The Presence, Origins and Potential Role of Bi-hormonal Endocrine Cells Within the Pancreatic Islets of Langerhans

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Abstract
The pancreatic islets of Langerhans contain a minority of endocrine cells that contain more than one hormone: predominantly combinations of glucagon, insulin and somatostatin. A recent paper from our laboratory examined the ontogeny of such cells in the human pancreas and found that they persisted throughout the lifespan but altered in relative abundance with age. Glucagon/insulin bi-hormonal cell number significantly increased with age whilst insulin/somatostatin and glucagon/somatostatin cells significantly decreased. Building on that study here we explore the possible origins and physiological role of bi-hormonal cells within the endocrine pancreas. During pancreas development in utero mono-hormonal endocrine cell lineages are defined by distinct signatures of transcription factor expression. Insufficient or inappropriately timed expression in sub-populations of endocrine cell progenitors may fail to suppress genes normally restricted to other endocrine cell types, resulting in residual populations of bi-hormonal cells. These have been identified postnatally by single cell transcriptomic or proteomic analysis and do not appear to have a metabolic role distinct from that of mono-hormonal cells. However, during hyperglycemic stress bi-hormonal cell sub-populations can proliferate and transdifferentiate into new beta-cells capable of glucose-stimulated insulin release. Transdifferentiation is reversible and in both type 1 and 2 diabetes some beta-cells can dedifferentiate to form hormone-null cells or alpha-cells. Thus, current evidence suggests that diverse phenotypic pools of endocrine cell phenotypes are retained within the islets into adult life that can undergo lineage changes in response to metabolic demand. There is preliminary evidence that these pathways can be therapeutically manipulated.

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