Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cells
The molecular mechanisms underpinning GWAS 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 ov...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Published: |
Nature Publishing Group
2018
|
| _version_ | 1826277782205759488 |
|---|---|
| author | Thomsen, S Raimondo, A Hastoy, B Sengupta, S Dai, X Bautista, A Censin, J Payne, A Umapathysivam, M Spigelman, A Barrett, A Groves, C Beer, N Manning Fox, J McCarthy, M Clark, A Mahajan, A Rorsman, O MacDonald, P Gloyn, A |
| author_facet | Thomsen, S Raimondo, A Hastoy, B Sengupta, S Dai, X Bautista, A Censin, J Payne, A Umapathysivam, M Spigelman, A Barrett, A Groves, C Beer, N Manning Fox, J McCarthy, M Clark, A Mahajan, A Rorsman, O MacDonald, P Gloyn, A |
| author_sort | Thomsen, S |
| collection | OXFORD |
| description | The molecular mechanisms underpinning GWAS 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 GWAS locus. |
| first_indexed | 2024-03-06T23:34:05Z |
| format | Journal article |
| id | oxford-uuid:6d0e0ce6-6b37-4969-a1d2-118e64b215c3 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T23:34:05Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:6d0e0ce6-6b37-4969-a1d2-118e64b215c32022-03-26T19:15:14ZType 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6d0e0ce6-6b37-4969-a1d2-118e64b215c3Symplectic Elements at OxfordNature Publishing Group2018Thomsen, SRaimondo, AHastoy, BSengupta, SDai, XBautista, ACensin, JPayne, AUmapathysivam, MSpigelman, ABarrett, AGroves, CBeer, NManning Fox, JMcCarthy, MClark, AMahajan, ARorsman, OMacDonald, PGloyn, AThe molecular mechanisms underpinning GWAS 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 GWAS locus. |
| spellingShingle | Thomsen, S Raimondo, A Hastoy, B Sengupta, S Dai, X Bautista, A Censin, J Payne, A Umapathysivam, M Spigelman, A Barrett, A Groves, C Beer, N Manning Fox, J McCarthy, M Clark, A Mahajan, A Rorsman, O MacDonald, P Gloyn, A Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cells |
| title | Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cells |
| title_full | Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cells |
| title_fullStr | Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cells |
| title_full_unstemmed | Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cells |
| title_short | Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic beta cells |
| title_sort | type 2 diabetes risk alleles in pam impact insulin release from human pancreatic beta cells |
| work_keys_str_mv | AT thomsens type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT raimondoa type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT hastoyb type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT senguptas type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT daix type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT bautistaa type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT censinj type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT paynea type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT umapathysivamm type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT spigelmana type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT barretta type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT grovesc type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT beern type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT manningfoxj type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT mccarthym type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT clarka type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT mahajana type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT rorsmano type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT macdonaldp type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells AT gloyna type2diabetesriskallelesinpamimpactinsulinreleasefromhumanpancreaticbetacells |