XPR1 mediates the pancreatic B-cell phosphate flush

Christopher J. Barker, Fernando Henrique Galvão Tessaro, Sabrina de Souza Ferreira, Rafael Simas, Thais S. Ayala, Martin Köhler, Subu Surendran Rajasekaran, Joilson O. Martins, Elisabetta Darè, Per Olof Berggren

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Abstract

Glucose-stimulated insulin secretion is the hallmark of the pancreatic β-cell, a critical player in the regulation of blood glucose concentration. In 1974, the remarkable observation was made that an efflux of intracellular inorganic phosphate (Pi) accompanied the events of stimulated insulin secretion. The mechanism behind this “phosphate flush,” its association with insulin secretion, and its regulation have since then remained a mystery. We recapitulated the phosphate flushintheMIN6m9β-cell line and pseudoislets. We demonstrated that knockdown of XPR1, a phosphate transporter present in MIN6m9 cells and pancreatic islets, prevented this flush. Concomitantly, XPR1 silencing led to intracellular Pi accumulation and a potential impact on Ca2+ signaling. XPR1 knockdown slightly blunted first-phase glucose-stimulated insulin secretion in MIN6m9 cells, but had no significant impact on pseudoislet secretion. In keeping with other cell types, basal Pi efflux was stimulated by inositol pyrophosphates, and basal intracellular Pi accumulated following knock-down of inositol hexakisphosphate kinases. However, the glucose-driven phosphate flush occurred despite inositol pyrophosphate depletion. Finally, while it is unlikely that XPR1 directly affects exocytosis, it may protect Ca2+ signaling. Thus, we have revealed XPR1 as the missing mediator of the phosphate flush, shedding light on a 45-year-old mystery.

Original languageEnglish
Pages (from-to)111-118
Number of pages8
JournalDiabetes
Volume70
Issue number1
Early online date21 Aug 2020
DOIs
Publication statusE-pub ahead of print - 21 Aug 2020

Bibliographical note

Funding Information:
Acknowledgments. The authors thank Professor S. Seino (Kobe University Graduate School of Medicine, Kobe, Japan) for the gift of MIN6m9 cells; Dr. J.H. Park (Soonchunhyang University College of Medicine, Cheonan, Korea), Dr. B. Leibiger and Dr. V.M. Lauschke (Karolinska Institutet, Stockholm, Sweden), Professor D. Piston (Washington University School of Medicine, St. Louis), and Dr. C. Reissaus (Novo Nordisk Research Center, Indianapolis) for advice about pseudoislets; and Professor A. Saiardi and Dr. M.S. Wilson (UCL, London, UK) for advice on Pi assays. Funding. This study was supported by the Vetenskapsrådet, the Novo Nordisk Foundation, Karolinska Institutet, the Swedish Diabetes Association, The Family Knut and Alice Wallenberg Foundation, Diabetes Research and Wellness Foundation, Stiftelsen för Strategisk Forskning, Berth von Kantzow’s Foundation, The Skandia Insurance Company Ltd., Strategic Research Programme in Diabetes at Karolinska Institutet, ERC-2013-AdG (338936-BetaImage), ERC-2018-AdG (834860 EYELETS), the Stichting af Jochnick Foundation, the Family Erling-Persson Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo grants 2010/02272-0, 2014/05214-1, and 2017/11540-7, CNPq (PQ-1D) grant 301617/ 2016-3, and Swedish Foundation for International Cooperation in Research and Higher Education and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior grants. Duality of Interest. P.-O.B. is Chief Executive Officer of the biotech company Biocrine AB, and C.J.B. and M.K. are consultants with this company. No other potential conflicts of interest relevant to this article were reported. Author Contributions. C.J.B. and P.-O.B. conceived the project. C.J.B., F.H.G.T., S.d.S.F., R.S., T.S.A., M.K., J.O.M., E.D., and P.-O.B. designed experiments. C.J.B., F.H.G.T., S.d.S.F., R.S., T.S.A., M.K., S.S.R., and E.D. carried out experiments. C.J.B., F.H.G.T., S.d.S.F., R.S., T.S.A., M.K., and E.D. analyzed data. C.J.B. and P.-O.B. wrote the article with input from all authors. C.J.B. and P.-O.B. are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
The authors thank Professor S. Seino (Kobe University Graduate School of Medicine, Kobe, Japan) for the gift of MIN6m9 cells; Dr. J.H. Park (Soonchunhyang University College of Medicine, Cheonan, Korea), Dr. B. Leibiger and Dr. V.M. Lauschke (Karolinska Institutet, Stockholm, Sweden), Professor D. Piston (Washington University School of Medicine, St. Louis), and Dr. C. Reissaus (Novo Nordisk Research Center, Indianapolis) for advice about pseudoislets; and Professor A. Saiardi and Dr. M.S. Wilson (UCL, London, UK) for advice on Pi assays. Funding. This study was supported by the Vetenskapsr?det, the Novo Nordisk Foundation, Karolinska Institutet, the Swedish Diabetes Association, The Family Knut and Alice Wallenberg Foundation, Diabetes Research and Wellness Foundation, Stiftelsen f?r Strategisk Forskning, Berth von Kantzow?s Foundation, The Skandia Insurance Company Ltd., Strategic Research Programme in Diabetes at Karolinska Institutet, ERC-2013-AdG (338936-BetaImage), ERC-2018-AdG (834860 EYELETS), the Stichting af Jochnick Foundation, the Family Erling-Persson Foundation, Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo grants 2010/02272-0, 2014/05214-1, and 2017/11540-7, CNPq (PQ-1D) grant 301617/ 2016-3, and Swedish Foundation for International Cooperation in Research and Higher Education and Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior grants.

Publisher Copyright:
© 2020 by the American Diabetes Association.

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