| Literature DB >> 30054598 |
Soren K Thomsen1,2, Anne Raimondo1,3, Benoit Hastoy1, Shahana Sengupta1,4, Xiao-Qing Dai5, Austin Bautista5, Jenny Censin6,7, Anthony J Payne7, Mahesh M Umapathysivam1, Aliya F Spigelman5, Amy Barrett1, Christopher J Groves1, Nicola L Beer1, Jocelyn E Manning Fox5, Mark I McCarthy1,7,8, Anne Clark1, Anubha Mahajan7, Patrik Rorsman1,8, Patrick E MacDonald5, Anna L Gloyn9,10,11.
Abstract
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.Entities:
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Year: 2018 PMID： 30054598 PMCID： PMC6237273 DOI： 10.1038/s41588-018-0173-1
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330