Abstract
Pancreatic exocrine and endocrine cells develop during embryonic life from endodermal progenitors. This process depends on activation of a hierarchy of transcription factors. Although information is available regarding the mesodermal signals controlling pancreas development, little is known about the role of environmental factors such as nutrients, including glucose, that also may impact development. Previously, we showed that glucose plays an important and specific role in beta cell development by activating the transition of Neurogenin3-positive endocrine progenitors into beta cells. Here, we examined the implication of glucose metabolism and more precisely the role of the hexosamine biosynthesis pathway (HBP) to understand the mechanisms by which glucose regulates beta cell development. We have established an in vitro model of endocrine and exocrine cells development from embryonic day 13.5 rat pancreases in a manner that replicates in vivo pancreas development perfectly. Using this model, we tested the effect of selective inhibitors and activators of the HBP and found that the HBP has a modest effect on cell proliferation and exocrine cell differentiation. On the other hand, beta cell development is tightly controlled by the HBP. Specifically, HBP activators increase beta cell development, whereas inhibitors repress such development. Importantly, both the HBP and glucose control the same steps in beta cell development.
Highlights
During development, the endodermal region committed to form the pancreas initially expresses the transcription factor Pdx-1, a marker of pancreatic progenitors expressed in mature beta cells [5,6,7]
We have shown that glucose controls beta cell development by activating expression of NeuroD, which is a direct target of NGN3 [18]
Inhibition of hexosamine biosynthetic pathway (HBP) Affects Pancreas Development—When E13.5 rat pancreases are dissected and cultured on filters floating at the air-medium interface, acinar and endocrine cells develop in a manner that replicates in vivo pancreatic development [17]
Summary
24584 JOURNAL OF BIOLOGICAL CHEMISTRY phosphate amidotransferase (GFAT) is the first enzyme in the HBP. GFAT transfers the amide group from glutamine to fructose-6-phosphate to form glucosamine-6-phosphate, a precursor of uridine diphosphate-GlcNAc. GFAT transfers the amide group from glutamine to fructose-6-phosphate to form glucosamine-6-phosphate, a precursor of uridine diphosphate-GlcNAc The latter is the major substrate for protein N- and O-glycosylation. When N-glycosylation is constitutive, O-glycosylation is a process (similar to phosphorylation) regulated by O-linked -N-acetylglucosamine transferase (OGT) and -D-N-acetylglucosaminidase (O-GlcNAcase), which are responsible for O-glycosylation and de-O-glycosylation mechanisms, respectively We perturbed the HBP with specific inhibitors and activators using our in vitro model of beta cell development from pancreatic progenitors and demonstrated that the HBP controls specific steps of pancreatic beta cell development
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