Metabolomics links increased heme iron intake to increased insulin-independent type 2 diabetes risk

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.Aug 20 2024

In a recent study published in Nature Metabolism, researchers combine traditional clinical indicators with cutting-edge metabolomics data to investigate the processes underlying dietary heme iron consumption and the risk of type 2 diabetes (T2D).

Study: Integration of epidemiological and blood biomarker analysis links haem iron intake to increased type 2 diabetes risk. Image Credit: hIphoto / Shutterstock.com

The health effects of heme iron

Red meat exhibits a high concentration of heme iron. Therefore, the consumption of red meat can lead to excess iron stores, which increases oxidative stress within the body through the generation of reactive oxygen species (ROS). However, plant-based meat products are often supplemented with heme to improve their meat flavor and appearance, thereby increasing the potential health risks, including T2D, associated with these products as well.

It remains unclear how heme iron intake increases T2D risk. In an effort to elucidate the biological mechanisms involved in this association, the researchers of the current study utilized metabolomics data from three large prospective adult cohorts in the United States. High-throughput metabolomics profiling was selected due to its recent success in enabling researchers to explore the interrelationships between nutrition, metabolic processes, and disease consequences.

About the study

The current study included data on 204,615 individuals, 79% of whom were female. These individuals participated in the Nurses’ Health Study (NHS), NHS2, or the Health Professionals Follow-up Study (HPFS).

The study participants' T2D diagnosis was determined using the 1997 National Diabetes Data Group or 1998 American Diabetes Association criteria. Individuals with cardiovascular disease, diabetes, or cancer, as well as those with unusual energy intakes, were excluded from the study.

Dietary data were collected from food frequency questionnaires provided to the study participants every four years. Blood samples were also obtained and analyzed for serum metabolic biomarkers of 37,544 and metabolomic profiles of 9,024 individuals.

Liquid chromatography and mass spectrometry were utilized for serum metabolomic analyses to determine how iron consumption may impact serum metabolic markers involved in glycemia, insulinemia, and inflammation.

Mediation analyses were performed to estimate the proportion of T2D risk due to red meat intake and dietary patterns attributed to heme iron intake. Elastic net models were used to create a multi-metabolite score for insulin-independent diabetes risk prediction for participants followed until T2D diagnosis, death, or June 2020 (NHS), June 2019 (NHS2), or January 2020 (HPFS).

Multivariate linear regressions allowed the researchers to examine associations between iron consumption and serum metabolic markers, whereas Cox proportional hazard regression models were used to calculate hazard ratios (HRs). Subgroup analyses were stratified by age, sex, race, body mass index (BMI), waist-hip ratios, phytate intake, and post-menopausal health status.

Restricted cubic splines were used to evaluate the dose-response relationship between heme iron intake and insulin-independent diabetes risk. Sensitivity analyses were also performed to limit the sample size to individuals with conventional metabolic or metabolomic data and those selected as controls in previous studies. All study results were adjusted for waist circumference, neighborhood socioeconomic status, as well as animal protein, animal fat, fruits, vegetables, and whole grain intake.

Study findings

Throughout the 36-year study period, 20,705 new-onset T2D cases were identified. Heme iron intake, but not non-heme iron, was found to increase the risk of T2D with an HR of 1.3. Dose-response analyses showed linear associations between heme iron consumption and insulin-independent diabetes; however, the slope for T2D risk flattened at higher levels of intake.

A one-mg/day increment in heme iron consumption was associated with a 0.2-fold higher metabolomic score and significantly associated with unfavorable serum biomarker profiles. Higher metabolomic scores were related to elevated T2D risk, with an HR of 2.1.

Each mg/day increase in heme iron consumption increased C-peptide triacylglycerol (TAG) /high-density lipoprotein cholesterol (HDL-C) ratio, C-reactive protein (CRP) leptin, and ferritin by 6.3%, 6%, 10%, 8.5%, 10%, and 28%, respectively. The corresponding reductions due to increasing heme iron consumption by one mg/day reduced HDL-C, adiponectin, and transferrin receptor (TfR)/ferritin ratio by 3.7%, 5%, and 23%, respectively.

Significant associations were observed between total iron and higher serum ferritin levels. Moreover, positive correlations between heme iron intake and red meats, especially unprocessed meat products, and the Western diet were also observed.

Contrastingly, heme iron was negatively associated with diets limiting red meat intake, such as the healthful plant-based diet (hPDI), Dietary Approaches to Stop Hypertension (DASH), Alternate Healthy Eating Index (AHEI), and Alternate Mediterranean Diet Scores (AMED). Taken together, heme iron could mediate 66% of the relationship between dietary variables and insulin-independent diabetes risk.

Heme iron intake correlated with unfavorable serum profiles of lipids, insulinemia, inflammation, and T2D-related metabolites. Uric acid, l-valine, l-alanine, l-tyrosine, C5 carnitine, and glycerolipids like diacylglycerols TAGs were found to mediate the heme iron-T2D association. Sensitivity and subgroup analyses showed similar results but stronger associations for individuals with lower BMIs.

Conclusions

Increased heme iron consumption is associated with an increased risk of T2D, with unprocessed red meat accounting for more than half of the risk and making up a moderate fraction of T2D-related dietary patterns. Serum metabolic and metabolomic indicators support the association.

The study findings have public health implications for reducing daily consumption of foods high in heme iron, particularly red meat and raising awareness of the potential health effects associated with incorporating plant-derived heme into plant-based meat substitutes. These results may also support the development of early preventative methods and individualized dietary recommendations.