Food Additive Mixtures, Glucose Metabolism, and Type 2 Diabetes Mellitus Risk: Mechanistic Insights from Epidemiology, Human Intervention Studies, and Experimental Models

Food additives are consumed as mixtures in ultra-processed foods, but their independent contribution to glucose dysregulation is difficult to separate from diet quality and food matrix. PubMed/MEDLINE, Embase, Web of Science Core Collection, Scopus, and CENTRAL were searched from inception to 30 April 2026, followed by a supplementary PubMed update on 26 July 2026. This critical narrative review integrates epidemiological, human-intervention, animal, ex vivo, and mechanistic evidence. Successive NutriNet-Santé analyses associate several additive co-exposure profiles, emulsifiers, preservatives, food colouring additives, and non-nutritive sweeteners with incident type 2 diabetes mellitus. However, these analyses use substantially overlapping participants, lack independent additive-specific cohort replication, and remain vulnerable to residual confounding. Experimental evidence is strongest for selected emulsifiers and sweeteners, which may alter gut microbiota, intestinal barrier function, inflammatory signalling, or short-term glycaemic responses. No human trial has demonstrated the complete pathway from additive exposure to clinically meaningful insulin resistance or diabetes, and null or compound-specific findings argue against a uniform class effect. Current evidence therefore supports biological plausibility, not causality or additive-specific clinical recommendations. Longer controlled feeding trials should test realistic mixtures while holding the food matrix constant and should incorporate exposure validation, repeated microbiome and metabolomic sampling, intestinal permeability measures, and validated insulin-sensitivity endpoints.