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.

Figure 1

Body weight gain in animals given access to saccharin-sweetened yogurt for 3 hr per day was significantly higher than in animals given access to glucose-sweetened yogurt. * p < 0.05 compared to Glucose

Figure 2

Blood glucose levels were significantly higher 15 min after the introduction of a novel sweet-tasting meal in animals previously exposed to saccharin-sweetened yogurt compared to animals previously exposed to glucose-sweetened yogurt (left panel). No differences in blood glucose levels were observed when no meal was provided (right panel). * p < 0.05 compared to glucose

Figure 3

Body weight gain prior to surgery in male rats given access to saccharin-sweetened yogurt was significantly greater compared to those given access to glucose-sweetened yogurt. * p < 0.05 compared to Glucose group

Figure 4

A) In animals that consumed at least 90% of 10 g of a 20% glucose solution in the first 30 min, blood glucose levels were significantly higher at 8 min, 12 min and 48 min in male rats previously exposed to saccharin-sweetened yogurt compared to those previously exposed to glucose-sweetened yogurt. B) Glucose AUC was significantly higher in animals previously exposed to saccharin-sweetened yogurt. C) Neither patterns of insulin levels nor insulin AUC (D) were different in animals previously exposed to glucose versus saccharin-sweetened yogurt * p< 0.05 compared to Glucose group

Figure 5

Body weight gain was not significantly different in animals given glucose-sweetened versus saccharin-sweetened yogurt in Experiment 3.

Figure 6

In animals that orally consumed at least 90% of 5 g of a 10% glucose solution within 15 minutes, blood glucose levels were significantly higher in male rats previously exposed to saccharin-sweetened yogurt compared to those previously exposed to glucose-sweetened yogurt (A and B). In contrast, no differences in glucose levels were observed when glucose was delivered directly into the stomach by gavage (C and D). * p < 0.05 compared to Glucose group

Figure 7

Body weight gain in Experiment 4 was significantly higher in animals given saccharin-sweetened yogurt compared to glucose-sweetened yogurt.

Figure 8

Blood glucose levels were significantly higher in animals previously given saccharin-sweetened yogurt following 5 ml of a 20% glucose solution in animals that consumed at least 90% of the solution from a cup within 8 minutes (A) or when animals were allowed to taste the solution and then given a gavage directly into the stomach (B), but not when the glucose solution bypassed the oral cavity and was delivered directly into the stomach (C). There were no differences in insulin levels between groups regardless of the method of delivery. * p < 0.05 compared to Glucose group

Figure 9

Body weight gain (A) and energy intake (B) were significantly greater in animals given a saccharin-sweetened solution compared to animals given a glucose-sweetened solution when a high-fat, high sugar maintenance diet was provided. * p < 0.05 compared to Glucose group

Figure 10

Blood glucose levels were significantly higher in animals previously given access to a saccharin-sweetened solution in animals that consumed at least 90% of 5 ml of a 20% glucose solution orally (A) within 8 minutes, but not when the same solution was delivered directly into the stomach by gavage (C). Levels of total GLP-1 were significantly lower 8 and 16 min following presentation of the glucose solution orally (B) but not following delivery of the glucose solution directly into the stomach by gavage (D). * p < 0.05 compared to Glucose group

Figure 11

AUC for blood glucose (A) was significantly lower when animals consumed the glucose orally compared to when it was delivered by gavage. In addition, when animals consumed the glucose orally, blood glucose AUC was lower in animals that had previously been exposed to glucose compared to animals previously exposed to saccharin. AUC of GLP-1 (B) was significantly higher when glucose was delivered by gavage compared to being consumed orally, and significantly lower in saccharin-exposed animals compared to glucose-exposed animals when animals consumed the glucose solution orally during the test. * p < 0.05 compared to Glucose group

Figure 12

Body weight gain (A) was significantly higher in rats maintained on a high-fat, sweetened diet and given saccharin-sweetened yogurt supplements compared to glucose-sweetened yogurt supplements. Total energy intake across all days of training (B) was also significantly higher in rats given the saccharin-sweetened yogurt. * p< 0.05 compared to Glucose group

Figure 13

Analysis of body composition indicated that animals given access to saccharin-sweetened yogurt supplements and maintained on high-fat, sweetened diets had significantly greater lean mass at the end of exposure compared to animals given glucose-sweetened yogurt. * p < 0.05 compared to Glucose group

Figure 14

In rats maintained on a high-fat, sweetened diet and given saccharin-sweetened yogurt diets, blood glucose levels were significantly more elevated at 8 and 16 min following consumption of 5 ml of a 20% glucose solution compared to animals given glucose-sweetened yogurt diets (A), while release of GLP-1 was significantly lower at 8 and 16 min in animals given saccharin-sweetened yogurts (B). Insulin release did not differ at any time point between groups (C). * p < 0.05 compared to Glucose group

Figure 15

In rats maintained on a high-fat, sweetened diet and given saccharin-sweetened yogurt diets, AUC calculated over the first 16 min for blood glucose was significantly higher following consumption of 5 ml of a 20% glucose solution compared to animals given glucose-sweetened yogurt diets (A), AUC for GLP-1 was significantly lower in animals given saccharin-sweetened yogurts (B) and there were no differences in AUC for Insulin between groups (C). * p < 0.05 compared to Glucose group