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Published on: August 29, 2022
Adipose Tissue Transferrin and Insulin Resistance
Donald A McClain1,2, Neeraj K Sharma1, Shalini Jain1
1Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Excessive body iron is linked to insulin resistance. Genetic regulation of transferrin (TF) in fat tissue impacts insulin sensitivity, revealing a new role for iron metabolism in diabetes development.
Area of Science:
- Metabolic Research
- Genetics
- Endocrinology
Background:
- Excess body iron stores are a known risk factor for diminished insulin sensitivity (SI) and type 2 diabetes.
- Transcriptional dysregulation of iron metabolism genes in adipocytes is hypothesized to contribute to insulin resistance.
Purpose of the Study:
- To investigate the genetic regulation of iron metabolism and its direct role in insulin sensitivity.
- To identify specific genes and genetic variants influencing iron homeostasis and SI.
Main Methods:
- Utilized gene expression, genotype, and SI data from an African American cohort (N=256) with replication in European ancestry cohorts.
- Conducted in vitro studies using human adipocytes to determine the functional role of a key gene in insulin resistance.
- Analyzed correlations between 62 iron homeostasis gene transcripts and SI in adipose tissue.
Main Results:
- Expression of 30 iron homeostasis genes in adipose tissue correlated with SI; transferrin (TF) and ferritin showed significant associations.
- A strong cis-regulatory variant for TF expression (rs6785596) was identified in adipose tissue and replicated across cohorts.
- TF knockdown in adipocytes reduced intracellular iron, impaired insulin-stimulated glucose uptake, and altered expression of 465 genes involved in glucose transport and metabolic pathways.
Conclusions:
- Genetic regulation of transferrin (TF) expression in adipose tissue represents a novel mechanism influencing insulin sensitivity.
- Findings highlight the critical role of adipose tissue iron metabolism in the development of insulin resistance and diabetes.
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