Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells
Nat Genet. 2018-07-27;50(8):1122-1131.
- 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.
- Consortium data used in this publication
- Previously published datasets analysed during the current study can be accessed as follows; transcriptomic data from sorted human islets are available from the European Genome-phenome Archive under the accession code EGAS00001000442, https://www.ebi.ac.uk/ega/studies/EGAS00001000442; tissue expression data for PAM from the GTEx consortium are available through the GTEx portal, https://www.gtexportal.org/home/gene/PAM; genotype data for primary human islets used in the analysis of exocytosis data are available from the European Genome-phenome Archive under accession code EGAD00001001601, https://www.ebi.ac.uk/ega/datasets/EGAD00001001601; secreted islet factors were analysed based on data available from the supplementary information of PMID: 21212933, https://link.springer.com/article/10.1007%2Fs00125-010-2012-5; Genetic associations for plasma PAM expression levels are available in the supplementary material to the article by Sun et al33. Data generated during this study are included in the published article (and its supplementary information files) or available upon reasonable request.
- Datasets
- DSR743ONG