Short-Term Effects of Nonnutritive Sweetener (Sucralose and Saccharin) Consumption on Glycemic Control and Gut Microbiota in Patients With Type 2 Diabetes: Protocol for a Double-Blind, Randomized, Placebo-Controlled, Crossover Trial (Preprint)

<sec> <title>BACKGROUND</title> Nonnutritive sweeteners (NNSs) are widely used as sugar substitutes to help individuals with diabetes manage glycemic control. However, emerging evidence suggests that even low doses of NNSs, such as saccharin and sucralose, may adversely affect metabolic health by impairing glycemic regulation, potentially through alterations in the gut microbiota. In Malaysia, where gut microbiome research is still limited, particularly among individuals with type 2 diabetes mellitus (T2DM), further investigation is warranted to inform safe and evidence-based use of NNSs. </sec> <sec> <title>OBJECTIVE</title> This study aims to evaluate the short-term effects of saccharin and sucralose consumption on glycemic control and gut microbiota composition in adults with T2DM. </sec> <sec> <title>METHODS</title> This is a double-blind, randomized, placebo-controlled, crossover trial. A total of 33 adults with T2DM will consume sucralose (5 mg/kg body weight), saccharin (2 mg/kg body weight), or a placebo (calcium carbonate) in capsule form daily for 7 days per intervention arm, with a 4-week washout period. Data collection will include anthropometric measurements, biochemical assessments for glycemic control, dietary records, physical activity levels, and stool samples. The homeostatic model assessment for insulin resistance will be used to assess insulin sensitivity, while 16S rRNA V3-V4 region sequencing will be conducted to profile gut microbiota composition. </sec> <sec> <title>RESULTS</title> Recruitment is planned to begin in January 2026 and is expected to conclude by September 2026, with study completion anticipated by March 2027. As of December 2025, no participants have been enrolled. </sec> <sec> <title>CONCLUSIONS</title> This trial will contribute novel insights into the effects of short-term NNS consumption on glycemic control and gut microbiota composition in individuals with T2DM. These findings may support evidence-based recommendations for NNS use in diabetes management and enhance understanding of microbiome-diet interactions in an ethnically diverse Asian population. </sec> <sec> <title>CLINICALTRIAL</title> ClinicalTrials.gov NCT07124585; https://clinicaltrials.gov/study/NCT07124585 </sec> <sec> <title>INTERNATIONAL REGISTERED REPORT</title> PRR1-10.2196/82695 </sec>