Abstract

Diabetes mellitus is a hyperglycemic syndrome characterized by a reduced production of insulin or of insulin action and a relative or absolute increase of glucagon, the main insulin counterregulatory hormone. The disease courses with mutilating chronic complications. The inability to produce or to respond to insulin, a hormone synthesized by pancreatic β-cells, leads to diabetes. There is an excruciating need of finding new approaches to protect or restore these cells once they are lost. The first rudimentary attempt to transplant the pancreas occurred in 1894 before insulin was isolated by Banting, Best and Collip in 1921. Current research is focusing on β-cell regeneration in the human pancreas, this probably being one of the most controversial aspects of research on DM1. As a more general definition, we may state that β-cell regeneration corresponds to the formation of new β-cells whether or not these cells were actually lost. The potential mechanisms of β-cell regeneration are the proliferation of these specific cells, their neogenesis from non-β-cell precursors, and their trans-differentiation from α-cells. There are favorable and unfavorable arguments regarding the ability of the human pancreas to regenerate β-cells within the context of DM1 and in other pathological conditions such as resections, fibrocystic disease and neoplasia. The enigma continues regarding whether the function of β-cells persists in diabetic patients through regeneration or neogenesis maintained in T1D. In this paper we discuss the history of Diabetes knowing from Insulin Discovery until α- cell transdifferentiating.

Keywords: Regeneration; Trans Differentiation; Beta-Cell; Pancreas Islet; Pancreas Gland

References

1. Becherel AH. “Descobrimento da radiação invisível emitida pelo urânio-1896-1897.
2. Gênesis 2: 21-22.
3. The discovery of insulin: what happened 80 years ago”. Annali Italiani di Medicina Interna3 (2001): 155-156.
4. Bekke IB. “Pancreas transplantation. Atlas of Clinical Transplantation”. In: Ari Hayule, Krioter Hockerstedt. Copyright @ recall med Ltd (1955): 96.
5. Ballinger WF and Lacy PE. “Transplantation of intact pancreatic islets in rats”. Surgery2 (1972): 175-186.
6. Scharp DW., et al. “Insulin independence after islet transplantation into type I diabetic patient”. Diabetes 4 (1990): 515-518.
7. IPTR- International Pancreas Transplant Register.
8. Shapiro AM., et al. “Islet Transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen”. The New England Journal of Medicine 27 343.4 (2000): 230-238.
9. Snarski E., et al. “Independence of exogenous insulin following immunoablation and stem cell reconstitution in newly diagnosed diabetes type 1”. Bone Marrow Transplantation 46 (2010): 562-566.
10. Van Megen KM., et al. “A Future for autologous hematopoietic stem cell transplantation in type 1 diabetes”. Frontiers in Immunology 9 (2018): 690.
11. Couri CEB., et al. “New Horizons in the treatment of type 1 Diabetes: More Intensive Immunosuppression and beta cell replacement”. Frontiers in Immunology 9 (2018): 1086.
12. Gianani R. “Beta cell regeneration in human pancreas”. Seminars in Immunopathology 1 (2011) : 237.
13. Dong S and Wu Hi. “Regenerating βcells of pancreas - potential developments in diabetes treatment”. Expert Opinion on Biological Therapy2 (2018): 175-185.
14. Pan G., et al. “Examining the therapeutic potential of various stem cell sources for differentiation into insulin-producing cells to treat diabetes”. Annales d Endocrinologie 1 (2019): 47-53.
15. Baeyens L., et al. “(Re) generating human beta cells: status, pitfalls and perspectives”. Physiological Reviews 3 (2018): 1143-1167.
16. Zhou Q and Melton DA. “Pancreas regeneration”. Nature 7705 (2018): 351-358.
17. Bhartiva D., et al. “Novel Insights into adult and cancer stem cell biology”. Stem Cells and Development 22 (2018): 1527-1539.
18. Miyatsuka T. “Chronology of endocrine differentiation and beta cell neogenesis”. Endocrine Journal 3 (2016): 205-211.
19. Verfaille CM. “Multipotent adult progenitor cells: an update”. Novartis Foundation Symposia (2005).
20. Dominguez-Bendala J., et al. “Pancreatic progenitors: There and back again”. Trends in Endocrinology and Metabolism 1 (2019): 4-11.
21. Karakose E., et al. “Advances in drug discovery for human beta cell regeneration”. Diabetologia8 (2018): 1693-1699.
22. Sneddon JB., et al. “Stem cell therapies for treating diabetes: progress and remaining challenges”. Cell Stem cell 6 (2018): 810-823.
23. Lysy PA. “Cellular therapy of diabetes: focus on the latest developments”. Medical Sciences 4 (2016): 401-407.
24. Wilcox NS., et al. “Life and death of βcells in Type 1 diabetes: a comprehensive review”. Journal of Autoimmunity 71 (2016): 51-58.
25. Stock PG and German MS. “A Path to insulin independence: The end of the Beginning”. Cell Stem Cell4 (2016): 431-433.
26. Kulijanin M., et al. “Quantitative proteomics evaluation of human multipotent stromal cell for β cell regeneration”. Cell Reports 9-208 (2018): 2524-2536.
27. Jiang Y., et al. “The Role of the TGFβ receptor signaling pathway in adult beta cell proliferation”. International Journal of Molecular Sciences 10 (2018): 3136.
28. Huising MO., et al. “Evidence for a neogenic niche at the periphery of pancreatic islet”. Bioessays11 (2018).
29. Schulz N., et al. “Critical role for adenosine receptor A2a in β- cell proliferation”. Molecular Metabolism 11 (2018): 1138-1146.
30. Xu J., et al. “Inhibition of TBK1/KKε promotes regeneration of pancreatic β- cells”. Scientific Reports 8 (2018): 15587.
31. Butler AE., et al. “In the setting of β-cell stress, the pancreatic duct gland transcriptome shows characteristics of an activated regenerative response”. The American Journal of Physiology: Gastrointestinal and Liver Physiology 5 (2018): G848-G854.
32. Ye L., et al. “Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis”. Development 8 (2015): 1407-1417.
33. Piran R., et al. “PAR2 regulates regeneration, transdifferentiation, and death”. Cell Death and Disease 11 (2016): e2452.
34. Thorel F., et al. “Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss”. Nature 7292 (2010): 1149-1459.
35. Habner JF and Stanojevic V. “α-cell role in β-cell generation and regeneration”. Islet3 (2012): 188-198.
36. Ota S., et al. “Involvement of pancreatic stellate cells in regeneration of remnant pancreas after partial pancreatectomy”. PLoS One (2016).
37. Saunders D and Powers AC. “Replicative capacity of β-cells and type 1 diabetes”. Journal of Autoimmunity 1 (2016): 59-68.
38. Lam CJ., et al. “βCells Persist in T1D pancreata without evidence of ongoing β- cell turnover or neogenesis”. The Journal of Clinical Endocrinology and Metabolism 8 (2017): 2467-2659.
39. Beamish CA., et al. “An increase in immature β-cells lacking Glut2 precedes the expansion of β-cell mass in the pregnant mouse”. PLoS One (2017): 0182256.
40. Chera S and Herrera PL. “Regeneration of pancreatic insulin-producing cells by in situ adaptative cell conversion”. Current Opinion in Genetics and Development 40 (2016): 1-10.
41. Ye R., et al. “Adiponectin-mediated antilipo toxic effects in regenerating pancreatic islet”. Endocrinology6 (2015): 2019-2028.