Data from several studies show that consuming a diet high in low-calorie sweeteners (LCS), mainly in diet sodas, is linked to the same metabolic disorders as consuming a diet high in added sugars, including an increased risk of developing type 2 diabetes. Sweet taste receptors, once thought to be unique to the mouth, have now been discovered in other parts of the body, including the intestine and the pancreas, where they play a role in blood sugar control. These newly identified receptors provide new avenues to explore how LCS may affect metabolism and health. This project is designed to examine the role of sweet taste signaling, both in the mouth and in the gut, on blood sugar control and how habitual consumption of LCS may affect sweet taste signaling and metabolism in people with obesity.

The overall goal of this research is to assess the role of oral and gut sweetness signaling in postprandial glucose metabolism and to determine how acute and chronic low-calorie sweetener (LCS) consumption may affect this signaling in people with obesity. The aims will determine the independent and combined contributions of pharmacological inhibition (Aim 1) or extra stimulation (Aim 2) of sweet taste signaling in the gut, mouth, or both on hormonal responses to an oral glucose tolerance test (OGTT) in two groups of subjects with obesity: habitual and non-habitual LCS consumers. Validated sensory evaluation techniques will also ascertain subjects' taste perception (Aim 3) to test the hypotheses that habitual consumption of LCS blunts perception of sweetness and, in turn, affects postprandial glucose regulation.

Inclusion Criteria:

• All races/ethnicities
• Habitual (> 5 diet sodas per week) and non-habitual (≤1 diet soda or 1 packet of LCS per week) LCS consumers
• 30 ≤ BMI <40 kg/m2
• Not severely insulin resistant (HOMA-IR2 < 2.6)

Exclusion Criteria:

• BMI < 30 and 40< BMI kg/m2
• HOMA-IR2>2.6
• Irregular LCS consumers (>1 diet sodas or packets of LCS per week but <5)
• Current smokers or quit smoking nicotine cigarettes for less than 6 months ago
• Pregnant, breastfeeding, menopausal
• Presence of anemia : <12g/dl for women and <13g/dl for men
• Blood donation in the past 8 weeks
• Presence of malabsorption syndrome
• History of bariatric surgery
• Presence of inflammatory intestinal disease, liver or kidney disease
• Have diabetes (fasting glucose level >126mg/dl or plasma glucose level 2h after glucose challenge >200 mg/dl)
• Taking any medication that might affect glucose metabolism or the results of our study

Consistent with the need to not compromise human subject protections, raw data that identifies participants will not be shared with anyone not included on our IRB approval. De-identified data, from participants who consented to share their de-identified data will be deposit in a data repository (e.g. Figshare).

We plan to share data no later than 6 months post-publication or 18 months from the award end date per ADA expectations.

Data will be available to qualified individuals within the scientific community for research purposes contingent upon IRB approval for secondary data analysis.