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Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial

International Journal of Obesity volume 46, pages 1122–1127 (2022)Cite this article

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Abstract

Background

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. We hypothesize that baseline DNAm level at TXNIP in blood may be associated with glycemic traits and their changes in response to weight-loss diet interventions.

Methods

We included 639 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss diet intervention. Baseline blood DNAm levels were profiled by high-resolution methylC-capture sequencing. We defined the regional DNAm level of TXNIP as the average methylation level over CpGs within 500 bp of cg19693031. Generalized linear regression models were used for main analyses.

Results

We found that higher regional DNAm at TXNIP was significantly correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (P < 0.05 for all). Significant interactions were observed between dietary protein intake and DNAm on changes in insulin (P-interaction = 0.007) and HOMA-IR (P-interaction = 0.009) at 6 months. In participants with the highest tertile of regional DNAm at TXNIP, average protein (15%) intake was associated with a greater reduction in insulin (β: −0.14; 95% CI: −0.24, -0.03; P = 0.011) and HOMA-IR (β: −0.15; 95% CI: −0.26, −0.03; P = 0.014) than high protein (25%) intake, whereas no significant associations were found in those with the lower tertiles (P > 0.05). The interaction was attenuated to be non-significant at 2 years, presumably related to decreasing adherence to the diet intervention.

Conclusions

Our data indicate that higher regional DNAm level at TXNIP was significantly associated with better fasting glucose, HbA1c, and HOMA-IR; and people with higher regional DNAm levels benefited more in insulin and HOMA-IR improvement by taking the average-protein weight-loss diet.

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Fig. 1: Association of blood regional DNAm level at TXNIP with baseline fasting glucose, HbA1c, and HOMA-IR.
Fig. 2: Changes in fasting insulin and HOMA-IR from baseline to 6 months according to tertiles of regional DNAm level around TXNIP in average- and high-protein diet groups.

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Acknowledgements

The authors thank all the POUNDS Lost participants for their dedication and contribution to the research. The study was supported by grants from the National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024), the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383), the Fogarty International Center (TW010790), and Tulane Research Centers of Excellence Awards. Xiang Li was the recipient of the American Heart Association Predoctoral Fellowship Award (19PRE34380036).

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Authors and Affiliations

  1. Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA

    Xiang Li, Lydia A. Bazzano, Qiaochu Xue & Lu Qi

  2. Digital Technologies Research Centre, National Research Council Canada, Ottawa, ON, Canada

    Xiaojian Shao

  3. Department of Pediatrics, Genomic Medicine Center, Children’s Mercy Kansas City, Kansas City, MO, USA

    Boryana S. Koseva & Elin Grundberg

  4. Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    Iris Shai

  5. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA

    George A. Bray

  6. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Frank M. Sacks & Lu Qi

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  1. Xiang Li
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Contributions

XL contributed to the study concept and design, analysis, and interpretation of the data, drafting and revising the manuscript. XS contributed to the statistical analysis with critical input. XS, QX, LAB, BSK, EG, and IS contributed to the interpretation of data, critical revision of the manuscript for important intellectual content. GAB and FMS contributed to the interpretation of data, critical revision of the manuscript for important intellectual content, and supervision. LQ contributed to the study concept and design, acquisition of the data, analysis, and interpretation of the data, and funding and study supervision. LQ is the guarantor and takes responsibility for the integrity of the data and the accuracy of the data analyses.

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Correspondence to Lu Qi.

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Li, X., Shao, X., Bazzano, L.A. et al. Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial. Int J Obes 46, 1122–1127 (2022). https://doi.org/10.1038/s41366-022-01084-5

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