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Islet neogenesis-associated protein-related pentadecapeptide improves the function of allograft after islets transplantation

  • Heng Chen , Mei Zhang , Yun Wang , Xiaozhu Yu , Yong Gu , Xinyu Xu , Kuanfeng Xu , Yun Cai , Min Sun , Hongwen Zhou and Tao Yang EMAIL logo
Published/Copyright: August 5, 2014

Abstract

Objective: To investigate the protective effects of a pentadecapeptide of islet neogenesis-associated protein (INGAP-PP) on transplanted islets function.

Methods: Islets were cultured in RPMI 1640 with or without INGAP-PP (10 μg/mL). After 24 h, the viability of the islets and glucose-stimulated insulin secretion (GSIS) were measured. The expression of genes B cell lymphoma/lewkmia2 (Bcl2) and protein kinase B (Akt) were detected by RT-PCR assay. Healthy rats transplanted with islets under the renal capsule were injected with INGAP-PP or saline in in the abdominal cavity. One week later, the expression of insulin nestin pancreatic (nestin) and duodenal homeobox 1 (Pdx1) and proliferating cell nuclear antigen (PCNA) in the transplanted islets were observed by immunohistochemistry. After that they were transplanted to the renal capsule of diabetic rats.

Results: 1. The amount of insulin released was increased in co-cultured group in concentration of 16.7 mmol/L glucose, which was (185.00±20.01 μU/mL) vs. (58.67±17.03 μU/mL). Gene expression of Bcl2 (0.61±0.22 vs. 0.50±0.21) and Akt (1.12±0.19 vs. 0.94±0.16) in the co-cultured group were increased compared with that of the control group. Islets viability in the co-cultured group (683.9±7.08) was higher than that of control group (547.9±8.02). The stimulating index (SI) of the co-cultured group was also higher than that of the control group. 2. The group of islets under the renal capsule which were co-cultured and injected with INGAP-PP had the more nestin expression in the islets.

Conclusions: The function of islet can be protected by the INGAP-PP, which will promote the viability, differentiation and regeneration of islet before transplantation. And it will be beneficial for the function of allograft after islets transplantation.


Corresponding author: Tao Yang, Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China, Phone/Fax: +86-25-83781781, E-mail:
aHeng Chen and Mei Zhang contributed equally to this work.

Conflict of interest statement

Ethical conduct of research: The experiments comply with the current laws of China.

Authors’ conflict of interest disclosure: The authors declare that they have no conflict of interest.

Funding source: This work was supported by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, and grants from Jiangsu Province clinical science and technology projects (BL2012026) and the National Natural Science Foundation of China (Grants No. 81270897 and 30971405).

References

1. Vinik A, Rafaeloff R, Pittenger G, Rosenberg L, Duguid W. Induction of pancreatic islet neogenesis. Horm Metab Res 1997;29:278–93.10.1055/s-2007-979037Search in Google Scholar

2. Gagliardino JJ, Del Zotto H, Massa L, Flores LE, Borelli MI. Pancreatic duodenal homeobox-1 and islet neogenesis-associated protein: a possible combined marker of activateable pancreatic cell precursors. J Endocrinol 2003;177:249–59.10.1677/joe.0.1770249Search in Google Scholar

3. Rafaeloff R, Pittenger GL, Barlow SW, Qin XF, Yan B, et al. Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters. J Clin Invest 1997;99:2100–9.10.1172/JCI119383Search in Google Scholar

4. Borelli MI, Stoppiglia LF, Rezende LF, Flores LE, Del Zotto H, et al. INGAP-related pentadecapeptide: its modulatory effect upon insulin secretion. Regul Pept 2005;131:97–102.10.1016/j.regpep.2005.07.003Search in Google Scholar

5. Pittenger GL, Taylor-Fishwick DA, Johns RH, Burcus N, Kosuri S, et al. Intramuscular injection of islet neogenesis-associated protein peptide stimulates pancreatic islet neogenesis in healthy dogs. Pancreas 2007;34:103–11.10.1097/01.mpa.0000240609.56806.43Search in Google Scholar

6. Tam J, Rosenberg L, Maysinger D. INGAP peptide improves nerve function and enhances regeneration in streptozotocin-induced diabetic C57BL/6 mice. Faseb J 2004;18:1767–9.10.1096/fj.04-1894fjeSearch in Google Scholar

7. Fleming A, Rosenberg L. Prospects and challenges for islet regeneration as a treatment for diabetes: a review of islet neogenesis associated protein. J Diabetes Sci Technol 2007;1: 231–44.10.1177/193229680700100214Search in Google Scholar

8. Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 2002;51:2148–57.10.2337/diabetes.51.7.2148Search in Google Scholar

9. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86.10.1056/NEJM199309303291401Search in Google Scholar

10. Ault A. Edmonton’s islet success tough to duplicate elsewhere 2003; Lancet 361:2054.10.1016/S0140-6736(03)13680-XSearch in Google Scholar

11. Mamode N, Sutherland DE. Transplantation for diabetes mellitus. Br J Surg 2003;90:1031–2.10.1002/bjs.4295Search in Google Scholar

12. Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54:2060–9.10.2337/diabetes.54.7.2060Search in Google Scholar

13. Lechner A, Nolan AL, Blacken RA, Habener JF. Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue. Biochem Biophys Res Commun 2005;327:581–8.10.1016/j.bbrc.2004.12.043Search in Google Scholar

14. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230–8.10.1056/NEJM200007273430401Search in Google Scholar

15. Rosenberg L, Wang R, Paraskevas S, Maysinger D. Structural and functional changes resulting from islet isolation lead to islet cell death. Surgery 1999;126:393–8.10.1016/S0039-6060(99)70183-2Search in Google Scholar

16. Ratner RE, Feeley D. Double-blind, placebo-controlled trial of Islet Neogenesis Gene Associated Protein (INGAP) in subjects with Type 1 Diabetes Mellitus (T1DM). American Diabetes Association Annual Meeting. San Diego, CA, 2005.Search in Google Scholar

17. Ratner RE, Feeley D. Double-blind, placebo-controlled trial of Islet Neogenesis Gene Associated Protein (INGAP) in subjects with Type 2 Diabetes Mellitus (T2DM). American Diabetes Association Annual Meeting. San Diego, CA, 2005.Search in Google Scholar

18. Zha M, Zhang M, Shan S, Xu KF, Chen H, et al. Effects of islet neogenesis-associated protein pentadecapeptide on cell mass and insulin secretion of pancreatic β-cells. J Endocrinol Invest 2012;35:634–9.Search in Google Scholar

19. Bohman S, King AJ. Islet alpha cell number is maintained in microencapsulated islet transplantation. Biochem Biophys Res Commun 2008;377:729–33.10.1016/j.bbrc.2008.10.059Search in Google Scholar

20. Herbert V, Lau KS, Gottlieb CW, Bleicher SJ. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab 1965;25:1375–84.10.1210/jcem-25-10-1375Search in Google Scholar

21. Chun S, Huang Y, Xie WJ, Hou Y, Huang RP, et al. Adhesive growth of pancreatic islet cells on a polyglycolic acid fibrous scaffold. Transplant Proc 2008;40:1658–63.10.1016/j.transproceed.2008.02.088Search in Google Scholar

22. Taylor-Fishwick DA, Rittman S, Kendall H, Roy L, Shi W, et al. Cloning genomic INGAP: a Reg-related family member with distinct transcriptional regulation sites. Biochim Biophys Acta 2003;1638:83–9.10.1016/S0925-4439(03)00042-5Search in Google Scholar

23. Pittenger GL, Vinik AI, Rosenberg L. The partial isolation and characterization of ilotropin, a novel islet-specific growth factor. Adv Exp Med Biol 1992;321:123–130; discussion 131–132.10.1007/978-1-4615-3448-8_13Search in Google Scholar PubMed

24. Garcia-Ocana A, Vasavada RC, Takane KK, Cebrian A, Lopez-Talavera JC, et al. Using beta-cell growth factors to enhance human pancreatic Islet transplantation. J Clin Endocrinol Metab 2001;86:984–8.Search in Google Scholar

25. Barbosa H, Bordin S, Stoppiglia L, Silva K, Borelli M, et al.. Islet Neogenesis Associated Protein (INGAP) modulates gene expression in cultured neonatal rat islets. Regul Pept 2006;136:78–84.10.1016/j.regpep.2006.04.015Search in Google Scholar

26. Li J, Wang Y, Yu X, Chen H, Wu Y, et al. Islet neogenesis-associated protein-related pentadecapeptide enhances the differentiation of islet-like clusters from human pancreatic duct cells. Peptides 2009;30:2242–9.10.1016/j.peptides.2009.09.003Search in Google Scholar

27. Biarnes M, Montolio M, Nacher V, Raurell M, Soler J, et al. Beta-cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia. Diabetes 2002;51:66–72.10.2337/diabetes.51.1.66Search in Google Scholar

28. Soldevila G, Buscema M, Doshi M, James RF, Bottazzo GF, et al. Cytotoxic effect of IFN-gamma plus TNF-alpha on human islet cells. J Autoimmun 1991;4:291–306.10.1016/0896-8411(91)90025-8Search in Google Scholar

29. Rosenberg L, Lipsett M, Yoon JW, Prentki M, Wang R, et al. A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice. Ann Surg 2004;240:875–84.10.1097/01.sla.0000143270.99191.10Search in Google Scholar PubMed PubMed Central

Received: 2014-3-19
Accepted: 2014-6-12
Published Online: 2014-8-5
Published in Print: 2014-11-1

©2014 by De Gruyter

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