Sucralose and Lactisole Additions to OGTT in Humans

Study Overview
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Brief Summary
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In the present study, our objective was to determine whether T1R2-T1R3 influences glucose metabolism bidirectionally via hyperactivation with sucralose and inhibition with sodium lactisole in mixture with glucose loads during tolerance tests in humans. In 12 healthy participants we conducted oral glucose tolerance tests (OGTTs) of 75 g glucose with and without the addition of the T1R2-T1R3 agonist, sucralose (5 mM). We also conducted OGTTs in 10 healthy participants with and without the addition of a T1R2-T1R3 antagonist, sodium lactisole (2 mM). Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants' sweet taste responses to sucralose, their sensitivities to sweetness inhibition by lactisole, and their BMIs.

Detailed Description
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The sweet taste receptor, T1R2-T1R3, is expressed in taste bud cells, where it conveys sweetness, and also in intestinal enteroendocrine cells, where it may facilitate glucose absorption and assimilation. There is evidence in mice through genetic knockout studies that T1r2-T1r3 is involved in endocrine and enteroendocrine responses to glucose loads. Yet, our understanding of the impact of T1R2-T1R3 on human glucose metabolism is less clear. In the present study, our objective was to determine whether T1R2-T1R3 influences glucose metabolism bidirectionally via hyperactivation with sucralose and inhibition with sodium lactisole in mixture with glucose loads during tolerance tests in humans. In 12 healthy participants we conducted oral glucose tolerance tests (OGTTs) of 75 g glucose with and without the addition of the T1R2-T1R3 agonist, sucralose (5 mM). We also conducted OGTTs in 10 healthy participants with and without the addition of a T1R2-T1R3 antagonist, sodium lactisole (2 mM). Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants' sweet taste responses to sucralose, their sensitivities to sweetness inhibition by lactisole, and their BMIs. The addition of sucralose to glucose elevated plasma insulin responses to the OGTT. Sucralose-sensitive participants, those who rated sucralose as sweetest, had a more pronounced elevation in peak plasma insulin to sucralose + glucose with early increases in plasma glucose and insulin area-under-the-curve (AUC) within the first 15 minutes. In lactisole-sensitive participants, whose sweetness was suppressed by low levels of lactisole, the addition of lactisole to glucose in the OGTT decreased plasma glucose AUC. Participants with higher BMI (>24 kg/m2) tended to be hyper-responsive to added sucralose, nearly doubling their peak levels of insulin to the sucralose + glucose OGTT . Manipulation of the T1R2-T1R3 receptor with a non-caloric agonist and an antagonist demonstrates that T1R2-T1R3 helps regulate glucose handling and metabolism in humans. Importantly, participants with BMI > 24 kg/m2 tended to rate sucralose as sweeter and showed exaggerated insulin increases when it was added to their OGTT.

Official Title
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Activation and Inhibition of the Sweet Taste Receptor T1R2-T1R3 Differentially Affect Glucose Tolerance in Humans

Conditions
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Neat OGTT, OGTT With Added Sucralose, OGTT With Added Lactisole

Intervention / Treatment
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* Dietary Supplement: TAS1R2/3 agonist or antagoinst admixture to oral glucose tolerance test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-diabetic No metabolic disease Should not have exercised in past 24 hours. Should have undergone overnight fast. BMI <30 kg/m2 Exclusion Criteria: Participants who reported consuming more than one serving of artificially sweetened beverages or snacks per day were excluded. Participants with diseases (e.g. metabolic syndrome and diabetes) and medications that may affect taste, digestion and absorption (e.g. anti-hypertensives, antibiotics, insulin, metformin, SGLT2 Inhibitors, sulfonylureas) were also excluded. Participants with BMI>30 kg/m2 were excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Participants were given oral glucose tolerance tests alone or with lactisole or sucralose in admixture with the glucose. All controls were within subjects in counterbalanced crossover design.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving oral glucose tolerane tests with TAS1R agonists<br>Participants received a standard oral glucose tolerance test alone and with the addition of the TAS1R2/3 agonist sucralose in admixture | Dietary Supplement: TAS1R2/3 agonist or antagoinst admixture to oral glucose tolerance test<br>* Participants drank a glucose beverage for an oral glucose tolerance test along or with admixture with the TAS1R2/3 agonist sucralose or the TAS1R2/3 antagonist lactisole.<br>|
| Experimental: Participants receiving oral glucose tolerane tests with TAS1R antagonists<br>Participants received a standard oral glucose tolerance test alone and with the addition of the the TAS1R2/3 antagonist lactisole in admixture | Dietary Supplement: TAS1R2/3 agonist or antagoinst admixture to oral glucose tolerance test<br>* Participants drank a glucose beverage for an oral glucose tolerance test along or with admixture with the TAS1R2/3 agonist sucralose or the TAS1R2/3 antagonist lactisole.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Glucose | Repeated plasma blood draws during OGTT will determine plasma glucose | 90 minutes | 
| Plasma Insulin | Repeated plasma blood draws during OGTT will determine plasma insulin | 90 minutes | 
| Plasma glucagon | Repeated plasma blood draws during OGTT will determine plasma glucagon | 90 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Taste responsivity to sucralose | How sweet sucralose tastes to participants is reported | 30 minutes | 
| Taste inhibition by lactisole | How effectively lactisole inhibits sweet taste for individual participants is assessed | 30 minutes | 
| Body-mass Index | Individual participant BMI was calculated | 15 minutes |