Heterogenous impairment of α-cell function in type 2 diabetes is linked to cell maturation state
In diabetes, glucagon secretion from pancreatic -cells is dysregulated. We examined -cells from human donors and mice using combined electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses -cell exocytosis by reducing P/Q-type Ca2+ channel activity, and this is disrupted in type 2 diabetes (T2D). Upon high-fat-feeding of mice, -cells shift towards a {beta}-cell-like electrophysiologic profile in concert with an up-regulation of the {beta}-cell Na+ channel isoform Scn9a and indications of impaired -cell identity. In human -cells we identify links between cell membrane properties and cell surface signalling receptors, mitochondrial respiratory complex assembly, and cell maturation. Cell type classification using machine learning of electrophysiology data demonstrates a heterogenous loss of electrophysiologic identity in -cells from donors with T2D. Indeed, a sub-set of -cells with impaired exocytosis is defined by an enrichment in progenitor markers suggesting important links between -cell maturation state and dysfunction in T2D. Key findingsO_LI-cell exocytosis is suppressed by glucose-dependent inhibition of P/Q-type Ca2+ currents C_LIO_LIDysfunction of -cells in type 2 diabetes is associated with a {beta}-cell-like electrophysiologic signature C_LIO_LIPatch-seq links maturation state, the mitochondrial respiratory chain, and cell surface receptor expression to -cell function C_LIO_LI-cell dysfunction occurs preferentially in cells enriched in endocrine lineage markers C_LI