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

被引：55

作者：

Thomsen, Soren K. ^{[1
,8
]}

Raimondo, Anne ^{[1
,9
]}

Hastoy, Benoit ^{[1
]}

Sengupta, Shahana ^{[1
,2
]}

Dai, Xiao-Qing ^{[3
,4
]}

Bautista, Austin ^{[3
,4
]}

Censin, Jenny ^{[5
,6
]}

Payne, Anthony J. ^{[6
]}

Umapathysivam, Mahesh M. ^{[1
]}

Spigelman, Aliya F. ^{[3
,4
]}

Barrett, Amy ^{[1
]}

Groves, Christopher J. ^{[1
]}

Beer, Nicola L. ^{[1
]}

Fox, Jocelyn E. Manning ^{[3
,4
]}

McCarthy, Mark I. ^{[1
,6
,7
]}

Clark, Anne ^{[1
]}

Mahajan, Anubha ^{[6
]}

Rorsman, Patrik ^{[1
,7
]}

MacDonald, Patrick E. ^{[3
,4
]}

Gloyn, Anna L. ^{[1
,6
,7
]}

机构：

[1] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[2] MRC Harwell Inst, Harwell, Oxon, England

[3] Univ Alberta, Dept Pharmacol, Edmonton, AB, Canada

[4] Univ Alberta, Alberta Diabet Inst, Edmonton, AB, Canada

[5] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England

[6] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

[7] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford, England

[8] Vertex Pharmaceut Europe Ltd, Milton Pk, Abingdon, Oxon, England

[9] Natl Hlth & Med Res Council, Canberra, ACT, Australia

来源：

NATURE GENETICS | 2018年 / 50卷 / 08期

基金：

英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院; 欧盟地平线“2020”;

关键词：

ALPHA-AMIDATING MONOOXYGENASE; SECRETORY GRANULE BIOGENESIS; CHROMOGRANIN-A; GENETIC ARCHITECTURE; NEUROENDOCRINE CELLS; LOW-FREQUENCY; HUMAN ISLETS; IN-VITRO; PROTEIN; EXPRESSION;

D O I：

10.1038/s41588-018-0173-1

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The molecular mechanisms underpinning susceptibility loci for type 2 diabetes (T2D) remain poorly understood. Coding variants in peptidylglycine alpha-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 beta-cell model and primary islets from cadaveric donors. Thus, our results demonstrate a role for PAM in beta-cell function, and establish molecular mechanisms for T2D risk alleles at this locus.

引用

页码：1122 / +

页数：16

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