Summary
A study integrating metabolomic, genomic, and lifestyle data identified 235 circulating metabolites linked to future type 2 diabetes risk, revealing genetic and lifestyle influences and proposing a 44-metabolite signature to enhance risk prediction; a separate retrospective cohort study found that pediatric heart transplant recipients of COVID-19–positive donor hearts had higher mortality at two and three years, especially with donor-recipient size mismatch, suggesting cautious use of such donors in pediatric transplants.
Editor: Deborah Sesok-Pizzini, MD, MBA, adjunct professor, Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Circulating metabolites, genetics, and lifestyle factors in relation to future risk of type 2 diabetes
April 2026—Diabetes affects 589 million adults worldwide and is expected to increase to more than 853 million adults affected by 2050. Type 2 diabetes (T2D) accounts for 90 percent of all diabetic cases, and its pathogenesis involves genetics, diet, and lifestyle risk factors. T2D is a highly complex disease that manifests as insulin resistance, β-cell dysfunction, and hyperglycemia. These metabolic dysfunctions affect many organ symptoms. The metabolites associated with T2D risk and their determinants are not well categorized. It is crucial to identify the molecular profile that characterizes the dysregulated metabolism contributing to the disease, as well as the genetic and environmental determinants of the T2D profile, to better understand T2D etiology. This may also help inform the design of more effective preventive strategies for targeting specific metabolic pathways. More than 100 circulating metabolites, the small molecules in the blood that provide information on the metabolic profile of each person, have been associated with T2D risk. These metabolites may be influenced by genetics, other health conditions, diet, and lifestyle. Therefore, it is necessary to integrate multimodal data into research to gain deeper insight into how various risk factors relate to metabolic profiles and to advance personalized prevention of T2D. The authors conducted a study in which they integrated multimodal data, including metabolomic, genomic, and lifestyle data, to better understand the genetic and nongenetic contributors to T2D metabolites. They examined 469 circulating metabolites in a pooled study of 23,634 initially T2D-free and racially- and ethnically-diverse people from 10 prospective cohorts. The authors sought to identify metabolites associated with incident T2D during up to 26 years of follow-up. They also conducted integrative analyses combining genomic data and diet and lifestyle risks to identify genetic determinants and the potential tissue origin of T2D-associated metabolites, as well as the relationship of diet and lifestyle factors. The authors also identified and validated a multimetabolite signature panel that represents the complex metabolic states that predict future T2D risk. During up to 26 years of follow-up, 4,000 incident T2D cases were identified. In a meta-analysis of the subsets, the authors identified 235 metabolites associated with incident T2D after adjusting for demographic, socioeconomic, and clinical factors, including body mass index and waist-hip ratio. These findings included 168 previously reported associations with T2D and 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle, arginine/proline, glycine, and histidine pathways. On further genetic analysis, these metabolites were linked to signaling pathways and clinical traits central to T2D, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation, and liver function. Of note, lifestyle factors, such as physical activity, obesity, and diet, explained greater variations in T2D-associated versus T2D-nonassociated metabolites. The authors concluded that a 44-metabolite signature improved T2D risk prediction beyond current standards. They stated that their metabolomic signature may be a powerful tool for future risk stratification and a monitoring tool to inform precision medicine T2D prevention and early intervention.
Li J, Hu J, Yun H, et al. Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes. Nat Med. 2026. doi.org/10.1038/s41591-025-04105-8
Correspondence: Dr. Jun Li at [email protected] or Dr. Qibin Qi at [email protected]