Abstract
Mature pancreatic cells develop during embryonic life from endodermal progenitors, and this developmental process depends on activation of a hierarchy of transcription factors. While information is available on mesodermal signals controlling pancreas development, little is known about environmental factors, such as the levels of nutrients including glucose, that may control this process. Here, we studied the effects of glucose on pancreatic cells development. We used an in vitro model where both endocrine and acinar cells develop from early pancreatic and duodenal homeobox-1 (PDX1)-positive embryonic pancreatic progenitors. We first showed that glucose does not have a major effect on global pancreatic cell proliferation, survival, and acinar cell development. On the other hand, glucose controlled both alpha and beta cell development. Specifically, the surface occupied by insulin-positive cells was 20-fold higher in pancreases cultured in presence than in absence of glucose, and this effect was dose-dependent over the range 0.5-10 mm. Glucose did not appear to control beta cell development by activating the proliferation of early progenitors or beta cells themselves but instead tightly regulated cell differentiation. Thus, glucose did not modify the pattern of expression of Neurogenin3, the earliest marker of endocrine progenitor cells, but was necessary for the expression of the transcription factor NeuroD, a direct target of Neurogenin3 known to be important for proper pancreatic endocrine cell development. We conclude that glucose interferes with the pancreatic endocrine cells development by regulating the transition between Ngn3 and upstream NeuroD.
Highlights
The mature mammalian pancreas contains two types of tissues: endocrine islet cells that produce hormones such as insu
We showed that in E13.5 rat embryonic pancreas cultured on a filter at the air-liquid interface, endocrine and acinar cells develop in a way that perfectly replicates pancreas development occurring in vivo [22]
Endocrine and acinar cells develop in a way that replicates pancreas development occurring in vivo [22, 34]
Summary
Several recent reports have shown that the nutritional environment during prenatal life is crucial for proper development of pancreatic beta cells These results have been obtained from a large panel of intrauterine growth retardation animal models and showed that undernutrition during prenatal life gives rise to a decrease in the number of beta cells that will form (18 –21). These studies were performed in vivo, restricting both the accessibility to the molecular process giving rise to this pancreatic phenotype and the ability to study the precise effect of specific nutrient on pancreatic development
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