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Figures & data
Figure 1. Proglucagon expression in α cells. Alternative cleavages of proglucagon to glucagon and GLP-1. The relative levels of expression of the pro-hormone covertases PC2 and PC1/3 determine the production of glucagon or GLP-1, respectively. Glucagon is a metabolic (gluconeogenic) hormone produced in fully differentiated α-cells and GLP-1 is both an insulinotropic (insulin-releasing) hormone and a growth and survival peptide produced in undifferentiated pro-α-cells. GRPP, glucagon-related polypeptide. GLP-2, glucagon-like peptide-2 involved in intestinal growth.
Figure 2. Simplified model of the embryological development of islet endocrine cells (reviewed in ref. Citation21). Stem/progenitor (Stem/Prog) cells arise from the primitive undifferentiated epithelium of the gut tube and express the transcription factor Pdx-1, a master regulator of pancreas development. The endocrine lineage appears soon after and is characterized by the pro-endocrine transcription factor Ngn3. The earliest endocrine cells, pro-α-cells, identified in early development express the proglucagon gene and the prohormone convertase PC1/3 resulting in the production of GLP-1. The division of lineages into α- and β-cells is determined by the relative expression levels of the transcription factors Arx and Pax4. Mature α-cells express PC2 resulting in the production of glucagon. Fully-differentiated β-cells express the insulin gene and produce insulin. GLP-1 is proposed to be a growth factor important for the expansion of pro-α-cells Glucagon, produced late in α-cell development, is proposed to inhibit the growth of pro-α-cells.
Figure 3. Model illustrating the B > A > B hypothesis of the autocrine/paracrine actions of SDF-1 and GLP-1 in α-cell-mediated regeneration of β-cells. Stromal cell-derived factor-1 (SDF-1) produced by injured β-cells acts on adjacent α-cells stimulating their de-differentiation to pro-α-cells. SDF-1 activates Akt and Jak/STAT signaling pathways in mature, fully-differentiated α-cells resulting in the expression of PC1/3 and the production of GLP-1. De-differentiated pro-α-cells express Ngn3, a hallmark of endocrine progenitor cells and Pax4, a master determinant of the differentiation of progenitor cells to β-cells. GLP-1 produced by pro-α-cells and SDF-1 signaling promote the trans-differentiation of pro-α into β-cells. GLP-1 and SDF-1 participate in the proliferation and the survival of both pro-α-cells and newly regenerated β-cells. A deficiency of glucagon and insulin, the products of fully-differentiated α- and β-cells, respectively, facilitates the transition of mature α to pro-α to β-cells, i.e., glucagon and insulin are inhibitory to the progression of de-differentiation and trans-differentiation. Wnt signaling might be involved in the signaling mediated by both SDF-1 and GLP-1 as both hormones activate β-catenin/Tcf7l2-mediated downstream Wnt signaling.Citation35,Citation36,Citation106 The transcription factors Arx and Irx2 and Pdx1, Pax6 and MafA define the phenotypes or mature α- and β-cells, respectively.Citation107,Citation108
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