Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

Abstract

Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety.

Introduction

Previous data from our lab, and others, indicates that sweet and fatty orosensory stimuli that do not reliably predict the post-ingestive energetic consequences of consumption can impair the ability of rats to regulate both short-term and longer-term food intake and body weight. For example, rats given dietary supplements with the high-intensity sweetener saccharin, which provides a strong sweet taste, but does not deliver calories, exhibit poorer caloric compensation for novel sweet-tasting pre-meals in short-term intake tests [1], [2]. Further, over the long-term, consumption of a saccharin-sweetened yogurt supplements resulted in increased energy intake, increased body weight gain and increased adiposity relative to consumption of the same supplements sweetened with glucose [3], [4], [5].

We have suggested that mechanisms that underlie the dysregulation of energy balance when consuming high-intensity sweeteners may involve reducing the validity of a predictive relationship between sweet taste and the delivery of energy or calories. Based on fundamental principles of Pavlovian conditioning, presentation of a cue without its anticipated consequence will weaken the ability of the cue to evoke the conditioned responses [6], [7], [8]. In the case of sweet tastes, high-intensity sweeteners provide a strong sweet cue, but without the delivery of an anticipated energetic or caloric outcome. This would be expected to weaken the validity of the sweet taste → calorie relationship. To the extent that the ability to anticipate the caloric consequences of intake contributes to energy, and ultimately body weight regulation, animals may both overeat and gain excess body weight when sweet tastes that do provide calories are encountered. Consistent with this hypothesis, we have recently demonstrated that consumption of non-caloric sweeteners selectively impairs the ability or rats to regulate intake and weight gain when they are maintained on a sweetened high-calorie diet [9]. We have recently extended the generality of this account by showing that energy balance can also be disrupted by exposure to fatty-tasting foods manufactured with fat substitutes that mimic the sensory properties of fat, but without calories [10]. Similar to effects seen with sweet tastes, positive energy balance is the result of the selective overconsumption fatty foods that do deliver energy.

While food intake, weight gain and adiposity are increased by exposure to such substitutes, the specific physiological mechanisms that contribute to overconsumption and impaired energy balance have not been specified. One potential mechanism is interference with physiological responses that anticipate the arrival of energy and nutrients upon consumption of foods. The role of experience with environmental cues in modulating such physiological responses have been the focus of study since the foundational work of Pavlov [11] and these “cephalic phase” responses have been documented in both pre-clinical rodent studies, as well as clinical studies in humans. Cephalic phase responses, such as the release of insulin, are thought to reflect fractional components of physiological responses recruited to efficiently metabolize ingested foods [11], [12], [13], [14], [15]. They may also serve to modulate meal size by generating satiety signals. The strength of such responses should be determined, at least in part, by the validity of the predictive relationship between taste cues and their consequences. Accordingly, the magnitude of cephalic phase responses should be weakened to the extent that exposure to taste cues that are not followed by energetic outcomes weakens the validity of the normal sweet taste → calorie predictive relationship.

Previous studies show that consuming noncaloric sweeteners can evoke cephalic phase responses in rats (e.g. [14], [16], [17], [18], [19]). However, whether the magnitude of these responses is reduced following extended experience with these sweeteners is presently unknown. Thus, the goal of the present studies was to determine whether experience with sweet tastes that do not predict energetic outcomes alters cephalic phase responses as indexed by the ability of rats to modulate blood glucose levels in response to sweet-tasting, high calorie foods. The hypothesis was that compared to animals given diets in which sweet taste always predicted the delivery of increased calories and glucose, animals given diets in which sweet taste did not predict calories (using saccharin) would show a hyperglycemic response to a sweet-tasting caloric load. In contrast, glycemic responses to sweet-tasting, caloric diets which bypass the oral cavity, thereby precluding cephalic phases reflexes evoked by oral taste, were expected to be similar between groups. In a series of experiments, we examined the effects of exposure to yogurt diet supplements (Experiments 1–4, 6) and solutions (Experiment 5) on glycemic responses to a novel, sweet-tasting test meal (Experiment 1), or a glucose solution (Experiments 2–6) to determine whether experience consuming sweet tastes that were not associated with calories or sugar resulted in alterations in blood glucose homeostasis. In addition, we examined whether levels of the peptide hormones insulin and GLP-1 were altered following experience with saccharin-sweetened diet supplements compared to glucose-sweetened diet supplements since release of both insulin and GLP-1 are critical in regulation of glucose homeostasis, and have been implicated in satiety and modulation of meal size (e.g. [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]).