Intraislet production of GLP-1 by activation of prohormone convertase 1/3 in pancreatic α-cells in mouse models of β-cell regeneration

The islet of Langerhans is a highly vascularized micro-organ consisting of not only beta-cells but multiple cell types such as alpha-, delta-, pancreatic polypeptide-and epsilon-cells that work together to regulate glucose homeostatis. We have recently proposed a new model of the neonatal islet formation in mice by a process of fission following contiguous endocrine cell proliferation in the form of branched cord-like structures in embryos and newborns. There exist large stretches of interconnected islet structures along large blood vessels in the neonatal pancreas, which, upon further development, segregate into smaller fragments (i.e., islets) that eventually become more spherical by internal proliferation as seen in the adult pancreas. alpha-cells span these elongated islet-like structures in the developing pancreas, which we hypothesize represent sites of fission and facilitate the eventual formation of discrete islets. The alpha-cells express both prohormone convertase 2 and 1/3 (PC 2 and PC 1/3, respectively), which resulted in the processing of the proglucagon precursor into glucagon-like peptide 1, thereby leading to local production of this important beta-cell growth factor. Furthermore, while alpha-cells in the adult basically only express PC 2, significant activation of PC 1/3 is also observed in mouse models of insulin resistance such as pregnant, ob/ob, db/db and prediabetic NOD mice, which may be a common mechanism in proliferating beta-cells. Our study suggests an important role of a-cells for beta-cell proliferation and further for the endocrine cell network within an islet.