RT Journal Article
SR Electronic
T1 Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 158642
DO 10.1101/158642
A1 Anne Raimondo
A1 Soren K. Thomsen
A1 Benoit Hastoy
A1 Mahesh M. Umapathysivam
A1 Xiao-Qing Dai
A1 Jocelyn E Manning Fox
A1 Amy Barrett
A1 Christopher J. Groves
A1 Austin Bautista
A1 Nicola L. Beer
A1 Anne Clark
A1 Patrick E. MacDonald
A1 Patrik Rorsman
A1 Anna L. Gloyn
YR 2017
UL http://biorxiv.org/content/early/2017/07/03/158642.abstract
AB 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 cell dysfunction. 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 cell model, PAM silencing caused decreased insulin content and altered dynamics of granule exocytosis. Analysis of primary human beta cells from cadaveric donors confirmed an effect on exocytosis in carriers of the p.D563G T2D-risk allele. Finally, we show that the granular packaging protein Chromogranin A 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 cell function, and uncover a novel mechanism for T2D-associated PAM alleles.