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

School of Biomedical Sciences

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

47 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

Keywords

Functional genomics
Genome-wide association studies
Type 2 diabetes

UN SDGs

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

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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.",

keywords = "Functional genomics, Genome-wide association studies, Type 2 diabetes",

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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T1 - Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells

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

Y1 - 2018/8/30

N2 - 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.

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.

KW - Functional genomics

KW - Genome-wide association studies

KW - Type 2 diabetes

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UR - https://pure.ulster.ac.uk/en/publications/type-2-diabetes-risk-alleles-in-pam-impact-insulin-release-from-h

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SN - 1061-4036

VL - 50

SP - 1122

EP - 1131

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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