Abstract 10659: Blood DNA Methylation at TXNIP and Glycemic Changes in Response to Weight-Loss Diet Interventions: The POUNDS Lost Trial

Abstract

Introduction: Thioredoxin Interacting Protein ( TXNIP ) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5'-cytosine-phosphate-guanine-3' (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes; however, little is known about whether the DNAm level at TXNIP in blood is associated with glycemic changes in response to weight-loss diet interventions. Hypothesis: We hypothesized that participants with varying DNAm level of TXNIP responded differentially to weight-loss diet interventions on glycemic changes. Method: We included 639 overweight and obese participants from Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, who were randomly assigned to 1 of 4 weight-loss diets varying in macronutrient contents. Blood DNAm levels were profiled by a high-resolution methylC-capture sequencing at baseline. We defined regional methylation level of TXNIP as average methylation level over CpGs within 500 bp of cg19693031. Results: Higher regional methylation level at TXNIP was correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (p<0.05 for all). Participants with distinct regional methylation level of TXNIP showed significantly different changes in fasting insulin (p-interaction=0.007) and HOMA-IR (p-interaction=0.009) in response to average- vs. high-protein diet intervention at 6 months, independent of weight loss. Among participants with an average-protein diet, higher regional methylation level at TXNIP was associated with a greater reduction of fasting insulin and HOMA-IR at 6 months, while an opposite association was found among those with a high-protein diet. Such difference was attenuated to be nonsignificant at 2 years. Conclusions: DNAm level at TXNIP in blood may modify the effects of diet interventions on changes in glycemic traits, independent of weight loss. Overweight and obese individuals with higher methylation level at TXNIP may benefit more in improving insulin and HOMA-IR by consuming an average-protein diet than a high-protein diet.