Clinical trial NCT03703141: Serum Insulin Response After Acute and Chronic Sucralose Ingestion in Healthy Volunteers With Variable Body Mass Index
Official title: Effect of Acute or Chronic Ingestion of Sucralose on Serum Insulin in Young and Healthy Adults: a Randomized, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy
Keywords: sucralose
insulin
AUC
young
inflammatory markers
intolerance
Lead sponsor: Hospital General de México Dr. Eduardo Liceaga
Sponsor class: OTHER_GOV
First posted: 2018-10-11
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: SCREENING

Brief summary: The consumption of non-caloric sweeteners has increased worldwide; Current publications suggest its consumption associates to insulin resistance.

The present study aims to demonstrate whether acute or chronic sucralose exposure affects insulin or carbohydrate metabolism or alters systemic inflammatory markers and microbiota in young, healthy adults.

In this prospective, randomized, double-blind, placebo-controlled clinical trial, three groups will be included with 30 healthy volunteers each. Group A will receive sucralose 48 mg/ day, group B 96 mg/day and group C plain water as placebo. Subjects will be exposed to acute (one day) and chronic (seventy days) oral sucralose ingestion. After acute or chronic exposure, volunteers will undergo into an Oral Glucose Tolerance Test (OGTT), taking blood samples at -15, 0, 15, 30, 45, 60, 75, 90, 105, 120 and 180 minutes, respectively.

Areas under the curve (AUC) for insulin and glucose, will be calculated from zero to one hundred and eighty minutes as described; for C peptide, glucagon, GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide) measure points will be at 0, 30 and 60 minutes only. Differences between one and seventy days AUC means will be compared between the three groups, adjusting for BMI. Besides, initial and final systemic inflammatory markers and inflammatory monocytes levels will be quantified and compare between acute and chronic exposure. Also, a comparison between the percentage of acute and chronic microbiome bacterial population in feces will be made.

Detailed description: Introduction Overweight and obesity have increased along with the rate of other non-communicable diseases worldwide. At the same time, the consumption of non-caloric sweeteners (NCS) has risen considerably among the general population. Although international organizations such as Joint FAO/WHO Expert Committee on Food Additives (JECFA) has demonstrated NCS are safe; two recent publications suggested its consumption associates with insulin resistance.

Although the authors attributed the metabolic effect to changes in the composition of intestinal microbiota as a consequence of NCS ingestion, these studies lacked a robust clinical methodology, as their design were not randomized, comparative studies and the effect of NCS on systemic inflammation biomarkers were neglected.

Outcomes The present study aims to demonstrate whether acute or chronic sucralose exposure affects insulin or carbohydrate metabolism or alters systemic inflammatory markers and microbiota in young, healthy adults.

Materials and methods It is a prospective, randomized, double-blind, placebo-controlled clinical trial, comparing three groups, with 30 healthy volunteers each, who will receive daily sucralose, for seventy days. After signing off informed consent, the first group will take 48 mg sucralose diluted in 60 mL of water; the second group will receive 96 mg / 60 ml a day, while the last group will receive 60 ml of plain water as placebo.

Inclusion criteria will be either sex, age between 18 and 35 years, with a body mass index (BMI) between 18.5 and 39.0, disease free, with light or moderate physical activity before entering the study, with a HOMA ≤3.8, non-smokers, non-alcohol drinkers, agreeing not to consume neither industrial food nor beverages related to NCS during the study, having Mexican ancestry, living in the Mexico City metropolitan area and signing informed consent to participate in the study.

Exclusion criteria Any acute disease by the time of recruitment, history of Type 1 or 2 diabetes, thyroid disease, adrenal glands disease, insulinoma, malabsorption syndrome, short bowel, HIV, any cancer, liver disease, renal disease, inflammatory bowel disease, have prescribed corticosteroids in the previous three months before enrollment or undergone to bariatric surgery. Having a BMI \<18.5 or \>39.0, working night shifts, unable to remain at the clinic for at least 5 hours, not accepting to stop consuming industrialized food or beverages containing NCS, not accepting to stop alcohol or tobacco consumption during the study, not consenting to participate, women in childbearing potential without pregnancy control or women pregnant or breastfeeding by the time of enrollment.

Each volunteer will be instructed to drink 60 mL of fluid containing either sucralose or water, every morning before meals for seventy days. Except on day one and day 70, when they will be requested to attend the clinic after fasting at least 8 hours. Two plastic containers to carry stool sample will be provided in advance to each participant and be requested to store a stool sample. At their arrival to the clinic the stool sample will be collected and labeled. Immediately after, they will be asked to drink the corresponding dose to day one or seventy in the presence of the investigators. Once the investigational material be drinking, an Oral Glucose Tolerance Test (OGTT), will be initiated, taking blood samples at

* 15, 0, 15, 30, 45, 60, 75, 90, 105, 120 and 180 minutes, respectively. Analysis Demographics per group will be described initially. Following, areas under the curve (AUC) for insulin and glucose, will be calculated from zero to one hundred and eighty minutes, as the measure points described above; for C peptide, glucagon, GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide) measure points will be at 0, 30 and 60 minutes only.

Mean differences of AUCs between one and seventy days will be compared between the three groups, adjusting for BMI. Besides, initial and final systemic inflammatory markers and inflammatory monocytes levels will be quantified and compared between acute and chronic exposure. Additionally, a comparison of changes between the percentage of acute and chronic microbiome population in feces will be made.

Eligibility criteria: Inclusion Criteria:

* Men or women
* Ages between 18 and 35 years
* Must not have suffered chronic noncommunicable or infectious diseases
* Must have been practicing light-moderate physical activity before the study
* Normal insulin resistance index according to a homeostatic model value of insulin resistance (HOMA-IR) ≤ 3.8
* Must not be smokers
* They must accept not to consume industrialized foods that contain non-caloric sweeteners during their participation in the study and be agree to receive weekly telephone reminders during the protocol
* Must accept not to consume industrialized beverages containing non-caloric sweeteners during their participation in the study
* Do not consume alcoholic beverages during their participation in the study, do not have alcoholism history and have not consumed alcoholic beverages for less than two weeks before entering to the protocol
* Must have Mexican ancestry
* The volunteers, their parents and grandparents must be from Mexico city metropolitan area
* They must sign the letter of inform consent, expressing their desire to participate as volunteers in the study

Exclusion Criteria:

* People who have any kind of serious illness at the time of the selection
* People who have been diagnosed with Diabetes Mellitus type 1 or type 2
* People who have been diagnosed with thyroid disease
* People who have been diagnosed with any adrenal glands disease
* People who have been diagnosed with insulinoma
* People who have been diagnosed with malabsorption syndrome
* People with short bowel history
* People who have been diagnosed with HIV
* People who have been diagnosed with any type of neoplasia
* People who have been diagnosed with acute or chronic liver disease
* People who have been diagnosed with kidney disease with compromise on serum glucose levels
* People who have been prescribed with corticosteroid in the last 3 months before entering to the study
* People who have been prescribed with any type of antibiotic, 4 weeks prior to entering to the protocol
* People who have been prescribed with any type of non-steroidal anti-inflammatory, 4 weeks prior to entering the protocol
* People who do not accept to remain in the Clinical Pharmacology Unit during the required time to carry out the oral glucose tolerance curves (4 hours, plus the preparation time)
* People with night jobs
* People who did not accept to abstain from consuming industrialized products containing non-caloric sweeteners during their participation in the study
* People who refused to abstain from consuming industrialized beverages containing non-caloric sweeteners during their participation in the study
* People who do not accept to abstain from consuming alcoholic beverages during their participation in the study
* People who have undergone bariatric surgery before the study
* People with inflammatory bowel disease history
* People who have smoked at least 3 cigarettes per week in the last 3 months
* People who do not sign the informed consent letter to participate in the study
* Women on reproductive age without contraception therapy.
* Pregnant women
* Women who are breastfeeding at the time of evaluating their admission to the study,

Primary outcomes:
measure: Serum insulin levels
timeFrame: Change the baseline serum insulin levels at 10 weeks sucralose consumption.
Secondary outcomes:
measure: C-peptide serum levels.
timeFrame: Change the baseline serum insulin levels at 10 weeks sucralose consumption.
measure: Glucose-dependent insulinotropic polypeptide serum levels.
timeFrame: Change the baseline serum glucose-dependent insulinotropic polypeptide levels at 10 weeks sucralose consumption.
measure: Glucagon serum levels
timeFrame: Change the baseline serum glucagon levels at 10 weeks sucralose consumption.
measure: Glucagon-like peptide-1 serum levels
timeFrame: Change the baseline serum systemic inflammatory response levels at 10 weeks sucralose consumption.
measure: Systemic inflammatory response (pCr, Tumor Necrosis Factor , Internferon -, IL-1, IL-6, IL-12, IL-17, e IL-23 serum levels)
timeFrame: Change the baseline serum systemic inflammatory response levels at 10 weeks sucralose consumption.
measure: Inflammatory monocytes (CD14hiCD16+ CD11c+CCR2hiCX3CR1lowCD206-) serum levels.
timeFrame: Change the baseline serum inflammatory monocytes levels at 10 weeks sucralose consumption.
measure: Anti-inflammatory markers (IL-4, IL-10, e IL-13) serum levels.
timeFrame: Change the baseline serum anti-inflammatory markers levels at 10 weeks sucralose consumption.
measure: Intestinal microbiota composition.
timeFrame: Change the baseline intestinal microbiota composition at 10 weeks sucralose consumption.
measure: Body Mass Index (BMI)
timeFrame: To compare the baseline body weight at 10 weeks sucralose consumption.
measure: Glucose area under the curve levels
timeFrame: Change the baseline serum glucose levels at 10 weeks sucralose consumption.
measure: C-peptide area under the curve levels
timeFrame: Change the baseline serum C-peptide levels at 10 weeks sucralose consumption.
measure: Glucagon area under the curve levels
timeFrame: Change the baseline serum glucagon levels at 10 weeks sucralose consumption.
measure: GLP-1 area under the curve levels
timeFrame: Change the baseline serum GLP-1 levels at 10 weeks sucralose consumption.
measure: Glucose-dependent insulinotropic polypeptide area under the curve levels.
timeFrame: Change the baseline serum glucose-dependent insulinotropic polypeptide levels at 10 weeks sucralose consumption.
Other outcomes:
Locations:
Study officials:
affiliation: Hospital General de Mexico Eduardo Liceaga
name: Guillermo Melendez, MD, MSc
role: PRINCIPAL_INVESTIGATOR
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