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

doi:10.1038/s41588-018-0173-1

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

Research output: Contribution to journal › Article › peer-review

58 Citations (Scopus)

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 language	English
Pages (from-to)	1122-1131
Number of pages	10
Journal	Nature Genetics
Volume	50
Issue number	8
Early online date	27 Jul 2018
DOIs	https://doi.org/10.1038/s41588-018-0173-1
Publication status	Published (in print/issue) - 30 Aug 2018

Funding

We acknowledge sharing of data from the GoT2D and T2D-GENES consortia before publication. We thank J. Galvanovskis (University of Oxford) for microscopy assistance, J. Lyon (Alberta Diabetes Institute IsletCore) for his work on human islet isolations, and J. Buteau and Y. Wang (both Alberta Diabetes Institute) for their assistance with imaging human pancreatic sections. We also thank the Human Organ Procurement and Exchange Program (Edmonton) and the Trillium Gift of Life Network (Toronto) and other organ procurement agencies for their efforts in obtaining human pancreata for research. A.L.G. is a Wellcome Trust Senior Fellow in Basic Biomedical Science. P.E.M. holds a 2016–2017 Killam Annual Professorship. M.I.M. is a Wellcome Senior Investigator. S.K.T. is a Radcliffe Department of Medicine Scholar. S.S. is funded by the Medical Research council (MC_ST_15019 [2015 DTG/DTA]). J.C. is funded by the Oxford – Medical Research Council Doctoral Training Partnership and the Nuffield Department of Clinical Medicine. This work was funded by the Wellcome Trust (095101 (A.L.G.), 200837 (A.L.G.), 098381 (M.I.M.), 106130 (A.L.G., M.I.M.), 203141 (M.I.M.), 090531 (P.R.)), Medical Research Council (MR/L020149/1) (M.I.M., A.L.G., P.R.), European Union Horizon 2020 Programme (T2D Systems) (A.L.G.), and National Institutes of Health (U01-DK105535; U01-DK085545) (M.I.M., A.L.G.). Human islet isolation and phenotyping was supported by funding from the Alberta Diabetes Foundation (P.E.M.F.). The research was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (A.L.G., M.I.M., P.R.). The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR or the Department of Health.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Functional genomics
Genome-wide association studies
Type 2 diabetes

Access to Document

10.1038/s41588-018-0173-1

Cite this

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

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

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.",

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

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doi = "10.1038/s41588-018-0173-1",

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Thomsen, SK, Raimondo, A, Hastoy, B, Sengupta, S, Dai, XQ, Bautista, A, Censin, J, Payne, AJ, Umapathysivam, MM, Spigelman, AF, Barrett, A, Groves, CJ, Beer, NL, Manning Fox, JE, McCarthy, MI, Clark, A, Mahajan, A, Rorsman, P, MacDonald, PE & Gloyn, AL 2018, 'Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells', Nature Genetics, vol. 50, no. 8, pp. 1122-1131. https://doi.org/10.1038/s41588-018-0173-1

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AU - Thomsen, Soren K.

AU - Raimondo, Anne

AU - Hastoy, Benoit

AU - Sengupta, Shahana

AU - Dai, Xiao Qing

AU - Bautista, Austin

AU - Censin, Jenny

AU - Payne, Anthony J.

AU - Umapathysivam, Mahesh M.

AU - Spigelman, Aliya F.

AU - Barrett, Amy

AU - Groves, Christopher J.

AU - Beer, Nicola L.

AU - Manning Fox, Jocelyn E.

AU - McCarthy, Mark I.

AU - Clark, Anne

AU - Mahajan, Anubha

AU - Rorsman, Patrick

AU - MacDonald, Patrick E.

AU - Gloyn, Anna L.

PY - 2018/8/30

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AB - 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.

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KW - Genome-wide association studies

KW - Type 2 diabetes

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ER -

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

Abstract

Funding

UN SDGs

Keywords

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