Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

Molecular mechanisms underpinning the genetic risk for type 2 diabetes (T2D) remain poorly understood, hindering translation into new therapies. Recently, genome-wide studies identified two coding variants in Peptidylglycine Alpha-amidating Monooxygenase(PAM) associated with T2D risk and measures of beta celldysfunction. Here, we demonstrate that both risk alleles impact negatively on overall PAM activity, but via distinct effects on expression and catalytic function. In a human beta cellmodel, PAM silencing caused decreased insulin content and altered dynamics of granule exocytosis. Analysis of primary human beta cellsfrom cadaveric donors confirmed an effect on exocytosisin carriers of the p.D563G T2D-risk allele. Finally, we show that the granular packaging protein ChromograninA is a PAM substrate and a strong candidate for mediating downstream effects on insulin secretion. Taken together, our results establish a role for PAM in beta cellfunction, and uncover a novel mechanism for T2D-associated PAM alleles.