Early changes in exosomal microRNAs after a one-week low-calorie diet predict sustained glycaemic and weight outcomes in patients with type 2 diabetes

<i>Background</i>: Exosomal microRNAs (miRNAs) are key regulators of type 2 diabetes (T2D), yet their rapid response to caloric restriction remains undefined. <i>Objective</i>: To characterise plasma exosomal miRNA changes after one week of a low-calorie diet (LCD) in adults with T2D and determine whether these early shifts predict weight and glycaemic outcomes at 12 and 24 weeks. <i>Methods</i>: Sixteen adults with T2D consumed 820-840 kcal day^-1 for seven days. Plasma exosomes collected at baseline and day 7 underwent small-RNA sequencing. Differential expression was set at |log₂ fold change| > 1 with <i>P</i> < 0.05 (DESeq2). Target-gene enrichment, correlations with clinical biomarkers, and linear models relating week-1 miRNA changes to body-weight and glycaemic indices at follow-up were performed. <i>Results</i>: Participants lost 3.2 ± 0.9 kg in the first week (<i>P</i> < 0.001). Thirty-two miRNAs were differentially expressed: miR-122-5p, miR-3158-3p and miR-483-5p were down-regulated, whereas miR-126-5p and miR-454-3p were up-regulated. Target genes were enriched in PI3K-Akt, FoxO and endocrine-resistance pathways. Early rises in miR-1268a and miR-6770-3p correlated with interleukin-6 and tumour necrosis factor-<i>α</i>. An increase in miR-494-3p predicted larger HbA1c reductions at 12 weeks (<i>β</i> = -0.47; 95% CI: -0.67 to -0.21) and 24 weeks (<i>β</i> = -0.50; 95% CI: -0.76 to -0.18). Conversely, greater miR-362-5p elevations at week 1 were associated with smaller weight loss. <i>Conclusions</i>: A single week of LCD induces swift, pathway-linked shifts in plasma exosomal miRNAs in T2D. miR-494-3p and miR-362-5p emerge as promising early biomarkers for long-term glycaemic improvement and weight reduction, respectively.