AUTHOR=Madhu Sri Venkata , Mishra Brijesh Kumar , Mannar Velmurugan , Aslam Mohd , Banerjee Basudev , Agrawal Vivek 

TITLE=TCF7L2 gene associated postprandial triglyceride dysmetabolism- a novel mechanism for diabetes risk among Asian Indians

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.973718

DOI=10.3389/fendo.2022.973718

ISSN=1664-2392

ABSTRACT=<sec><title>Aim</title><p><italic>TCF7L2</italic> gene is believed to increase the risk of T2DM by its effects on insulin secretion. However, the exact mechanism of this enhanced risk is not clearly known. While <italic>TCF7L2</italic> gene has been shown to affect lipid metabolism, these effects have remained largely unexplored in the context of diabetes risk.</p></sec><sec><title>Methods</title><p>Postprandial lipid responses to a standardized fat challenge test were performed in 620 Asian Indian subjects (310 with NGT and 310 with T2DM/prediabetes) and compared between the risk and wild genotypes of the rs7903146 <italic>TCF7L2</italic> gene. In 30 subjects scheduled to undergo abdominal surgery (10 each with NGT, Prediabetes and T2DM), adipocyte <italic>TCF7L2</italic> gene expression was also performed by real time qPCR and confirmed by protein expression in western blot.</p></sec><sec><title>Results</title><p>T allele of rs7903146 <italic>TCF7L2</italic> gene was confirmed as the risk allele for <italic>T2DM</italic> (OR=1.8(1.2-2.74), p=0.005). TT+CT genotypes of rs7903146 <italic>TCF7L2</italic> gene showed significantly higher 4hrTg (p&lt;0.01), TgAUC (p&lt;0.01), peakTg (p&lt;0.01) as well as higher postprandial plasma glucose (p=.006) levels and HOMA-IR (p=0.03) and significantly lower adiponectin levels (p=0.02) as compared to CC genotype. The expression of <italic>TCF7L2</italic> gene in VAT was 11-fold higher in prediabetes group as compared to NGT (P&lt;0.01) and 5.7-fold higher in T2DM group as compared to NGT group(P=0.003) and was significantly associated with PPTg and glucose levels.</p></sec><sec><title>Conclusion</title><p>There is significant PPTg dysmetabolism associated with the risk allele of rs7903146 polymorphism as well as adipocyte expression of <italic>TCF7L2</italic> gene. Significant upregulation of TCF7L2 gene expression in VAT that correlates with PPTg and glycaemia is also seen in Asian Indians with glucose intolerance. Modulation of PPTg metabolism by <italic>TCF7L2</italic> gene and the resultant <italic>PPHTg</italic> may be a novel mechanism that contributes to its diabetes risk in them.</p></sec>