(Poly)phenols and diabetes: From effects to mechanisms by systematic multigenomic analysis.

Diabetes is a chronic and multifactorial metabolic disease with increasing numbers of patients worldwide, characterized by loss of pancreatic β-cell mass and function with subsequent insulin deficiency. Thus, restoring functional β-cells could significantly impact disease management. The beneficial effects of natural compounds, namely (poly)phenols, in diabetes have gained increasing interest, due to their pleiotropic actions in several cellular processes, including in glucose homeostasis. These compounds are able to modulate nutri(epi)genomic mechanisms by interacting with cell signaling proteins and transcription factors (TFs). However, the underlying mechanisms of action, particularly of (poly)phenol metabolites resulting from digestion and colonic microbiota action, are yet to be elucidated. This study explored the multigenomic effects of (poly)phenols and their metabolites to uncover modulatory networks and mechanisms linked to diabetes. Published studies on gene expression alterations modulated by (poly)phenolic compounds or (poly)phenol-rich extracts were integrated, encompassing studies conducted on individuals with diabetes, animal models mimicking diabetes, and pancreatic β-cell lines. Bioinformatic analysis identified differentially expressed genes and potential regulatory factors, with roles in cell signaling pathways (FoxO, AMPK, p53), endocrine resistance, immune system pathways, apoptosis, and cellular senescence. Interestingly, in silico 3D docking analyses revealed potential interactions between key TFs (FOXO1, PPARG, SIRT1, and MAFA) and some metabolites. Apigenin, luteolin, and naringenin glucuronide forms showed the best binding capacity to SIRT1. The integrative analysis of (poly)phenol metabolites data highlights the potential of these molecules for nutraceutical/pharmaceutical development aimed at managing diabetes whose incidence increases with age.
Competing Interests: Declaration of Competing Interest This research was funded by national funds through FCT—Foundation for Science and Technology, I.P. (Portugal), under the [DOI 10.54499/UIDB/04567/2020] and [DOI 10.54499/UIDP/04567/2020] projects. R.M. is funded by the FCT Scientific Employment Stimulus contract [DOI: 10.54499/CEECINST/00002/2021/CP2788/CT0004] and A.G. by the FCT Scientific Employment Stimulus contract. M.I.F. is funded by the FCT PhD grant 2023.01737.BDANA and received a Fulbright Research Award 23/24.
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