PT  - JOURNAL ARTICLE
AU  - Anne Raimondo
AU  - Soren K. Thomsen
AU  - Benoit Hastoy
AU  - Mahesh M. Umapathysivam
AU  - Xiao-Qing Dai
AU  - Jocelyn E Manning Fox
AU  - Amy Barrett
AU  - Christopher J. Groves
AU  - Austin Bautista
AU  - Nicola L. Beer
AU  - Anne Clark
AU  - Patrick E. MacDonald
AU  - Patrik Rorsman
AU  - Anna L. Gloyn
TI  - Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function
AID  - 10.1101/158642
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 158642
4099  - http://biorxiv.org/content/early/2017/07/03/158642.short
4100  - http://biorxiv.org/content/early/2017/07/03/158642.full
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.