Evolving function and potential of pancreatic alpha cells

Abstract

The alpha cells that co-occupy the islets in association with beta cells have been long recognized as the source of glucagon, a hyperglycemia-producing and diabetogenic hormone. Although the mechanisms that control the functions of alpha cells, glucagon secretion, and the role of glucagon in diabetes have remained somewhat enigmatic over the fifty years since their discovery, seminal findings during the past few years have moved alpha cells into the spotlight of scientific discovery. These findings obtained largely from studies in mice are: Alpha cells have the capacity to trans-differentiate into insulin-producing beta cells. Alpha cells contain a GLP-1 generating system that produces GLP-1 locally for paracrine actions within the islets that likely promotes beta cell growth and survival and maintains beta cell mass. Impairment of glucagon signaling both prevents the occurrence of diabetes in conditions of the near absence of insulin and expands alpha cell mass. Alpha cells appear to serve as helper cells or guardians of beta cells to ensure their health and well-being. Of potential relevance to the possibility of promoting the transformation of alpha to beta cells is the observation that impairment of glucagon signaling leads to a marked increase in alpha cell mass in the islets. Such alpha cell hyperplasia provides an increased supply of alpha cells for their transdifferentiation into new beta cells. In this review we discuss these recent discoveries from the perspective of their potential relevance to the treatment of diabetes.

Keywords: GLP-1; alpha cells; beta cells; diabetes; proglucagon; transdifferentiation.

Figure 1

Proglucagon cleavages by prohormone convertases generate multiple proglucagon-derived peptides. In the pancreatic islets (left) proglucagon in mature alpha cells is cleaved by prohormone convertase 2 (PC2) producing glucagon (Gluca) as the major bioactive peptide, leaving the glucagon-like peptides (GLPs) within the inactive major proglucagon fragment (MPGF). In conditions of beta cell injuries, paracrine signaling from beta cells activates the prohormone convertase 1/3 (PC1/3) in immature pro-alpha cells resulting in the production of glucagon-like peptide-1 (GLP-1). GLP-1 is conjectured to promote the regeneration of injured beta cells. In the intestine (right) the bioactive peptides derived from cleavage of proglucagon by PC1/3 in the intestinal L-cells are the GLPs. Glucagon remains in the inactive proglucagon fragment glicentin. After its secretion GLP-1 is cleaved by the diaminopeptidyl peptidase-4 (Dpp4), which inactivates insulin-releasing (insulinotropic) actions resulting in the formation of an amino-terminally truncated peptide with insulin-like actions (insulinomimetic).

Figure 2

Pathway depicting neogenesis of beta cells in the adult pancreas. A reduction in beta cell mass owing to injury promotes the expansion of facultative stem/progenitor (progen) cells that express the transcription factor Pdx1, a master determinant of the pancreas lineage. A subpopulation of stem/progen cells transition into endocrine progenitor (endocrine progen) cells that express the endocrine lineage-specific transcription factor Ngn3. The undifferentiated endocrine cells proceed to differentiate into immature alpha cells, pro-alpha cells. The fate of pro-alpha cells is determined by the relative cellular levels of the transcription factors Arx and Pax4. High Arx/Pax4 determines the mature alpha cell fate, whereas a high Pax4/Arx ratio leads to differentiation into beta cells. Alpha cells can directly transdifferentiate into beta cells in conditions of severe beta cell ablation and in genetically manipulated mice in which Arx expression is suppressed or Pax4 is over-expressed. Distinguishing features between pro-alpha cells and mature alpha cells are that pro-alpha cells express PC1/3, produce GLP-1, and express the GLP-1 receptor, whereas mature alpha cells do not. Lineage tracing experiments in which Pax4 is over-expressed in the pro-alpha cell lineage have shown that glucagon suppresses the expansion of stem/progenitor cells, as severe depletion of mature alpha cells by their transdifferentiation into beta cells drastically lowers glucagon levels and stimulates the expansion of stem/progenitor cells.

Figure 3

Model of proposed paracrine interactions between beta and alpha cells in response to injury of beta cells. Regeneration factors (RegenFs) produced by injured beta cells act on adjacent alpha cells to induce the expression of prohormone convertase 1/3 (PC1/3) and the formation of GLP-1 from the cleavage of proglucagon. GLP-1 acts via paracrine signaling on beta cells to promote their regeneration (proliferation and survival). RegenFs, such as stromal cell-derived factor-1 (SDF-1), act on beta cells via autocrine signaling to promote survival. Since immature alpha cells express GLP-1 receptors feedback of GLP-1 might stimulate the proliferation of the cells and be involved in the development of the alpha cell hyperplasia that is seen in conditions of beta cell injury.