Pancreatic islets are vital endocrine regulators of
systemic metabolism, and recent investigations have increasingly focused on
understanding human islet biology. Studies of isolated human islets have
advanced understanding of the development, function, and regulation of cells
comprising islets, especially pancreatic α-
and β-cells. However, the multicellularity of
the intact islet has stymied specific experimental approaches—particularly in genetics
and cell signaling interrogation. This barrier has been circumvented by the
observation that islet cells can survive dispersion and reaggregate to form
‘pseudoislets’, organoids that retain crucial physiological functions,
including regulated insulin and glucagon secretion. Recently, exciting advances
in the use of pseudoislets for genetics, genomics, islet cell transplantation,
and studies of intra-islet signaling and islet cell interactions have been
reported by investigators worldwide. Here we review molecular and cellular
mechanisms thought to promote islet cell reaggregation, summarize methods that
optimize pseudoislet development, and detail recent insights about human islet
biology from genetic and transplantation-based pseudoislet experiments. Owing
to robust, international programs for procuring primary human pancreata,
pseudoislets should serve as both a durable paradigm for primary organoid
studies and as an engine of discovery for islet biology, diabetes, and
metabolism research.