Revisiting the Link Between Meat Intake and the Risk of Type 2 Diabetes in American Indians: Insights Based on Lipidomic Profiles

Type 2 diabetes is a burgeoning health crisis, affecting more than 500 million people worldwide (1). More alarmingly, the majority have developed complications when diagnosis is made (2). The epidemiology of type 2 diabetes differs among various racial and ethnic populations (3). In the U.S., prevalence of type 2 diabetes is highest among American Indians and is more than twice that among non-Hispanic Whites (4). Given the daunting diabetes disparities that American Indians face, effective intervention strategies are urgently needed to curb the high burden of type 2 diabetes in this population. The role of diet as one of the key modifiable factors in determining the risk of type 2 diabetes has been well established (5). Accumulating evidence from both large prospective studies and meta-analyses demonstrated positive associations of high consumption of processed meat and unprocessed red meat with risk of type 2 diabetes (6–9). Red meat contains heme iron and saturated fat, while meat processing can produce harmful chemicals like nitrates and advanced glycation end products, all of which were related to reduced insulin sensitivity, pancreatic β-cell function, or both and thereby were associated with increased risk of type 2 diabetes (10–12). However, the biological mechanisms that link processed and red meat intake with altered glucose hemostasis are not yet fully characterized. Further, data among minority populations, especially Indian Americans, remain limited.

With the advancement of omics technology, lipidomics has emerged as a powerful tool in nutritional epidemiology for its capacity to identify reliable biomarkers of dietary exposures, primarily lipid molecules. In previous studies investigators have explored markers of habitual red meat and/or processed meat intake using a lipidomics approach (13–15). Meanwhile, abnormal lipid metabolism is implicated in the etiology of type 2 diabetes, and lipidomic profiles associated with type 2 diabetes and β-cell function have been demonstrated (16,17). Nevertheless, whether lipidomic changes play a role in the association between meat intake (e.g., unprocessed red meat and processed meat) and type 2 diabetes remains unclear. Determining the lipidomic signatures of meat intake in relation to risk of type 2 diabetes may provide mechanistic insights into the epidemiological observations and inform tailored dietary recommendations, particularly for the high-risk populations.

Reported in this issue of Diabetes Care, Wen et al. (18) examined lipidomic markers of habitual unprocessed red meat and processed meat intake and further evaluated their associations with incident type 2 diabetes among 1,816 American Indian participants (mean age 40 years, 63% female) in the Strong Heart Family Study. The authors report several significant findings. Of the 1,542 plasma lipids (518 known) quantified based on untargeted liquid chromatography–mass spectrometry, 29 lipids (15 known), mostly plasmalogens, were associated with red meat intake, while 14 lipids (8 known), mainly sphingomyelins, were related to processed meat consumption. None of the lipids overlapped for unprocessed red and processed meat intake. During a follow-up of ∼5 years, 3 of the 15 red meat–related lipids [phosphatidylcholine PC(p-36:3)/PC(o-36:4), phosphatidylethanolamine PE(p-38:5)/PE(o-38:6) A, and PE(p-38:5)/PE(o-38:6) B] and 2 of the 8 processed meat–related lipids [sphingomyelin SM(d42:2) and SM(d42:2) A] were associated with higher risk of type 2 diabetes, independent of conventional risk factors (Fig. 1). In longitudinal analysis with repeated measurements, 20 meat-related lipids were linked to altered fasting glucose or insulin metrics, among which 11 lipids, including the 3 red meat–related lipids that were associated with type 2 diabetes risk, significantly mediated the positive association between unprocessed red or processed meat intake and fasting glucose levels, with the mediation percentage ranging from 9.7% to 22.7% (Fig. 1).

Figure 1.

Lipidomic markers of processed meat and unprocessed red meat intake in relation to risk of type 2 diabetes in American Indians. A total of 1,542 plasma lipids (518 known) were quantified using untargeted liquid chromatography–mass spectrometry.

This work is informative and presents several notable strengths. The study was conducted in American Indians and renders valuable evidence to inform targeted nutritional strategies tailored to this minority population. Extensive coverage of the blood lipidome was achieved through quantification of >1,500 lipid species across 14 classes. Comprehensive lipidomic profiling enhances the likelihood of detecting new lipid biomarkers associated with meat intake that have not previously been reported. The longitudinal analyses of lipidomic markers and glucose/insulin homeostasis metrics not only reinforce the primary findings on type 2 diabetes but also help shed light on the potential pathways underlying the association between meat intake–related lipids and increased diabetes risk.

There are several limitations within the study as well. Since meat cooking methods (e.g., broiling, barbequing, roasting) might differentially modulate diabetes risk linked with meat consumption (19), whether meat cooking methods and doneness preferences are related to diabetes risk beyond the effect of meat intake deserves further exploration. The relatively small sample size and short follow-up duration resulted in limited cases of incident diabetes, which reduced the statistical power to obtain accurate estimates, potentially accounting for the nonsignificant association between meat intake and diabetes risk. Furthermore, meat intake and related lipidomic markers were quantified through cross-sectional analyses at baseline, and whether lipid profiles altered as a result of meat intake was uncertain. The temporal relationship requires validation through repeated-measures, longitudinal studies. It is noteworthy that residual confounding from dietary factors may be possible in this study. Unprocessed red and processed meat are often consumed with other unhealthy dietary items, such as french fries, refined grains, and sugar-sweetened beverages (20). The possibility that detected lipids and increased diabetes risk more actually reflect other dietary factors coexisting with meat intake rather than meat intake per se could not be ruled out (21,22). Lastly, some of the detected lipids were unknown compounds—potentially exciting findings, even though their chemical structure and biological function remain to be determined. Future studies to follow up these are warranted.

Overall, this study represents an important step toward understanding how meat intakes are associated with risk of type 2 diabetes in American Indians. The identification of mediating lipidomic markers adds mechanistic insights to the observed associations of red and processed meat intake with type 2 diabetes and paves the way for tailored dietary interventions for populations at risk. For further clarification of the mechanisms involved, investigations are warranted on which compounds in processed meat intake may explain the lipidomic changes. Future studies shall also include consideration of the impact of cooking methods. In recognizing the intricate regulatory networks that underpin the diet-disease relationship, integration of lipidomics with other omics technologies may enable a deeper understanding of the biological response to meat intake and its association with diabetes risk.