Epigenetic Signatures of Type 2 Diabetes Remission and Substantial Weight Loss: The Role of DNA Methylation in Response to Low-Calorie Diet Intervention.

Low-calorie diet (LCD) interventions can lead to remission of type 2 diabetes (T2D), but the underlying mechanisms are not well understood. As a diet-sensitive regulator of gene expression, DNA methylation may reveal pathways underlying remission. However, whether individuals with different responses to LCD-induced T2D remission and weight loss exhibit distinct DNA methylation patterns remains unclear. A 3-month intensive weight loss intervention (815-835 kcal/d) and a following 3-month weight loss maintenance phase were conducted among participants with T2D. DNA methylation was measured using the Infinium Methylation EPIC BeadChip (935K) at 4 timepoints. Differentially methylated cytosine-phosphate-guanine (CpG) sites and regions were analyzed to identify changes between those who achieved T2D remission and weight loss >12 kg and those who did not. Predictive models based on DNA methylation profiles at baseline and week 1 were developed to forecast individual responses to LCD. Seventeen individuals (mean age 36.8 [8.5] years, 29.4% women) were included, and 11 of them achieved T2D remission. Of the 784,965 CpG sites, the microarray identified 8 and 13 CpG sites differentially methylated for T2D remission and weight loss status, respectively, mapping to 9 gene regions, including PKFP, PON1, and SERINC5. Pathway analysis mapped these genes to glucose and lipid metabolism pathways. Methylation-inferred scores showed a greater improvement in predicting T2D remission and weight loss status following the LCD intervention than the base models (area under curve ranges: 0.86-0.88 vs. 0.73-0.80). Variation in DNA methylation profiles across individuals with differing responses to the LCD, highlighting the epigenetic roles in the effects of the LCD on weight loss and T2D remission. Baseline DNA methylation status may serve as a predictor of T2D remission in response to LCD intervention. This trial was registered at the https://clinicaltrials.gov/study/NCT05472272?cond=NCT05472272&rank=1 as NCT05472272.