Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function
| Autor: | A Clark, Austin Bautista, Nicola L. Beer, Anne Raimondo, Amy Barrett, M Umapathysivam, J. E. Manning Fox, Anna L. Gloyn, P Rorsman, Christopher J. Groves, B Hastoy, Patrick E. MacDonald, Dai X-Q., Soren K. Thomsen |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0303 health sciences
medicine.medical_specialty Insulin medicine.medical_treatment 030302 biochemistry & molecular biology Chromogranin A Monooxygenase Biology Exocytosis Cell biology 03 medical and health sciences Endocrinology Internal medicine medicine biology.protein Gene silencing Allele Beta cell Peptidylglycine alpha-amidating monooxygenase 030304 developmental biology |
| DOI: | 10.1101/158642 |
| Popis: | Molecular mechanisms underpinning the genetic risk for type 2 diabetes (T2D) remain poorly understood, hindering translation into new therapies. Recently, genome-wide studies identified two coding variants inPeptidylglycine Alpha-amidating Monooxygenase(PAM) associated with T2D risk and measures of beta cell dysfunction. Here, we demonstrate that both risk alleles impact negatively on overall PAM activity, but via distinct effects on expression and catalytic function. In a human beta cell model,PAMsilencing caused decreased insulin content and altered dynamics of granule exocytosis. Analysis of primary human beta cells from cadaveric donors confirmed an effect on exocytosis in carriers of the p.D563G T2D-risk allele. Finally, we show that the granular packaging protein Chromogranin A is a PAM substrate and a strong candidate for mediating downstream effects on insulin secretion. Taken together, our results establish a role for PAM in beta cell function, and uncover a novel mechanism for T2D-associatedPAMalleles. |
| Databáze: | OpenAIRE |
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