β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions

Lu Zhu; Joana Almaça; Prasanna K. Dadi; Hao Hong; Wataru Sakamoto; Mario Rossi; Regina J. Lee; Nicholas C. Vierra; Huiyan Lu; Yinghong Cui; Sara M. McMillin; Nicole A. Perry; Vsevolod V. Gurevich; Amy Lee; Bryan Kuo; Richard D. Leapman; Franz M. Matschinsky; Nicolai M. Doliba; Nikhil M. Urs; Marc G. Caron; David A. Jacobson; Alejandro Caicedo; Jürgen Wess

doi:10.1038/ncomms14295

β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions

Lu Zhu, Joana Almaça, Prasanna K. Dadi, Hao Hong, Wataru Sakamoto, Mario Rossi, Regina J. Lee, Nicholas C. Vierra, Huiyan Lu, Yinghong Cui, Sara M. McMillin, Nicole A. Perry, Vsevolod V. Gurevich, Amy Lee, Bryan Kuo, Richard D. Leapman, Franz M. Matschinsky, Nicolai M. Doliba, Nikhil M. Urs, Marc G. CaronDavid A. Jacobson, Alejandro Caicedo, Jürgen Wess

Medicine

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Abstract

β-Arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-Arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-Arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.

Original language	English (US)
Article number	14295
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14295
State	Published - Feb 1 2017

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Zhu, L., Almaça, J., Dadi, P. K., Hong, H., Sakamoto, W., Rossi, M., Lee, R. J., Vierra, N. C., Lu, H., Cui, Y., McMillin, S. M., Perry, N. A., Gurevich, V. V., Lee, A., Kuo, B., Leapman, R. D., Matschinsky, F. M., Doliba, N. M., Urs, N. M., ... Wess, J. (2017). β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. Nature communications, 8, [14295]. https://doi.org/10.1038/ncomms14295

β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. / Zhu, Lu; Almaça, Joana; Dadi, Prasanna K.; Hong, Hao; Sakamoto, Wataru; Rossi, Mario; Lee, Regina J.; Vierra, Nicholas C.; Lu, Huiyan; Cui, Yinghong; McMillin, Sara M.; Perry, Nicole A.; Gurevich, Vsevolod V.; Lee, Amy; Kuo, Bryan; Leapman, Richard D.; Matschinsky, Franz M.; Doliba, Nicolai M.; Urs, Nikhil M.; Caron, Marc G.; Jacobson, David A.; Caicedo, Alejandro; Wess, Jürgen.

In: Nature communications, Vol. 8, 14295, 01.02.2017.

Research output: Contribution to journal › Article › peer-review

Zhu, L, Almaça, J, Dadi, PK, Hong, H, Sakamoto, W, Rossi, M, Lee, RJ, Vierra, NC, Lu, H, Cui, Y, McMillin, SM, Perry, NA, Gurevich, VV, Lee, A, Kuo, B, Leapman, RD, Matschinsky, FM, Doliba, NM, Urs, NM, Caron, MG, Jacobson, DA, Caicedo, A & Wess, J 2017, 'β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions', Nature communications, vol. 8, 14295. https://doi.org/10.1038/ncomms14295

Zhu, Lu ; Almaça, Joana ; Dadi, Prasanna K. ; Hong, Hao ; Sakamoto, Wataru ; Rossi, Mario ; Lee, Regina J. ; Vierra, Nicholas C. ; Lu, Huiyan ; Cui, Yinghong ; McMillin, Sara M. ; Perry, Nicole A. ; Gurevich, Vsevolod V. ; Lee, Amy ; Kuo, Bryan ; Leapman, Richard D. ; Matschinsky, Franz M. ; Doliba, Nicolai M. ; Urs, Nikhil M. ; Caron, Marc G. ; Jacobson, David A. ; Caicedo, Alejandro ; Wess, Jürgen. / β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. In: Nature communications. 2017 ; Vol. 8.

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title = "β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions",

abstract = "β-Arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-Arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-Arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.",

author = "Lu Zhu and Joana Alma{\c c}a and Dadi, {Prasanna K.} and Hao Hong and Wataru Sakamoto and Mario Rossi and Lee, {Regina J.} and Vierra, {Nicholas C.} and Huiyan Lu and Yinghong Cui and McMillin, {Sara M.} and Perry, {Nicole A.} and Gurevich, {Vsevolod V.} and Amy Lee and Bryan Kuo and Leapman, {Richard D.} and Matschinsky, {Franz M.} and Doliba, {Nicolai M.} and Urs, {Nikhil M.} and Caron, {Marc G.} and Jacobson, {David A.} and Alejandro Caicedo and J{\"u}rgen Wess",

note = "Funding Information: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, NIH), ADA grant 7-11-BS-34 (N.M.D.) Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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AU - Sakamoto, Wataru

AU - Rossi, Mario

AU - Lee, Regina J.

AU - Vierra, Nicholas C.

AU - Lu, Huiyan

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AU - Gurevich, Vsevolod V.

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AU - Leapman, Richard D.

AU - Matschinsky, Franz M.

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AU - Urs, Nikhil M.

AU - Caron, Marc G.

AU - Jacobson, David A.

AU - Caicedo, Alejandro

AU - Wess, Jürgen

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β-Arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions

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