Nutritional systems biology of type 2 diabetes

Abstract

Type 2 diabetes (T2D) has become an increasingly challenging health burden due to its high morbidity, mortality, and heightened prevalence worldwide. Although dietary and nutritional imbalances have long been recognized as key risk factors for T2D, the underlying mechanisms remain unclear. The advent of nutritional systems biology, a field that aims to elucidate the interactions between dietary nutrients and endogenous molecular entities in disease-related tissues, offers unique opportunities to unravel the complex mechanisms underlying the health-modifying capacities of nutritional molecules. The recent revolutionary advances in omics technologies have particularly empowered this incipient field. In this review, we discuss the applications of multi-omics approaches toward a systems-level understanding of how dietary patterns and particular nutrients modulate the risk of T2D. We focus on nutritional studies utilizing transcriptomics, epigenomomics, proteomics, metabolomics, and microbiomics, and integration of diverse omics technologies. We also summarize the potential molecular mechanisms through which nutritional imbalances contribute to T2D pathogenesis based on these studies. Finally, we discuss the remaining challenges of nutritional systems biology and how the field can be optimized to further our understanding of T2D and guide disease management via nutritional interventions.

Fig. 1

Nutritional factors and omics technologies used in nutritional systems biology

Fig. 2

Potential mechanisms underlying high-fat-diet-induced diabetes based on recent nutritional systems biology studies. High-fat diet can affect metabolites (left branch), microbiota (middle), and NAD⁺/NADH ratio (right). Left branch: The perturbed metabolites may affect methyl donors such as cysteine, methionine, SAM, and SAH, leading to changes in DNA methylation. Altered DNA methylation regulates gene expression through multiple mechanisms, such as promoter and gene body methylation. Middle branch: Butyrate-producing bacteria have been found to be decreased in gut microbiota, leading to lower levels of short-chain fatty acids (SCFAs) such as butyrate, which could modulate histone deacetylase (HDAC) activities to induce histone modifications and chromatin structural changes. Epigenomic changes may directly alter transcriptional activities or indirectly by reshaping the circadian rhythm including impaired CLOCK/BMAL1 recruitment to chromatin and induction of PPAR-γ recruitment. Right branch: Decreased NAD⁺/NADH ratio by HFD can switch off AMPK and SIRT1 signaling, leading to downregulation of PGC-1 and subsequent mitochondria dysfunction. The upstream regulatory mechanisms depicted from all three branches will trigger in perturbations of various biological processes such as lipid metabolism, Krebs cycle, fatty acid synthesis, oxidative phosphorylation, cell cycle, and inflammatory responses that lead to insulin resistance and compromised β cell functions that are primary features of T2D