Non-Sugar Sweeteners and Glycemic Regulation: Controlled Feeding Trials in Middle-Aged and Older Adults with Prediabetes

Abstract

Type 2 diabetes (T2D) and prediabetes represent a major share of the overall metabolic disease burden across the globe. Middle-aged and older adults, who account for over a third of those with T2D, with nearly half having prediabetes, are at increased risk of glucose intolerance and insulin resistance and are among the highest consumers of widely used non-sugar sweeteners (NSS). NSS are often recommended as healthier alternatives to traditional sugar, yet the understanding of their effects remains limited due to mixed results and a lack of rigorous study designs. To overcome the limitations of the currently available research, two separate three-arm randomized controlled feeding trials were conducted to isolate glycemic responses for four distinct NSS types. Adults (≥40 years) with prediabetes followed a standardized eucaloric diet for a 2-week lead-in period, followed by a 4-week randomized intervention period (trial 1: sucralose, aspartame, or control; trial 2: acesulfame potassium [Ace-K], saccharin, or control). NSS doses were individualized to body weight, using 25% of the acceptable daily intake (NSS mg/kg body weight). All intervention arms received identical diets matched to usual U.S. intake, except for NSS dosing, delivered via a study beverage and capsules. Outcomes, including 24-hr glycemic control (continuous glucose monitoring, CGM), glucose tolerance (2-hour oral glucose tolerance test, OGTT), and insulin sensitivity, were assessed pre- and post-intervention. The results from these pilot studies indicate no significant differences in glycemic control or insulin sensitivity among the four NSS types and the control group over the 4-week intervention in middle-aged and older adults with prediabetes. CGM-derived area under the curve (AUC, mg·h/dL) did not differ significantly between sweetener type and control groups in either trial, with no differences observed for aspartame vs control (Δ = +2.12 ± 11.6 vs +1.56 ± 8.0; p = 0.973), sucralose vs control (Δ = +1.62 ± 10.5 vs +1.56 ± 8.0; p = 0.935), Ace-K vs control (Δ = +1.8 ± 10.9 vs +2.3 ± 11.4; p = 0.972), or saccharin vs control (Δ = +1.2 ± 4.6 vs +2.3 ± 11.4; p = 0.870), indicating no effect of NSS consumption on overall glycemic exposure under free-living conditions. Further research is warranted to address longer-term effects, diverse populations, and explore mechanistic pathways to clarify the effects of NSS across settings.