Distinct molecular processes are engaged during histogenesis and epithelial to mesenchymal transition (EMT) is the key evolutionarily conserved process that facilitate the organ developmental processes. Molecular programs governing EMT are embedded within the developmental programs and operate in cells of different tissues. Among different cell types, EMT in pancreatic β-cells is of larger interest as the existence of EMT in these cell types is highly debated. Although, in vitro generation of human islet derived mesenchymal progenitor cells has been proved beyond doubt, the in vivo occurrence of EMT in pancreatic β cells remain enigmatic. Understanding the in-depth process of EMT in in vivo human β cells is challenged by the limited application of lineage-tracing studies, which is otherwise feasible in mice. Understanding the EMT of β-cells would greatly facilitate the generation of clinically relevant β-cells either by enhancing endogenous β-cells, by long term in vitro islet culture or by differentiation of pluripotent stem cells to functional β-cells. In this review we update on the recent progress in understanding the EMT of β-cells and to what extent the investigation has helped in resolving the mystery of existence of EMT in pancreatic β-cells.

Impairment in the function of insulin-producing pancreatic β-cells is a hallmark of both type 1 and 2 diabetes (T1D/T2D). Despite nearly a century of efforts to combat acute diabetes burden, there is yet no precise treatment regimen existing. Enhancing the endogenous β-cells either by protecting them from apoptosis or dedifferentiation is a classic alternative approach to retain the β-cell pool. Recent reports have acknowledged the protein homeostasis mediated by the ubiquitin-proteasome system as one of the essential components in maintaining the β-cell pool. Degradation of the targeted substrate by the proteasome is majorly regulated by the ubiquitination status of the targeted protein dictated by E3 ligases and deubiquitinase enzymes. Imbalance in the function of these enzymes results in the malfunction of β-cells and in turn, hyperglycemia. Ubiquitination involves the covalent attachment of one or more ubiquitin moieties to the target protein by E3 ubiquitin ligases and deubiquitinases (DUBs) are the enzymes which antagonize the action of E3 ligases. Having knowledge about different E3 ligases and deubiquitinases in the process of differentiation and dedifferentiation of β-cells, probably paves the way for designing novel modulators that enhance either the differentiation or abate the dedifferentiation process. In this review, we will discuss the importance of the balanced ubiquitination process, an understanding of which would facilitate the restraining of β-cells from exhaustion.

Diabetes is a metabolic disease caused majorly due to loss of insulin secreting β-cells. Along with apoptosis, recent reports revealed dedifferentiation to be the added reason for the reduced β-cell mass. The Ubiquitin Proteasome system comprising of E3 ligase and deubiquitinases (DUBs) control several key aspects of pancreatic β-cell functions. The role of deubiquitinases in orchestrating the dedifferentiation process in several cancers have been well deciphered, but its role in dedifferentiation of pancreatic β-cells remains elusive. In this study, screening for key DUBs that regulate dedifferentiation, identified USP1 to be specifically involved in the process. Inhibition of USP1 either by genetic intervention or small molecule inhibitor ML323 restored epithelial phenotype of β-cells, but not with inhibition of other DUBs. Conversely overexpression of USP1 was sufficient to dedifferentiate β-cells, even in absence of dedifferentiation inducing cues. Mechanistic insight showed USP1 to probably mediate its effect via modulating the expression of Inhibitor of Differentiation (ID) 2. Further, in an in vivo streptozotocin (STZ) induced dedifferentiation mouse model system, treatment with ML323 rescued the hyperglycaemic state. Overall, this study assigns a novel role to USP1 in dedifferentiation of β-cells and its inhibition may have a therapeutic application of reducing the β-cell loss during diabetes.

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