Weight Loss Thread

AS & Blood Glucose Regulation

The main hypothesis here is that the sweet perception alters glycemic and insulin responses, and sweet receptors in the gut are activated in response to AS, increasing glucose uptake. In relation to the former, a trial in morbidly obese subjects but with normal insulin sensitivity [assessed by HOMA-IR] found greater peak plasma glucose levels and insulin response to a 75g oral glucose tolerance test [OGTT] 10-mins after a pre-load with 48mg of the AS sucralose [33]. This study has challenged prior research looking at sucralose, which was considered to have no impact on carbohydrate metabolism in multiple studies looking at glycemic responses [34].


It is difficult to reconcile the current literature in relation to glycemic or insulin responses from sucralose. In the SCF review of sucralose safety, a 6-month study in Type-2 diabetics found a consistent increase above baseline in HbA1c, a marker of long-term glycemic control, in subjects given 667mg sucralose daily. However, this occurred in the absence of impacts on any other markers of glucose regulation, including insulin or blood glucose levels [35]. The SCF review ultimately concluded that as the amounts administered were greater than consumption levels even in high consumers, any effect would be so small as to be clinically insignificant [35]. In the trial finding greater peak plasma glucose and insulin responses to an OGTT, the responses still remained within normal range for OGTT and amounted to nominal differences between sucralose group and controls [36]. The inconsistencies in the literature are synopsized by trials in sucralose: one study reported higher blood glucose levels, one study found lower blood glucose levels, and nine studies found no changes [36].


A recent systematic review of 28 trials of aspartame, sucralose, saccharin, and acesulfame-K confirmed the inconsistencies evident in the literature: some trials have found effects of AS on glucose metabolism while many have not found any interaction, and the significant heterogeneity between subjects, AS used, placebo, and outcome variables, limits comparisons [36]. Another issue is the comparison of AS to placebo, where arguably the appropriate trial design is a comparison with a caloric sweetener [3]. This is because, assuming AS do act to stimulate glucose uptake, this would occur in the context of low gut concentrations of glucose, while a caloric sweetener like sucrose would result in a greater amount of glucose absorbed [37]. This may explain why, in trials using OGTT, the observed differences in absorption are largely nominal [38].


Another issue is that the research in relation to the second limb of the hypothesis, the underlying mechanism of activating glucose transporters in the gut, is as inconsistent as the effects on blood glucose and/or insulin itself. One proposed mechanism is activation of glucagon-like peptide-1 [GLP-1], which has been assessed in 11 studies included in a systematic review: aspartame has been found to lower GLP-1, sucralose and acesulfame-K to increase GLP-1 concentrations [36]. Again, this is not consistent: a trial administering 72mg aspartame and 24mg sucralose or water before a 75g OGTT found no effect of either AS on GLP-1, insulin or glucose in Type-2 diabetics, although healthy subjects had a significantly higher GLP-1 area-under-the-curve from sucralose, but not aspartame [39].


An example of the noted limitations of trial design and resulting findings is evident in two trials. The first used diet soda as an intervention in healthy humans, with a beverage containing 46mg sucralose plus 26mg acesulfame-K, and found GLP-1 increased in response to OGTT compared to water [40]. However, the trial failed to control for compounds in the diet soda – including citric acid, potassium benzoate, phosphoric acid, potassium citrate, natural flavorings and colorings – which may have influenced the results [40]. Consequently, a subsequent trial administered 52mg sucralose, 200mg acesulfame-K, or 46mg sucralose plus 26mg acesulfame-K to healthy subjects, and found no effect of either treatment on GLP-1, blood glucose, or insulin concentrations (41). This is consistent with a trial showing no effect of sucralose administered through intraduodenal glucose feeding on GLP-1 or glucose uptake [42]. Taken as a whole, there are a number of trials that show some effect of AS on GLP-1 and glycemic response [39][40], while other studies [41][42] and a systematic review of 11 studies measuring GLP-1 [37] suggest that the majority of human studies have found no effect of AS on intestinal sweet taste receptors and glucose uptake. The biological basis for the limited studies finding such effect in humans remains unexplained [37].


A criticism of this area has been that, based on in vitro and animal model studies, many authors have reached outside the data to make speculative assumptions on the consequences of sweet-taste receptor activation on glucose regulation [37]. While potential mechanisms have been elucidated in vitro and in animal models, with limited supporting human data, the question begs: are the nominal effects of any clinical relevance? The overall body of evidence for a direct effect of AS on glycemic control is limited [3]. It would be an overreach on the basis of the evidence to say that AS influence blood glucose, insulin, and/or GLP-1 in humans; it would equally be an overreach to say they are biologically inert.