Schematic representation of open questions related to the origin, status and stress-mediated fate of four hypothetical beta cell subtypes, each represented by a different colour. (a) The origin of beta cell heterogeneity. Are the different beta cell subtypes stable or are they able to switch from one phenotype to another? If so, what signals regulate such switches: metabolic demand, pregnancy, age? (b) Distribution of beta cell subtypes. Do different beta cell subtypes interact within islets? Are they clustered in different islets (perhaps in different regions of the pancreas) or are they scattered randomly among the islets? (c) Effects of metabolic stress on beta cell heterogeneity. When stressed, how do different beta cell subtypes react? Do they undergo apoptosis, senescence, subtype plasticity or trans-differentiation to non beta cells (the latter is not shown)? Are some subtypes more sensitive or resistant to specific stresses?