Sweeteners, sweet antagonists, and metabolism

Sugars and sweeteners are proposed to stimulate human sweet taste via the receptor, T1R2-T1R3. T1R2-T1R3 is a heterodimeric GPCR expressed in oral taste tissue. T1R2-T1R3 binds sugars, non-nutritive sweeteners, and sweet taste blockers. It was recently discovered that T1R2-T1R3 is also expressed in extra-oral tissues including the intestine, hypothalamus, pancreas, and adipose. This finding is striking because non-nutritive sweeteners are believed to be metabolically inert. Hence, it raises the question of whether T1R2-T1R3 plays a role not only sweet taste perception but also in regulatory and metabolic physiology. The purpose of this research project is to investigate the perceptual and physiological functions of T1R2-T1R3 using a pharmacological approach in human participants. In the first aim, I determined whether glucose and fructose behave as partial agonists of the sweet taste receptor and can enhance or suppress each other in mixture. In the second aim, I sought to assess and improve the sweetness of glucose and its metabolic profile relative to fructose and sucrose. In the third aim, I conducted psychophysical studies to determine whether metabolically active drugs act on the sweet taste receptor. In the fourth aim, I conducted glucose tolerance studies to determine whether sweet taste stimuli influence glucose metabolism. And in the fifth aim, I conducted glucose tolerance tests to determine whether sweet taste inhibitors influence glucose metabolism. I found that sweeteners and antagonists had both perceptual and physiological functions. In the first aim, I demonstrated that glucose is a poor sweetener relative to fructose because it is not a full agonist of the sweet receptor. In the second aim, I demonstrated that glucose can be rendered almost indistinguishable from sucrose at the same caloric level with the addition of a non-nutritive sweetener. Thus, the difference in glucose and fructose sweetness can be overcome when adding stevioside to glucose. In the third aim, I demonstrated that clofibric acid, a lipid lowering prescription drug, inhibits sweet taste perception. Since it has been shown to inhibit T1R3 in vitro, I conclude from our data that it is also a T1R3 inhibitor in vivo. In the fourth aim, I demonstrated that high potency sweeteners (HPS), which are thought to be metabolically inert, enhance insulin and glucose responses relative to a standard OGTT. And in the fifth aim, I found that sweet taste blockers caused an opposite reaction and slowed glucose rise in the blood relative to a standard OGTT. As a sugar receptor, T1R2-T1R3 imparts a powerful influence on human health by guiding food choice and metabolism. My findings are of public health relevance because excessive intake of sweet tasting compounds such as sugars and other sweeteners are a major long-term health concern. Overconsumption of dietary sugars, particularly in the form of sweetened beverages, is thought to promote obesity, diabetes, fatty liver disease, and metabolic syndrome. Despite efforts to curb intake of sweet beverages, the typical American consumes 50 liters of caloric and non-caloric soft drinks per year and even more in sugar-added foods and confections. As the prevalence of metabolic diseases grows, there is a greater need to understand the perceptual and physiological mechanisms, drives, and responses for sweet tasting compounds.Ph.D.Includes bibliographical referencesby Matthew C. Koche