of \<12 mU/L

Exclusion Criteria:

* Diabetes or altered glucose metabolism (abnormal fasting glucose, glucose intolerance or elevated glycated hemoglobin)
* Use of antibiotics in the last 3 months
* Use of probiotics through pharmaceutical products
* Liver or kidney disease
* Use of medications that could interfere with insulin sensitivity
* Severe intestinal diseases
* History of bariatric surgery
* Pregnancy or lactation

Primary outcomes:
measure: Liver insulin sensitivity
timeFrame: baseline and 30 days after the intervention
measure: Muscle insulin sensitivity
timeFrame: baseline and 30 days after the intervention
Secondary outcomes:
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Study officials:
affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
name: Paloma Almeda-Valdes, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Romo-Romo A, Aguilar-Salinas CA, Gomez-Diaz RA, Brito-Cordova GX, Gomez-Velasco DV, Lopez-Rocha MJ, Almeda-Valdes P. Non-Nutritive Sweeteners: Evidence on their Association with Metabolic Diseases and Potential Effects on Glucose Metabolism and Appetite. Rev Invest Clin. 2017 May-Jun;69(3):129-138. doi: 10.24875/ric.17002141.
citation: Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S. Sucralose affects glycemic and hormonal responses to an oral glucose load. Diabetes Care. 2013 Sep;36(9):2530-5. doi: 10.2337/dc12-2221. Epub 2013 Apr 30.
citation: Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, Elinav E. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014 Oct 9;514(7521):181-6. doi: 10.1038/nature13793. Epub 2014 Sep 17.
citation: Romo-Romo A, Aguilar-Salinas CA, Brito-Cordova GX, Gomez-Diaz RA, Almeda-Valdes P. Sucralose decreases insulin sensitivity in healthy subjects: a randomized controlled trial. Am J Clin Nutr. 2018 Sep 1;108(3):485-491. doi: 10.1093/ajcn/nqy152.
citation: Lertrit A, Srimachai S, Saetung S, Chanprasertyothin S, Chailurkit LO, Areevut C, Katekao P, Ongphiphadhanakul B, Sriphrapradang C. Effects of sucralose on insulin and glucagon-like peptide-1 secretion in healthy subjects: a randomized, double-blind, placebo-controlled trial. Nutrition. 2018 Nov;55-56:125-130. doi: 10.1016/j.nut.2018.04.001. Epub 2018 Apr 21.