Short-Term Consumption of Sucralose with, but Not without, Carbohydrate Impairs Neural and Metabolic Sensitivity to Sugar in Humans

Abstract

There is a general consensus that overconsumption of sugar-sweetened beverages contributes to the prevalence of obesity and related comorbidities such as type 2 diabetes (T2D). Whether a similar relationship exists for no- or low-calorie "diet" drinks is a subject of intensive debate and controversy. Here, we demonstrate that consuming seven sucralose-sweetened beverages with, but not without, a carbohydrate over 10 days decreases insulin sensitivity in healthy human participants, an effect that correlates with reductions in midbrain, insular, and cingulate responses to sweet, but not sour, salty, or savory, taste as assessed with fMRI. Taste perception was unaltered and consuming the carbohydrate alone had no effect. These findings indicate that consumption of sucralose in the presence of a carbohydrate rapidly impairs glucose metabolism and results in longer-term decreases in brain, but not perceptual sensitivity to sweet taste, suggesting dysregulation of gut-brain control of glucose metabolism.

Keywords: diabetes; fMRI; glucose tolerance; indirect calorimetry; insula; low-calorie sweetener; midbrain; obesity; taste perception.

Figure 1:. Human Study overview.

Participants visited the lab 13 times. Measurements were divided into pre-exposure measurements, exposure sessions and post-exposure measurements. NQ: Nutrition Questionnaire; M-STP: Monell forced-choice Sweet Taste Preference test; TLFB: time line follow back; fMRI: functional magnetic resonance imaging; OGTT: Oral Glucose Tolerance Test. See STAR Methods for more details.

Figure 2.. Changes in insulin sensitivity.

(A) Oral Glucose Tolerance Test (OGTT) blood plasma glucose (top row) and insulin (bottom row) for the pre and post beverage exposure measurements in young adults. (B) Relative change in first phase (i.e., 0-30 min) OGTT plasma insulin incremental area under the curve, iAUC_0-30, (left) and OGTT plasma insulin iAUC_0-120 (right) from pre to post beverage exposure and in young adults. Post beverage exposure, iAUC_0-30 insulin was significantly elevated in the Combo group compared to the sugar and LCS groups (false discovery rate corrected t tests; both P=0.03). For iAUC_0-120 insulin, change differed between the LCS and Combo groups (t(1,36)= 3.63, p(fdr)=0.003). (C) Change in plasma insulin plotted per individual in the adolescents study. The adolescent study was terminated because two participants in the Combo group showed highly elevated insulin (and HOMA-IR) levels post beverage exposure. Permutation testing (n=1000) indicated that the difference scores of this group are significantly different from the sucrose and sucralose groups together (p=0.043). Although this result is in line with the results from the adults study, it should be interpreted with care due to the low number of subjects. (D) An extra control group was recruited to rule out that maltodextrin, rather than the combination, leads to changes in insulin sensitivity. Results show no change in first phase OGTT plasma insulin iAUC_0-30 nor in plasma insulin iAUC_0-120 from pre to post beverage exposure in young adults.

Figure 3.. Changes in brain response to sweet taste in human young adults

Relative change in plasma insulin iAUC_0-30m from pre to post beverage exposure was significantly related to fMRI BOLD change in the young adults Combo group during sucrose ingestion. The relation indicates that percent increase in blood insulin is negatively associated with fMRI BOLD responses to tasting sugar in the anterior cingulate, left anterior insula, right substantia nigra/ventral tegmental area (VTA), and right middle insula. All reported clusters are corrected for a cluster-wise FWE correction threshold of P<0.05. Multiple coronal, sagittal and axial brain slices are shown at highlighted MNI stereotaxic coordinates. Activation color maps are thresholded at p<0.001 (unc.) for visual purposes and based on T-values associated with the negative linear relationship between fMRI BOLD and relative change in plasma insulin iAUC_0-30m. Correlational graphs of this relationship are shown for peak voxels in the highlighted areas for the Combo group (blue), and for the sucralose and sucrose groups (grey).