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Insulin regulates glucagon-like peptide-1 secretion by pancreatic alpha cells

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Abstract

Purpose

Proglucagon is expressed in both pancreatic alpha cells and intestinal epithelial L cells and is cleaved into glucagon and glucagon-like peptide-1 (GLP-1) by different prohormone convertases (PCs). Recent studies have shown that α-cells can also secrete GLP-1, which may improve islet function. However, little is known about the factors influencing GLP-1 secretion by α cells. In this study, we investigated whether insulin promotes GLP-1 secretion by α cells, as well as the mechanisms underlying this phenomenon.

Methods

We cultured the alpha-cell line In-R1-G9 in low- or high-glucose medium in the presence or absence of insulin to determine the influence of glucose concentrations on the actions of insulin. We also treated In-R1-G9 cells with insulin for different times and at different doses. Then GLP-1 and glucagon protein expression levels were estimated. Moreover, ERK and phosphatidylinositol-3-kinase/AKT (PI3K/AKT) pathway activity levels and prohormone convertase expression levels were evaluated to elucidate the mechanism underlying the effects of insulin on GLP-1 secretion by α-cells.

Results

Insulin promoted GLP-1 secretion in a time- and dose-dependent manner under high-glucose conditions. Inhibiting the PI3K/AKT pathway with LY294002 and the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway with PD98059 reduced GLP-1 secretion, respectively, in inhibitor-treated cells compared with insulin-treated cells. Moreover, insulin increased prohormone convertase 1/3 expression levels in the corresponding group of IN-R1-G9 cells compared with the control group of cells.

Conclusion

Insulin facilitates GLP-1 secretion by pancreatic alpha cells by inducing PC1/3 expression under high-glucose conditions, a phenomenon that may be associated mainly with PI3K/AKT pathway activation.

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References

  1. E. Mannucci, F. Tesi, G. Bardini et al. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes Nutr. Metab. 17, 336–342 (2004)

    CAS  PubMed  Google Scholar 

  2. C. Over, D.M. Berman, N.S. Kenyon et al.The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl Acad. Sci. USA 103, 2334–2339 (2006)

    Article  Google Scholar 

  3. D.J. Steiner, A. Kim, K. Miller, M. Hara Pancreatic islet plasticity: Interspecies comparison of islet architecture and composition. Islets 2, 135–145 (2010)

    Article  Google Scholar 

  4. R.H. Unger, L. Orci, The essential role of glucagon in the patho-genesis of diabetes mellitus. Lancet 1, 14–16 (1975)

    Article  CAS  Google Scholar 

  5. J.S. Moon, K.C. Won, Pancreatic α-cell dysfunction in type 2 diabetes: old kids on the block. Diabetes Metab. J. 39, 1–9 (2015)

    Article  Google Scholar 

  6. F. Thorel, V. Népote, I. Avril et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149–1154 (2010)

    Article  CAS  Google Scholar 

  7. C.H. Chung, E. Hao, R. Piran et al. Pancreatic beta cell neogenesis by direct conversion from mature alpha cells. Stem Cells 28, 1630–1638 (2010)

    Article  CAS  Google Scholar 

  8. L. Ye, M.A. Robertson, D. Hesselson, D.Y. Stainier, R.M. Anderson, Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis. Development 142, 1407–1417 (2015)

    Article  CAS  Google Scholar 

  9. P. Collombat, X. Xu, P. Ravassard et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 138, 449–462 (2009)

    Article  CAS  Google Scholar 

  10. Y.P. Yang, F. Thorel, D.F. Boyer, P.L. Herrera, C.V. Wright, Context-specific alpha-to-beta-cell reprogramming by forced Pdx1 expression. Genes Dev. 25, 1680–1685 (2011)

    Article  CAS  Google Scholar 

  11. R.D. Wideman, I.L. Yu, T.D. Webber et al. Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1. Proc. Natl Acad. Sci. USA 103, 13468–13473 (2006)

    Article  CAS  Google Scholar 

  12. G.E. Fava, E.W. Dong, H. Wu, Intra-islet glucagon-like peptide 1. J. Diabetes Complicat. 30, 1651 (2016)

    Article  Google Scholar 

  13. G.E. Lim, P.L. Brubaker, Glucagon-like peptide 1 secretion by the L-cell: the view from within. Diabetes 55, S70 (2006)

    Article  CAS  Google Scholar 

  14. P. Marchetti, R. Lupi, M. Bugliani et al. A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia 55, 3262–3272 (2012)

    Article  CAS  Google Scholar 

  15. Z. Liu, V. Stanojevic, S. Avadhani, T. Yano, J.F. Habener, Stromal cell-derived factor-1 (SDF-1)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis activation induces intra-islet glucagon-like peptide-1 (GLP-1) production and enhances beta cell survival. Diabetologia 54, 2067–2076 (2011)

    Article  CAS  Google Scholar 

  16. H. Ellingsgaard, I. Hauselmann, B. Schuler et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011)

    Article  CAS  Google Scholar 

  17. K. Timper, E. Dalmas, E. Dror et al. Glucose-dependent insulinotropic peptide stimulates glucagon-like peptide 1 production by pancreatic islets via interleukin-6, produced by α cells. Gastroenterology 151, 165 (2016)

    Article  CAS  Google Scholar 

  18. R.D. Wideman, I.L. Yu, T.D. Webber et al. Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1). Proc. Natl Acad. Sci. USA 103, 13468–13473 (2006)

    Article  CAS  Google Scholar 

  19. S. Piro, L.G. Mascali, F. Urbano et al. Chronic exposure to GLP-1 increases GLP-1 synthesis and release in a pancreatic alpha cell line (α-TC1): evidence of a direct effect of GLP-1 on pancreatic alpha cells. PLoS ONE 9, e90093 (2014)

    Article  Google Scholar 

  20. G.E. Lim, G.J. Huang, N. Flora et al. Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell. Endocrinology 150, 580–591 (2008)

    Article  Google Scholar 

  21. B. Domenico, A. Mathieu, M. Philippe et al. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59, 1202–1210 (2010)

    Article  Google Scholar 

  22. P.J. Lefèbvre, Early milestones in glucagon research. Diabetes Obes. Metab. 13(Suppl. 1), 1–4 (2011)

    Article  Google Scholar 

  23. S. Dhanvantari, N.G. Seidah, P.L. Brubaker, Role of prohormone convertases in the tissue-specific processing of proglucagon. Mol. Endocrinol. 10, 342–355 (1996)

    CAS  PubMed  Google Scholar 

  24. S. Vasu, R.C. Moffett, N.H. McClenaghan, P.R. Flatt, Differential molecular and cellular responses of GLP-1 secreting L-cells and pancreatic alpha cells to glucotoxicity and lipotoxicity. Exp. Cell Res. 336, 100–108 (2015)

    Article  CAS  Google Scholar 

  25. R. Takaki, J. Ono, M. Nakamura et al. Isolation of glucagon-secreting cell lines by cloning insulinoma cells. In Vitr. Cell. Dev. Biol. 22, 120–126 (1986)

    Article  CAS  Google Scholar 

  26. N.M. Whalley, L.E. Pritchard, D.M. Smith et al. Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells? J. Endocrinol. 211, 99–106 (2011)

    Article  CAS  Google Scholar 

  27. S. Muntoni, S. Muntoni, Insulin resistance: pathophysiology and rationale for treatment. Ann. Nutr. Metab. 58, 25–36 (2011)

    Article  CAS  Google Scholar 

  28. K. Kisanuki, H. Kishikawa, E. Araki et al. Expression of insulin receptor on clonal pancreatic alpha cells and its possible role for insulin-stimulated negative regulation of glucagon secretion. Diabetologia 38, 422–429 (1995)

    Article  CAS  Google Scholar 

  29. C.M. Taniguchi, B. Emanuelli, C.R. Kahn, Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85–96 (2006)

    Article  CAS  Google Scholar 

  30. Y. Anini, P.L. Brubaker, Muscarinic receptors control glucagon-like peptide 1 secretion by human endocrine L cells. Endocrinology 144, 3244–3250 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81670706 and 81770818), National Special Scientific Research Fund of Public Welfare Profession (No. 201502007), National Key Research and Development Plan (No. 2016YFC0901204).

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Author notes

  1. These two authors are co-first authors: Pan Liu, Jia Song.

Authors and Affiliations

  1. Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250000, China

    Pan Liu, Jia Song, He Liu, Fei Yan, Tianyi He, Lingshu Wang, Xinguo Hou & Li Chen

  2. Institute of Endocrinology and Metabolism, Shandong University, Jinan, 250000, China

    Pan Liu, Jia Song, He Liu, Fei Yan, Tianyi He, Lingshu Wang, Xinguo Hou & Li Chen

  3. Key Laboratory of Endocrinology and Metabolism, Shandong Province in Medicine & Health, Jinan, 250000, China

    Pan Liu, Jia Song, He Liu, Fei Yan, Tianyi He, Lingshu Wang, Xinguo Hou & Li Chen

  4. Baylor College of Medicine, Houston, TX, USA

    Huying Shen

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  1. Pan Liu
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  2. Jia Song
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  3. He Liu
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Correspondence to Xinguo Hou or Li Chen.

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Liu, P., Song, J., Liu, H. et al. Insulin regulates glucagon-like peptide-1 secretion by pancreatic alpha cells. Endocrine 62, 394–403 (2018). https://doi.org/10.1007/s12020-018-1684-3

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  • DOI: https://doi.org/10.1007/s12020-018-1684-3

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