Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells

Soren K. Thomsen, Anne Raimondo, Benoit Hastoy, Shahana Sengupta, Xiao Qing Dai, Austin Bautista, Jenny Censin, Anthony J. Payne, Mahesh M. Umapathysivam, Aliya F. Spigelman, Amy Barrett, Christopher J. Groves, Nicola L. Beer, Jocelyn E. Manning Fox, Mark I. McCarthy, Anne Clark, Anubha Mahajan, Patrick Rorsman, Patrick E. MacDonald, Anna L. Gloyn

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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.

Original languageEnglish
Pages (from-to)1122-1131
Number of pages10
JournalNature Genetics
Volume50
Issue number8
Early online date27 Jul 2018
DOIs
Publication statusPublished - 30 Aug 2018

Keywords

  • Functional genomics
  • Genome-wide association studies
  • Type 2 diabetes

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    Thomsen, S. K., Raimondo, A., Hastoy, B., Sengupta, S., Dai, X. Q., Bautista, A., Censin, J., Payne, A. J., Umapathysivam, M. M., Spigelman, A. F., Barrett, A., Groves, C. J., Beer, N. L., Manning Fox, J. E., McCarthy, M. I., Clark, A., Mahajan, A., Rorsman, P., MacDonald, P. E., & Gloyn, A. L. (2018). Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells. Nature Genetics, 50(8), 1122-1131. https://doi.org/10.1038/s41588-018-0173-1