Experimental, Drug-free, Cross-sectional, Single-centre Study to Assess the Association Between Metabotypes of Dietary (poly)phenols and Beta-cell Mass and Function.

Chronic diseases, such as cardiovascular diseases (CVD) and cardiometabolic diseases (CMD), including type 2 diabetes (DT2), represent one of the most important public health problems. Lifestyle intervention can help prevent or delay the development of diabetes mellitus. In this regard, several nutritional guidelines have been developed to promote cardiovascular and metabolic health. These recommendations promote regular consumption of fruit and vegetables, whole grains, healthy sources of protein; foods that are particularly rich in polyphenols, with known health benefits. However, their application to improve cardiometabolic health is hampered by the heterogeneity of individual response to the consumption of dietary (poly)phenols. In an intervention study entitled 'Aggregate Metabolic Phenotypes for (Poly)Phenols: Development of an Oral (Poly)Phenol Challenge Test (OPCT)', the variability of the urinary concentration of phenolic metabolites among 300 volunteers after consumption of (poly)phenol-rich tablets was assessed and predictive algorithms were generated to identify and group individuals with similar metabolic/phenotypic profiles (metabotyping). The role of these specific metabotypes (MTs) on cardiometabolic health and, more specifically, on human pancreatic beta-cell function (BCF) and mass (BCM) of individuals remains to be explored. Identifying, in fact, an association between different MTs and a higher/lower BCM/BCF would allow to evaluate the potential risk of individuals to develop metabolic diseases, as well as to act with dietary interventions aimed at protecting and preventing possible damage to pancreatic beta-cells.

In this study "Food (poly)phenol Metabotypes and Beta-cell mass ad function" (META-BETA), we intend to address - specifically - the effects on a tissue fundamental for metabolic health, namely pancreatic beta-cells. To achieve this goal, the investigators intend to focus on the action of active molecules derived from food (poly)phenols, on the function and mass of pancreatic beta-cells. In order to take into account interindividual differences, they will also explore the effects of specific metabolites derived from (poly)phenols in beta-cells derived from individuals with opposite MTs and Disposition Index, previously identified in the OPCT study.

The project is divided into two parts:

1. Association study: the association between different MTs and disposition index was explored in 300 healthy adult subjects, previously enrolled in the OPCT study. In four paired subgroups (n=10), recruited in two opposite MTs and with maximum difference in disposition index, BCFxM will be evaluated with a mixed meal complete with all macronutrients in a balanced way. In addition, BCM will be measured with the PET-CT method (beta-cell specific radioligand, Ga-exendin-4). The ratio between BCFxM (MMTT) and BCM (PET-CT) will provide the in vivo BCF data. Furthermore, during a short interview, data on the lifestyle of the subjects in the study will be collected.
2. Cause-effect study: Induced pluripotent stem cells (iPSCs), derived from peripheral blood mononuclear cell (PBMCs), from 2 subjects matched for each MT, with different BCF and BCM, will be differentiated into beta-cells where the effects of polyphenol metabolites will be evaluated. Experiments will be conducted both in control conditions and in the presence of lipotoxicity induced by stearic acid (SA).

The primary objective of this study is therefore to identify specific metabotypes (MTs) that are associated with different pancreatic beta-cell mass and function (BCFxM).