Food (poly)phenol metabotypes and beta-cell mass and function

Food (poly)phenol intake is associated to a reduced risk of cardiometabolic diseases, including type 2 diabetes (T2D). The underlying mechanisms remain largely unknown. Some (poly)phenols may act directly on β-cells (bC)– which are key to maintain glucose (G) homeostasis - but no mechanistical studies exist in human β-cells/islets. Furthermore, distinct metabolic phenotypes (metabotypes, MT) of the response to (poly)phenols exist, and may be a primary determinant of differential exposure of bC to the putative bC enhancers/disruptors derived from (poly)phenols. We aim to i. assess whether different class(es) of (poly)phenol MT are associated with different bC function (bCF) and/or mass (bCM); ii. prove a cause-effect relationship between MT-specific candidate bC enhancers/disruptors and bC function and/or viability (in vitro surrogate index of bCM) by exploiting the experimental model of human bC derived from induced pluripotent stem cells (iPSC).

• Association study: association between different (poly)phenol MT and HOMA-β, a surrogate index of  bC functional mass (βCFxM) will be sought in 300 healthy subjects. In 2 matched subgroups (n=20 each), recruited from the two MT with maximum difference in HOMA-β, βCFxM and splanchnic oral G handling, tracked with oral 6,6-2H-G, will be measured by 180 minutes 75 g OGTT. Moreover, bCM will be measured by a PET-CT method (bC specific radioligand 68Ga-exendin4). The ratio of βCFxM (OGTT) to βCM (PET-CT) assesses in vivo βCF. Splanchnic oral G handling will be compared to gut microbiota (exploratory secondary endpoint).
• Cause-effect study: MT-specific metabolites will be screened in the human bC line βH5 to select candidate bC enhancers/disruptors of βCF/viability. iPSC (blood cell derived) of 3 matched subjects per each MT, with different βCFxM, will be differentiated into bC. iPSC-derived bC will be exposed to βH5-selected bC enhancers/disruptors and βCF/viability will be evaluated.

The results of the present project will allow i. the identification of specific metabotypes associated with different βCFxM (i.e. different T2D risk), in which tailored dietary advice may decrease specific disease risk; ii. the identification of novel (poly)phenol- and metabotype-related β-cell enhancers/disruptors and their mechanisms of action, thereby opening the avenue to novel tools for the assessment of and the intervention on T2D risk, both at the population and at the individual level. Both lines of evidence will be instrumental in developing and ushering in (poly)phenol metabotype (endotype)-specific nutrition in common practice: one size does NOT fit all.