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

by Rorsman, Patrik , Manning Fox, Jocelyn E , Hastoy, Benoit , Groves, Christopher J , Gloyn, Anna L , Barrett, Amy , Macdonald, Patrick E , Umapathysivam, Mahesh M , Beer, Nicola L , Xiao-Qing, Dai , Thomsen, Soren K , Clark, Anne , Bautista, Austin , Raimondo, Anne

in Alleles / Beta cells / Cadavers / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Exocytosis / Genetics / Genomes / Glucose / Insulin / Insulin secretion / Molecular modelling / Peptidylglycine monooxygenase / Secretion

2017

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

2017

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

2017

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Paper

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

Rorsman, Patrik,

Manning Fox, Jocelyn E,

Hastoy, Benoit,

Groves, Christopher J,

Gloyn, Anna L,

Barrett, Amy,

Macdonald, Patrick E,

Umapathysivam, Mahesh M,

Beer, Nicola L,

Xiao-Qing, Dai,

Thomsen, Soren K,

Clark, Anne,

Bautista, Austin,

Raimondo, Anne

2017

Overview

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.

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Publisher

Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory

Subject

/ Diabetes mellitus (non-insulin dependent)

/ Exocytosis