Glycemic Impact of Non-Nutritive Sweeteners in Health and Type 2 Diabetes

Foods and beverages sweetened with non-nutritive sweeteners (NNSs) are increasingly common in modern diets and widely promoted as healthy alternatives to their sugar-sweetened counterparts, with attendant benefits for individuals with preclinical or clinical metabolic disease. Despite this position, the evidence base supporting the purported health benefits of NNSs is limited and equivocal, particularly in individuals with type 2 diabetes. This review discusses the metabolic effects of NNSs from the standpoint of epidemiological studies and focuses on evidence from the hitherto limited number of prospective clinical trials, as well as potential modes of interaction. Non-nutritive sweeteners are capable of binding to sweet taste receptors (STRs, a heterodimer of T1R2-T1R3) in a wide variety of tissues, including the tongue, pancreas, and small intestine. In cellular, tissue and preclinical models, the binding of NNSs to intestinal STRs triggers the release of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which, in turn, evoke pancreatic insulin release. Sweet taste receptor activation also triggers release of the intestinotrophic peptide, glucagon-like peptide 2 (GLP-2), which augments the expression and function of the primary apical glucose transporter in the intestine, sodium-glucose co-transporter-1 (SGLT-1). In addition, the NNSs saccharin and sucralose disrupt the composition of the gut microbiome in both pre-clinical and clinical settings in health, and do so in a manner that is individualized and causally related to glucose intolerance. Correspondingly, NNSs have the potential to impact metabolic outcomes directly via host-mediated pathways, as well as secondary to changes in the hosted microbiota. To date, most clinical trials have focused on the acute or subacute effects of NNSs on gut hormone release, glycemic control, and weight management. There is now broad recognition that longer-term, prospective randomized clinical trials are required to add mechanistic insight into how NNSs impact glycemic control in health and in type 2 diabetes.