Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells.
Soren K ThomsenAnne RaimondoBenoit HastoyShahana SenguptaXiao-Qing DaiAustin BautistaJenny C CensinAnthony J PayneMahesh M UmapathysivamAliya F SpigelmanAmy BarrettChristopher J GrovesNicola L BeerJocelyn E Manning FoxMark I McCarthyAnne ClarkAnubha MahajanPatrik RorsmanPatrick E MacDonaldAnna L GloynPublished in: Nature genetics (2018)
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.
Keyphrases
- type diabetes
- glycemic control
- endothelial cells
- cardiovascular disease
- stem cells
- induced apoptosis
- single cell
- insulin resistance
- skeletal muscle
- induced pluripotent stem cells
- genome wide
- mesenchymal stem cells
- adipose tissue
- copy number
- cell proliferation
- bone marrow
- endoplasmic reticulum stress
- cell cycle arrest
- weight loss