Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state.
Dai X-Q., Camunas-Soler J., Briant LJB., Dos Santos T., Spigelman AF., Walker EM., Arrojo E Drigo R., Bautista A., Jones RC., Avrahami D., Lyon J., Nie A., Smith N., Zhang Y., Johnson J., Manning Fox JE., Michelakis ED., Light PE., Kaestner KH., Kim SK., Rorsman P., Stein RW., Quake SR., MacDonald PE.
In diabetes, glucagon secretion from pancreatic α cells is dysregulated. The underlying mechanisms, and whether dysfunction occurs uniformly among cells, remain unclear. We examined α cells from human donors and mice using electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses α 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, α cells shift toward a "β cell-like" electrophysiological profile in concert with indications of impaired identity. In human α cells we identified links between cell membrane properties and cell surface signaling receptors, mitochondrial respiratory chain complex assembly, and cell maturation. Cell-type classification using machine learning of electrophysiology data demonstrated a heterogenous loss of "electrophysiologic identity" in α cells from donors with type 2 diabetes. Indeed, a subset of α cells with impaired exocytosis is defined by an enrichment in progenitor and lineage markers and upregulation of an immature transcriptomic phenotype, suggesting important links between α cell maturation state and dysfunction.