ADCY5 couples glucose to insulin secretion in human islets

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ADCY5 couples glucose to insulin secretion in human islets. / Hodson, David J; Mitchell, Ryan K; Marselli, Lorella; Pullen, Timothy J; Gimeno Brias, Silvia; Semplici, Francesca; Everett, Katy L; Cooper, Dermot M F; Bugliani, Marco; Marchetti, Piero; Lavallard, Vanessa; Bosco, Domenico; Piemonti, Lorenzo; Johnson, Paul R; Hughes, Stephen J; Li, Daliang; Li, Wen-Hong; Shapiro, A M James; Rutter, Guy A.

In: Diabetes, Vol. 63, No. 9, 09.2014, p. 3009-21.

Research output: Contribution to journalArticlepeer-review

Harvard

Hodson, DJ, Mitchell, RK, Marselli, L, Pullen, TJ, Gimeno Brias, S, Semplici, F, Everett, KL, Cooper, DMF, Bugliani, M, Marchetti, P, Lavallard, V, Bosco, D, Piemonti, L, Johnson, PR, Hughes, SJ, Li, D, Li, W-H, Shapiro, AMJ & Rutter, GA 2014, 'ADCY5 couples glucose to insulin secretion in human islets', Diabetes, vol. 63, no. 9, pp. 3009-21. https://doi.org/10.2337/db13-1607

APA

Hodson, D. J., Mitchell, R. K., Marselli, L., Pullen, T. J., Gimeno Brias, S., Semplici, F., Everett, K. L., Cooper, D. M. F., Bugliani, M., Marchetti, P., Lavallard, V., Bosco, D., Piemonti, L., Johnson, P. R., Hughes, S. J., Li, D., Li, W-H., Shapiro, A. M. J., & Rutter, G. A. (2014). ADCY5 couples glucose to insulin secretion in human islets. Diabetes, 63(9), 3009-21. https://doi.org/10.2337/db13-1607

Vancouver

Hodson DJ, Mitchell RK, Marselli L, Pullen TJ, Gimeno Brias S, Semplici F et al. ADCY5 couples glucose to insulin secretion in human islets. Diabetes. 2014 Sep;63(9):3009-21. https://doi.org/10.2337/db13-1607

Author

Hodson, David J ; Mitchell, Ryan K ; Marselli, Lorella ; Pullen, Timothy J ; Gimeno Brias, Silvia ; Semplici, Francesca ; Everett, Katy L ; Cooper, Dermot M F ; Bugliani, Marco ; Marchetti, Piero ; Lavallard, Vanessa ; Bosco, Domenico ; Piemonti, Lorenzo ; Johnson, Paul R ; Hughes, Stephen J ; Li, Daliang ; Li, Wen-Hong ; Shapiro, A M James ; Rutter, Guy A. / ADCY5 couples glucose to insulin secretion in human islets. In: Diabetes. 2014 ; Vol. 63, No. 9. pp. 3009-21.

Bibtex

@article{a45ac328d9ad4ccab657e893bf62c6f6,
title = "ADCY5 couples glucose to insulin secretion in human islets",
abstract = "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.",
keywords = "Adenylate Cyclase, Calcium, Diabetes Mellitus, Type 2, Glucagon-Like Peptide 1, Glucose, Humans, Insulin, Insulin-Secreting Cells, Polymorphism, Single Nucleotide, RNA, Messenger, Risk",
author = "Hodson, {David J} and Mitchell, {Ryan K} and Lorella Marselli and Pullen, {Timothy J} and {Gimeno Brias}, Silvia and Francesca Semplici and Everett, {Katy L} and Cooper, {Dermot M F} and Marco Bugliani and Piero Marchetti and Vanessa Lavallard and Domenico Bosco and Lorenzo Piemonti and Johnson, {Paul R} and Hughes, {Stephen J} and Daliang Li and Wen-Hong Li and Shapiro, {A M James} and Rutter, {Guy A}",
note = "{\textcopyright} 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.",
year = "2014",
month = sep,
doi = "10.2337/db13-1607",
language = "English",
volume = "63",
pages = "3009--21",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
number = "9",

}

RIS

TY - JOUR

T1 - ADCY5 couples glucose to insulin secretion in human islets

AU - Hodson, David J

AU - Mitchell, Ryan K

AU - Marselli, Lorella

AU - Pullen, Timothy J

AU - Gimeno Brias, Silvia

AU - Semplici, Francesca

AU - Everett, Katy L

AU - Cooper, Dermot M F

AU - Bugliani, Marco

AU - Marchetti, Piero

AU - Lavallard, Vanessa

AU - Bosco, Domenico

AU - Piemonti, Lorenzo

AU - Johnson, Paul R

AU - Hughes, Stephen J

AU - Li, Daliang

AU - Li, Wen-Hong

AU - Shapiro, A M James

AU - Rutter, Guy A

N1 - © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PY - 2014/9

Y1 - 2014/9

N2 - 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.

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.

KW - Adenylate Cyclase

KW - Calcium

KW - Diabetes Mellitus, Type 2

KW - Glucagon-Like Peptide 1

KW - Glucose

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Polymorphism, Single Nucleotide

KW - RNA, Messenger

KW - Risk

U2 - 10.2337/db13-1607

DO - 10.2337/db13-1607

M3 - Article

C2 - 24740569

VL - 63

SP - 3009

EP - 3021

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -