Imperial College London
Alternate

DrTimothyPullen

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Honorary Lecturer
 
 
 
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Contact

 

t.pullen Website

 
 
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Location

 

329ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hodson:2014:10.2337/db13-1607,
author = {Hodson, DJ and Mitchell, RK and Marselli, L and Pullen, TJ and Brias, SG and Semplici, F and Everett, KL and Cooper, DMF and Bugliani, M and Marchetti, P and Lavallard, V and Bosco, D and Piemonti, L and Johnson, PR and Hughes, SJ and Li, D and Li, W-H and Shapiro, AMJ and Rutter, GA},
doi = {10.2337/db13-1607},
journal = {Diabetes},
pages = {3009--3021},
title = {ADCY5 couples glucose to insulin secretion in human islets},
url = {http://dx.doi.org/10.2337/db13-1607},
volume = {63},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic β-cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism toward ATP at concentrations of the sugar >8 mmol/L. However, calcium transient generation and functional connectivity between individual human β-cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in β-cell ADCY5 expression and impaired glucose signaling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action.
AU  - Hodson,DJ
AU  - Mitchell,RK
AU  - Marselli,L
AU  - Pullen,TJ
AU  - Brias,SG
AU  - Semplici,F
AU  - Everett,KL
AU  - Cooper,DMF
AU  - Bugliani,M
AU  - Marchetti,P
AU  - Lavallard,V
AU  - Bosco,D
AU  - Piemonti,L
AU  - Johnson,PR
AU  - Hughes,SJ
AU  - Li,D
AU  - Li,W-H
AU  - Shapiro,AMJ
AU  - Rutter,GA
DO  - 10.2337/db13-1607
EP  - 3021
PY  - 2014///
SN  - 0012-1797
SP  - 3009
TI  - ADCY5 couples glucose to insulin secretion in human islets
T2  - Diabetes
UR  - http://dx.doi.org/10.2337/db13-1607
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000341505300018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
VL  - 63
ER  -
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