Control of pancreatic β cell regeneration by glucose metabolism

Shay Porat; Noa Weinberg-Corem; Sharona Tornovsky-Babaey; Rachel Schyr-Ben-Haroush; Ayat Hija; Miri Stolovich-Rain; Daniela Dadon; Zvi Granot; Vered Ben-Hur; Peter White; Christophe A. Girard; Rotem Karni; Klaus H. Kaestner; Frances M. Ashcroft; Mark A. Magnuson; Ann Saada; Joseph Grimsby; Benjamin Glaser; Yuval Dor

doi:10.1016/j.cmet.2011.02.012

Control of pancreatic β cell regeneration by glucose metabolism

Shay Porat, Noa Weinberg-Corem, Sharona Tornovsky-Babaey, Rachel Schyr-Ben-Haroush, Ayat Hija, Miri Stolovich-Rain, Daniela Dadon, Zvi Granot, Vered Ben-Hur, Peter White, Christophe A. Girard, Rotem Karni, Klaus H. Kaestner, Frances M. Ashcroft, Mark A. Magnuson, Ann Saada, Joseph Grimsby, Benjamin Glaser^*, Yuval Dor

^*Corresponding author for this work

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

260 Scopus citations

Abstract

Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K _ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.

Original language	English
Pages (from-to)	440-449
Number of pages	10
Journal	Cell Metabolism
Volume	13
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2011.02.012
State	Published - 6 Apr 2011

Bibliographical note

Funding Information:
Y.D. was supported by grants from JDRF, NIH (Beta-cell Biology Consortium), ICRF (Barbara Goodman PC-RCDA), EU (ERC and the Seventh Framework Programme under grant agreement n°241883), the Leona M. and Harry B. Helmsley Charitable Trust, and the Dutch Friends of Hebrew University. B.G. was supported by a grant from JDRF. F.M.A. was supported by the Wellcome Trust. This work was supported in part through core services provided by the DERC at the University of Pennsylvania from a grant sponsored by NIH DK 19525. J.G. is an employee and shareholder of Hoffmann-La Roche. We thank Chris Wright for the generous gift of pdx1 antisera; Antonello Pileggi and Camillo Ricordi for advice on islet transplantation; and Dick Insel, Avigail Dreazen, and Oded Meyuhas for discussions.

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Porat, S., Weinberg-Corem, N., Tornovsky-Babaey, S., Schyr-Ben-Haroush, R., Hija, A., Stolovich-Rain, M., Dadon, D., Granot, Z., Ben-Hur, V., White, P., Girard, C. A., Karni, R., Kaestner, K. H., Ashcroft, F. M., Magnuson, M. A., Saada, A., Grimsby, J., Glaser, B., & Dor, Y. (2011). Control of pancreatic β cell regeneration by glucose metabolism. Cell Metabolism, 13(4), 440-449. https://doi.org/10.1016/j.cmet.2011.02.012

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abstract = "Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.",

author = "Shay Porat and Noa Weinberg-Corem and Sharona Tornovsky-Babaey and Rachel Schyr-Ben-Haroush and Ayat Hija and Miri Stolovich-Rain and Daniela Dadon and Zvi Granot and Vered Ben-Hur and Peter White and Girard, {Christophe A.} and Rotem Karni and Kaestner, {Klaus H.} and Ashcroft, {Frances M.} and Magnuson, {Mark A.} and Ann Saada and Joseph Grimsby and Benjamin Glaser and Yuval Dor",

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Porat, S, Weinberg-Corem, N, Tornovsky-Babaey, S, Schyr-Ben-Haroush, R, Hija, A, Stolovich-Rain, M, Dadon, D, Granot, Z, Ben-Hur, V, White, P, Girard, CA, Karni, R, Kaestner, KH, Ashcroft, FM, Magnuson, MA, Saada, A, Grimsby, J, Glaser, B & Dor, Y 2011, 'Control of pancreatic β cell regeneration by glucose metabolism', Cell Metabolism, vol. 13, no. 4, pp. 440-449. https://doi.org/10.1016/j.cmet.2011.02.012

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T1 - Control of pancreatic β cell regeneration by glucose metabolism

AU - Porat, Shay

AU - Weinberg-Corem, Noa

AU - Tornovsky-Babaey, Sharona

AU - Schyr-Ben-Haroush, Rachel

AU - Hija, Ayat

AU - Stolovich-Rain, Miri

AU - Dadon, Daniela

AU - Granot, Zvi

AU - Ben-Hur, Vered

AU - White, Peter

AU - Girard, Christophe A.

AU - Karni, Rotem

AU - Kaestner, Klaus H.

AU - Ashcroft, Frances M.

AU - Magnuson, Mark A.

AU - Saada, Ann

AU - Grimsby, Joseph

AU - Glaser, Benjamin

AU - Dor, Yuval

N1 - Funding Information: Y.D. was supported by grants from JDRF, NIH (Beta-cell Biology Consortium), ICRF (Barbara Goodman PC-RCDA), EU (ERC and the Seventh Framework Programme under grant agreement n°241883), the Leona M. and Harry B. Helmsley Charitable Trust, and the Dutch Friends of Hebrew University. B.G. was supported by a grant from JDRF. F.M.A. was supported by the Wellcome Trust. This work was supported in part through core services provided by the DERC at the University of Pennsylvania from a grant sponsored by NIH DK 19525. J.G. is an employee and shareholder of Hoffmann-La Roche. We thank Chris Wright for the generous gift of pdx1 antisera; Antonello Pileggi and Camillo Ricordi for advice on islet transplantation; and Dick Insel, Avigail Dreazen, and Oded Meyuhas for discussions.

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Y1 - 2011/4/6

N2 - Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.

AB - Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.

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Control of pancreatic β cell regeneration by glucose metabolism

Abstract

Bibliographical note

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