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A stem cell line, derived by reprogramming native human islet cells, consistently generates pure populations of endocrine pancreatic clusters following differentiation cues. Two protocols were developed directing the differentiation of that cell line to pancreatic cells that expressed or lacked expression of the key beta cell maturation-associated factor NKX6-1. The population of stem cell derived endocrine pancreatic clusters that was most consistently capable of regulating blood glucose in rodent models of diabetes lacked NKX6-1 but did manifest high expression of other key drivers of endocrine cell specification and maturation, ISL1 and MAFA. These data support the hypothesis that MAFA and ISL-1, but not NKX6-1, are reliable in vitro markers of committed endocrine pancreatic cells. The population with low NKX6-1 and high in vivo potency was further characterized by transcriptome profiling as an endocrine-committed population progressively maturing in vitro to a state proximal to the native islet.