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GPR44 is a pancreatic protein restricted to the human beta cell

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Abstract

Aims

To address questions regarding onset and progression of types 1 and 2 diabetes (T1D/T2D), surrogate imaging biomarkers for beta cell function and mass are needed. Here, we assess the potential of GPR44 as a surrogate marker for beta cells, in a direct comparison with clinically used biomarker VMAT2.

Methods

GPR44 surface availability was assessed by flow cytometry of human beta cells. RNA transcription levels in different pancreas compartments were evaluated. The density of GPR44 receptor in endocrine and exocrine tissues was assessed by the radiolabeled GPR44 ligand [3H]AZD 3825. A direct comparison with the established beta cell marker VMAT2 was performed by radiolabeled [3H]DTBZ.

Results

GPR44 was available on the cell surface, and pancreatic RNA levels were restricted to the islets of Langerhans. [3H]AZD 3825 had nanomolar affinity for GPR44 in human islets and EndoC-βH1 beta cells, and the specific binding to human beta cells was close to 50 times higher than in exocrine preparations. The endocrine-to-exocrine binding ratio was approximately 10 times higher for [3H]AZD 3825 than for [3H]DTBZ.

Conclusion

GPR44 is a highly beta cell-specific target, which potentially offers improved imaging contrast between the human beta cell and the exocrine pancreas.

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Acknowledgments

The study was supported by grants from JDRF, Diabetesfonden, Barndiabetesfonden, and Tore Nilssons Foundation for Medical Research. O.E.s position was supported by ExoDiab (Excellence of Diabetes Research in Sweden) and O.K.s position was supported by the National Institutes of Health (2U01AI065192-06).

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, 751 83, Uppsala, Sweden

    Ewa Hellström-Lindahl & Olof Eriksson

  2. Department of Immunology, Genetics and Pathology, Uppsala University, 751 83, Uppsala, Sweden

    Angelika Danielsson, Fredrik Ponten & Olle Korsgren

  3. Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden

    Angelika Danielsson

  4. Endocells, 216 BD Saint Germain, 75007, Paris, France

    Paul Czernichow

  5. Department of Radiology, Oncology and Radiation Sciences, Uppsala University, 751 83, Uppsala, Sweden

    Lars Johansson

Authors
  1. Ewa Hellström-Lindahl
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  2. Angelika Danielsson
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  3. Fredrik Ponten
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  4. Paul Czernichow
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  5. Olle Korsgren
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  6. Lars Johansson
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  7. Olof Eriksson
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Corresponding author

Correspondence to Olof Eriksson.

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Conflict of interest

Paul Czernichow is an employee of EndoCells. The remaining authors report no conflicts of interest.

Ethical standard

All work involving human tissue was conducted according to the principles expressed in the Declaration of Helsinki and in the European Council’s Convention on Human Rights and Biomedicine. Consent for organ donation (for clinical transplantation and for use in research) was obtained from the relatives of the deceased donors by the donor’s physicians and documented in the medical records of the deceased subject. The study was approved by the Regional Ethics Committee in Uppsala, Sweden (http://www.epn.se) according to the Act concerning the Ethical Review of Research Involving Humans (2003:460), Permit Number: Dnr 2009/371 (from April 10, 2013).

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Additional information

Managed by Antonio Secchi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

592_2015_811_MOESM1_ESM.pdf

Supplementary Fig. 1. Representative saturation binding experiments to assess affinity (Kd) and receptor density (Bmax) of [3H]AZD 3825 (A-C) and [3H]DTBZ (D-E). Homogenized human pancreatic endocrine (A, D) or exocrine (B, E) preparations was used. [3H]AZD 3825 binding to pure human beta cells was assessed by EndoC-βH1 cell homogenates (C). Supplementary material 1 (PDF 55 kb)

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Hellström-Lindahl, E., Danielsson, A., Ponten, F. et al. GPR44 is a pancreatic protein restricted to the human beta cell. Acta Diabetol 53, 413–421 (2016). https://doi.org/10.1007/s00592-015-0811-3

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  • DOI: https://doi.org/10.1007/s00592-015-0811-3

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