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The molecular mechanisms underpinning susceptibility loci for type 2 diabetes (T2D) remain poorly understood. Coding variants in peptidylglycine α-amidating monooxygenase (PAM) are associated with both T2D risk and insulinogenic index. Here, we demonstrate that the T2D risk alleles impact negatively on overall PAM activity via defects in expression and catalytic function. PAM deficiency results in reduced insulin content and altered dynamics of insulin secretion in a human β-cell model and primary islets from cadaveric donors. Thus, our results demonstrate a role for PAM in β-cell function, and establish molecular mechanisms for T2D risk alleles at this locus.

Original publication

DOI

10.1038/s41588-018-0173-1

Type

Journal article

Journal

Nat Genet

Publication Date

08/2018

Volume

50

Pages

1122 - 1131

Keywords

Alleles, Amidine-Lyases, Animals, Cell Line, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, HEK293 Cells, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Mixed Function Oxygenases, Polymorphism, Single Nucleotide