Chronically elevated exogenous glucose elicits antipodal effects on the proteome signature of differentiating human pancreatic progenitors

The past decade revealed that cell identity changes, such as dedifferentiation or transdifferentiation, accompany the insulin-producing β-cell decay in most diabetes conditions. Mapping and controlling the mechanisms governing these processes is thus extremely valuable for managing the disease progression. Extracellular glucose is known to impact cell identity by impacting the redox balance. Here we use global proteomics and pathway analysis to map the response of differentiating human pancreatic progenitors to chronically increased in vitro glucose levels. We show that exogenous high glucose levels impact different protein subsets in a concentration-dependent manner. In contrast, regardless of concentration, high exogenous glucose elicits an antipodal effect on the proteome landscape, inducing both beneficial and detrimental changes in regard to achieving the desired islet cell fingerprint. Furthermore, we identified that only a subgroup of these effects and pathways are regulated by changes in redox balance. Our study highlights a complex yin-yang action of exogenous glucose on differentiating pancreas progenitors with a distinct proteome signature.