Metabolic Effects of Non-Nutritive Sweeteners

Background

Consumption of non-nutritive sweeteners is common practice in the US, and these chemicals are generally thought to be metabolically inert. However, recent data obtained from animal studies demonstrate that non-nutritive sweeteners play an active metabolic role within the gastrointestinal tract. Sweet-taste receptors, including the T1R family and Alpha-gustducin, respond not only to caloric sugars such as sucrose, but also to non-nutritive sweeteners, including sucralose (Splenda ) and acesulfame-K . In both humans and animals, these receptors have been shown to be present in glucagon-like-peptide-1 (GLP-1) secreting L cells of the gut mucosa as well as in lingual taste buds , and serve as critical mediators of GLP-1 secretion . We have demonstrated in a previous study that diet soda augments glucose-stimulated GLP-1 secretion . In addition, there is evidence in animals that activation of intestinal sweet-taste receptors by non-nutritive sweeteners enhances intestinal glucose absorption via upregulation of the glucose transporter, GLUT2 .

Aims

The purpose of this study is to broadly explore the effects of non-nutritive sweeteners on glucose and glucoregulatory hormones in healthy humans. To this end, we plan the following:

Primary Aim: To confirm that the non-nutritive sweetener sucralose (versus other ingredients in diet soda) augments glucose-stimulated GLP-1 secretion

Secondary Aims:

• To study whether increased GLP-1 secretion due to non-nutritive sweeteners alters gastric emptying or satiety
• To determine a dose-response relationship for non-nutritive sweeteners on glucose-stimulated GLP-1 secretion
• To determine whether non-nutritive sweeteners alter the rate of intestinal glucose absorption
• To test whether non-nutritive sweeteners affect levels of other incretin or gut hormones

Methods

Healthy men and women ages greater than or equal to 18 years, and prepubertal children ages 6-12 years, across a wide range of body mass indices will participate in a variety of paired experiments, in randomized order, with each subject serving as his or her own control. In each experiment, the subject will ingest either a non-nutritive sweetener or control, and a glucose load (oral glucose tolerance test). The following measurements will be obtained:

• Serial measurement of glucose, insulin, C-peptide, GLP-1, and other incretin and gut hormones
• Rate of gastric emptying using acetaminophen labeling in the oral glucose or mixed meal
• Measurement of hunger and satiety using validated questionnaires
• Measurement of intestinal glucose absorption using a glucose analog

• MAIN STUDY:

Inclusion criteria

• Age greater than or equal to 18 years
• No known active medical conditions

Exclusion criteria

• Current use of prescription or non-prescription medication. Certain exceptions are permitted, including topical medications, vitamins, and hormonal contraceptives. Other medications may be permitted at the discretion of the investigators.
• Recent (past 2 months) use of drugs that alter glucose metabolism (e.g. metformin), alter gastric pH (e.g. proton pump inhibitors) or gastric emptying (e.g. metoclopramide)
• ALT or AST more than 1.5 times the upper limit of normal
• Positive urine pregnancy test
• Known allergy, sensitivity or other contraindication to any study food or drug or its vehicle
• Psychiatric or cognitive disorder that will, in the opinion of the investigators, limit the subject's ability to provide informed consent, or to comply with study procedures
• Body weight less than 50 kg
• Diabetes (fasting blood glucose of 126 mg/dl or higher, or 2-hour blood glucose of 200 or higher on oral glucose tolerance testing)
• Glycosuria

PEDIATRIC PILOT STUDY:

Inclusion criteria

• Age 6-12 years at enrollment
• Body weight at least 17 kg
• Prepubertal (Tanner stage I breasts in girls, or testicular volumes less than or equal to 3 mL in boys)
• No known active medical conditions

Exclusion criteria

• Current use of prescription or non-prescription medication. Certain exceptions are permitted, including topical medications and vitamins. Other medications may be permitted at the discretion of the investigators.
• Recent (past 2 months) use of drugs that alter glucose metabolism (e.g. metformin), alter gastric pH (e.g. proton pump inhibitors) or gastric emptying (e.g. metoclopramide)
• ALT or AST more than 1.5 times the upper limit of normal
• Known allergy, sensitivity or other contraindication to any study food or drug or its vehicle
• Psychiatric or cognitive disorder that will, in the opinion of the investigators, limit the subject's ability to provide assent, and/or the subject s parent/guardian to provide informed consent, or to comply with study procedures
• Abnormal glucose tolerance (fasting blood glucose of 100 mg/dl or higher, or 2-hour blood glucose of 140 or higher on oral glucose tolerance testing)
• Glycosuria