Fig. 1

Illustration of cellular plasticity between the different pancreatic lineages and the signaling pathways involved in pancreatic β-cell regeneration. In the regenerative scenarios—acinar to β cell, ductal to β cell, and α to β cell—a transition state involving Ngn3 activation is necessary for the reprogramming to occur, with the exception of δ to β cell conversion (see [3] and main text for further details). a Acinar cells can be converted into β cells in vivo by overexpression of Ngn3, Pdx1, and MafA in mice (1). Hyperglycemia can inhibit (shown by a cross) in vivo reprogramming of acinar cells by Pdx1, Ngn3, and MafA. Furthermore, acinar cells can become β cells in vitro and in vivo after exposure to ciliary neurotrophic factor (CNTF) and epidermal growth factor (EGF) (2); this regenerative event is dependent on PKA/STAT3 signaling-mediated Ngn3 activation. b Ductal cells can be reprogrammed into β cells in vivo after genetic deletion of the ubiquitin ligase Fbxw7 (1). Such reprogramming can also be induced in vivo in mice after treatment with gastrin, EGF, and medium hyperglycemia (2). Interestingly, this ductal to β cell conversion requires a progenitor-like intermediate state that involves Ngn3 activation. c Similarly, α cells can be converted into β cells by ectopic activation of Pax4 in α cells in the adult pancreas, either by transgenic overexpression of Pax4 or indirectly by suppressing Arx (1). In a recent report, it was shown that treatment with an artemisinin (for example, artemether) [9] or long-term administration of gamma-amino butyric acid (GABA) [8] results in robust conversion of α cells to β cells in vitro and in vivo (2). Both compounds act through the GABA_A receptor; artemether treatment increases gephryin protein levels, which potentiates GABA_A receptor signaling while inhibiting mTOR signaling (shown by a cross). Strikingly, both artemisinin and GABA treatments inhibit Arx function or expression, leading to induction of Pax4 expression, concomitantly inhibiting glucagon secretion and inducing insulin expression. Although the in vivo α to β switch in itself is independent of Ngn3, the conversion of endogenous α to β cells appears to trigger α-cell neogenesis from ductal cells by reactivation of Ngn3 in GABA-treated pancreas. d Finally, δ cells can be reprogrammed into β cells in early puberty, although this conversion is independent of Ngn3 activation