A journey from the insulin gene to reprogramming pancreatic tissue

Authors

  • Kevin Docherty Institute of Medical Sciences, University of Aberdeen

DOI:

https://doi.org/10.15277/bjd.2022.371

Keywords:

gene therapy and diabetes, embryonic stem cells and diabetes, reprogramming and diabetes, pancreatic transcription factors, Islets of Langerhans

Abstract

This article was written as a contribution to mark the centenary of the first administration of insulin to a human in 1922. Writing from an Aberdeen perspective, an introductory passage will place emphasis on the role of JJR MacLeod, under whose supervision the discovery of insulin by Banting and Best was made. The major thrust of the article, however, will be on the cloning and sequencing of the human insulin gene, and the impact it had on the scientific career of the author. It initiated a journey to find alternative therapies for diabetes that led sequentially though gene therapy, embryonic stem cell-derived islets, and reprogramming. Our experience in these areas will be described, with emphasis on the strengths and weaknesses of each of these approaches.

References

Bliss M. The Discovery of Insulin. 1982 Toronto: McClelland and Stewart: London MacMillan. ISBN 13:9780771015762

Bliss M, Banting FG, Best CH, Collip JB. Banting, Best and Collips’s accounts of the discovery of insulin. Bulletin of the History of Medicine 1982;56: 554-568. http:jstor.org/stable/44441518

Bell GI, Pictet RL, Rutter WJ, et al. Sequence of the human insulin gene. Nature 1980;284:26-32. https://doi.org/10.1038/284026a0

Williams MJ. JJR Macleod: the co-discoverer of insulin. Proc Roy Coll Physi- cians Edinb 1993;23:1–125. PMID:11613051

Boam DSW, Clark AR, Docherty K. Positive and negative regulation of the human insulin gene by multiple trans-acting factors. J Biol Chem 1990; 265:8285-96. https://doi.org/10.1016/S0021-9258(19)39070-2

Boam DSW, Docherty K. A tissue-specific nuclear factor binds to multiple sites in the human insulin gene enhancer. Biochem J 198p;264:233-9.

Hammond-Kosack MCU, Dobrinski B, Lurz R, et al. The human insulin linked polymorphic region exhibits an altered DNA structure. Nucleic Acids Res 1990;20:231-6.https://doi.org/10.1093/nas/20.2.231

Bailey CJ, Docherty K. Exploring the feasibility of insulin gene therapy. In: Frontiers of insulin secretion and pancreatic B-cell research. Flatt, PR and Lenzen S (eds). 1995 Smith-Gordon, London pp.1-78.

Docherty K. Gene therapy for Diabetes Mellitus. Clin Sci 1997; 92:321-30. https://doi.org/10.1042/cs0920321

Shaw JAM, Delday MI, Hart AJ, et al. Secretion of bioactive insulin follow- ing plasmid-mediated gene transfer to non-neuroedocrine cell lines, pri- mary cultures and rat skeletal muscle in vivo. J Endocrinol 2002;172: 653-672. https://doi.org/10.1677/joe.0.1720653

Hay CW, Docherty K. Enhanced expression of a furin cleavable proinsulin. J Mol Endocrinol 2003;31:597-607. https://doi.org/10.1677/jme.0.0310597

Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppres- sive regimen. N Engl J Med 2000;343:230-8. https://doi.org/10.1056/ NEJM200007273430401

Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005; 54:2060-69. https://doi.org/10.2337/dia- betes.54.7.2060

Docherty K, Bernardo AS, Vallier L. Embryonic stem cell therapy for diabetes mellitus. Semin Cell Dev Biol 2007;18:827-38. https://doi.org/10.1016/ j.semcdb.2007.09.009

Rezania A, Bruin JE, Arora P, et al. Reversal of diabetes with insulin-pro- ducing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 2014;32:1121-33. https://doi.org/10.1038/nbt.3033

Pagliuca FW, Millman JR, Gurtler M, et al. Generation of functional human pancreatic beta cells in vitro. Cell 2014;159:428-39. https://doi.org/ 10.1016/j.cell.2014.09.040

Docherty FM, Riemondy KA, Castro-Gutierrez R, et al. ENTPD3 Marks Mature Stem Cell-Derived β-Cells Formed by Self-Aggregation In Vitro. Diabetes 2021;70:2554-67.https://doi.org/10.2337/db20-0873

Tosh D, Slack JM. How cells change their phenotype. Nat Rev Mol Cell Biol 2002;3:187-94. https://doi.org/10.1038/nrm761

Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126: 663-76. https://doi.org/10.1016/j/cell.2006.07.024

Lima MJ, Muir KR, Docherty HM, et al. Suppression of epithelial-to-mes- enchymal transitioning enhances ex vivo reprogramming of human ex- ocrine pancreatic tissue toward functional insulin-producing beta-like cells. Diabetes 2013;62:2821-33. https://doi.org/10.2337/db12-1256

Angadi PV and Kale AD Epithelial to mesenchymal transition – A fundamental mechanism in cancer progression: An overview. Indian J. Health Sci 2015 18 77-84

Muir KR, Lima MJ, Docherty HM, et al. Krueppel like factor 4 Overexpres- sion Initiates a Mesenchymal-to-Epithelial Transition and Redifferentiation of Human Pancreatic Cells following Expansion in Long Term Adherent Culture. PLoS One 2015;10:e0140352. https://doi.org/10.1371/ journal.pone.0140352

Collombat P, Mansouri A, Hecksher-Sorensen J, et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 2003;17: 2591-2603. https://doi.org/10.1101/gad.269003

Gage BK, Asadi A, Baker RK, et al. The Role of ARX in Human Pancreatic Endocrine Specification. PLoS One 2015;10:e0144100. https://doi.org/ 10.1371/journal.pone.0144100

Grimm D, Wehland M, Pietsch J, et al. Growing Tissues in Real and Simu- lated Microgravity: New Methods for Tissue Engineering. Tissue Engineer- ing 2014;20:555-66. https://doi.org/10.1089/ten.TEB.2013.0704

Lima MJ, Muir KR, Docherty HM, et al. Generation of Functional β-Like Cells from Human Exocrine Pancreas. PloS One 2016;11:e0156204. https://doi.org/10.1371/journal.pone.0156204

Docherty K, Lima MJ, Vaughan B. Cell Therapy for Diabetes. Impact 2016; 2:83-5.

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Published

2022-12-22