SpringerLink
Log in

Islet isograft transplantation improves insulin sensitivity in a murine model of type 2 diabetes

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Type 2 diabetes develops in the presence of chronic overnutrition and genetic susceptibility, and causes insulin resistance and relative insulin deficiency. We hypothesized that islet transplantation can improve insulin sensitivity by modifying the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues.

Methods

Eight-week-old male mice were used as both recipients and donors in this study. To induce type 2 diabetes with partial β-cell failure, the mice were fed a high-fat diet for 4 weeks and then injected with low-dose streptozotocin. Approximately 400 islet cells from a donor mouse were injected into the renal capsule of a recipient mouse for islet transplantation. After 6 weeks following transplantation, the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues were quantitatively compared between islet-transplanted and non-transplanted groups.

Results

Intravenous glucose tolerance test showed that whereas the non-transplanted mice failed to show notable reductions in the glucose level, the islet-transplanted mice showed significant reductions in the serum glucose level to ~200 mg/dL at 6 weeks after islet transplantation. The islet-transplanted mice showed significantly higher Matsuda index and significantly lower HOMA-IR than did the non-transplanted mice, thus signifying improved insulin sensitivity.

Conclusions

Islet transplantation resulted in improvements in multiple indices of insulin sensitivity in a murine model of type 2 diabetes. Islet transplantation may be utilized to improve insulin sensitivity in patients with type 2 diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. D.M. Muoio, C.B. Newgard, Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9(3), 193–205 (2008)

    Article  CAS  PubMed  Google Scholar 

  2. V.T. Samuel, G.I. Shulman, The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J. Clin. Invest. 126(1), 12–22 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  3. G. Sesti, Pathophysiology of insulin resistance. Best. Pract. Res. Clin. Endocrinol. Metab. 20(4), 665–679 (2006)

    Article  CAS  PubMed  Google Scholar 

  4. Y. Chen, J. Lippincott-Schwartz. Selective visualization of GLUT4 storage vesicles and associated Rab proteins using IRAP-pHluorin. in Rab GTPases: Methods and Protocols, ed. by G. Li (Humana Press, New York, NY, 2015), p. 173–179

  5. J.E Hall, M.E Hall. Guyton and Hall Textbook of Medical Physiology, 14th edn. (Elsevier, Philadelphia, PA, 2020)

  6. S. Huang, M.P. Czech, The GLUT4 glucose transporter. Cell Metab. 5(4), 237–252 (2007)

    Article  CAS  PubMed  Google Scholar 

  7. B.G. Topp, L.L. Atkinson, D.T. Finegood, Dynamics of insulin sensitivity, β-cell function, and β-cell mass during the development of diabetes in fa/fa rats. Am. J. Physiol. Endocrinol. Metab. 293(6), E1730–1735 (2007)

    Article  CAS  PubMed  Google Scholar 

  8. M. Weiss, D.F. Steiner, L.H. Philipson. Insulin biosynthesis, secretion, structure, and structure activity relationships. in Insulin Biosynthesis, Secretion, Structure, and Structure-activity Relationships, eds. by K.R Feingold, B. Anawalt, A. Boyce, G. Chrousos, W.W. de Herder, K. Dungan, A. Grossman, J.M. Hershman, H.J. Hofland, G. Kaltsas, C. Koch, P. Kopp, M. Korbonits, R. McLachlan, J.E. Morley, M. New, J. Purnell, F. Singer, C.A. Stratakis, D.L. Trence, D.P. Wilson (Endotext, MDText.com, Inc., South Dartmouth, MA, 2000)

  9. K. Færch, D. Vistisen, G. Pacini, S.S. Torekov, N.B. Johansen, D.R. Witte, A. Jonsson, O. Pedersen, T. Hansen, T. Lauritzen, M.E. Jørgensen, B. Ahrén, J.J. Holst, Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation. Diabetes 65(11), 3473–3481 (2016)

    Article  PubMed  Google Scholar 

  10. K.D. Copps, M.F. White, Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55(10), 2565–2582 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. C.K. Ho, G. Sriram, K.M. Dipple, Insulin sensitivity predictions in individuals with obesity and type II diabetes mellitus using mathematical model of the insulin signal transduction pathway. Mol. Genet. Metab. 119(3), 288–292 (2016)

    Article  CAS  PubMed  Google Scholar 

  12. B.M. Koeppen, B.A. Stanton. Berne and Levy Physiology, 7th edn. (Elsevier, Philadelphia, PA, 2017)

  13. P. Dandona, A. Aljada, A. Bandyopadhyay, Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25(1), 4–7 (2004)

    Article  CAS  PubMed  Google Scholar 

  14. R. Feinstein, H. Kanety, M.Z. Papa, B. Lunenfeld, A. Karasik, Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J. Biol. Chem. 268(35), 26055–26058 (1993)

    Article  CAS  PubMed  Google Scholar 

  15. P.E. Scherer, S. Williams, M. Fogliano, G. Baldini, H.F. Lodish, A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270(45), 26746–26749 (1995)

    Article  CAS  PubMed  Google Scholar 

  16. A.A. Elmarakby, J.C. Sullivan, Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc. Ther. 30(1), 49–59 (2012)

    Article  CAS  PubMed  Google Scholar 

  17. J.L. Evans, B.A. Maddux, I.D. Goldfine, The molecular basis for oxidative stress-induced insulin resistance. Antioxid. Redox Signal. 7(7-8), 1040–1052 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. S. Furukawa, T. Fujita, M. Shimabukuro, M. Iwaki, Y. Yamada, Y. Nakajima, O. Nakayama, M. Makishima, M. Matsuda, I. Shimomura, Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114(12), 1752–1761 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Z. Cheng, Y. Tseng, M.F. White, Insulin signaling meets mitochondria in metabolism. Trends Endocrinol. Metab. 21(10), 589–598 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. J.L. Rains, S.K. Jain, Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med. 50(5), 567–575 (2011)

    Article  CAS  PubMed  Google Scholar 

  21. G. Bánhegyi, P. Baumeister, A. Benedetti, D. Dong, Y. Fu, A.S. Lee, J. Li, C. Mao, E. Margittai, M. Ni, W. Paschen, S. Piccirella, S. Senesi, R. Sitia, M. Wang, W. Yang, Endoplasmic reticulum stress. Ann. N. Y. Acad. Sci. 1113(1), 58–71 (2007)

    Article  PubMed  Google Scholar 

  22. A.M. Shapiro, M. Pokrywczynska, C. Ricordi, Clinical pancreatic islet transplantation. Nat. Rev. Endocrinol. 13(5), 268–277 (2017)

    Article  CAS  PubMed  Google Scholar 

  23. M.D. Bellin, F.B. Barton, A. Heitman, J.V. Harmon, R. Kandaswamy, A.N. Balamurugan, D.E.R. Sutherland, R. Alejandro, B.J. Hering, Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am. J. Transplant. 12(6), 1576–1583 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. T. Berney, S. Ferrari-Lacraz, L. Buhler, J. Oberholzer, N. Marangon, J. Philippe, J. Villard, P. Morel, Long-term insulin-independence after allogeneic islet transplantation for type 1 diabetes: over the 10-year mark. Am. J. Transplant. 9(2), 419–423 (2009)

    Article  CAS  PubMed  Google Scholar 

  25. M.R. Rickels, R.P. Robertson, Pancreatic islet transplantation in humans: recent progress and future directions. Endocr. Rev. 40(2), 631–668 (2019)

    Article  PubMed  Google Scholar 

  26. C.J. Greenbaum, Insulin resistance in type 1 diabetes. Diabetes Metab. Res. Rev. 18(3), 192–200 (2002)

    Article  CAS  PubMed  Google Scholar 

  27. H. Yki-Järvinen, E. Helve, V.A. Koivisto, Hyperglycemia decreases glucose uptake in type I diabetes. Diabetes 36(8), 892–896 (1987)

    Article  PubMed  Google Scholar 

  28. S. Zuniga-Guajardo, B. Zinman, The metabolic response to the euglycemic insulin clamp in type I diabetes and normal humans. Metabolism 34(10), 926–930 (1985)

    Article  CAS  PubMed  Google Scholar 

  29. M.R. Rickels, A. Naji, K.L. Teff, Insulin sensitivity, glucose effectiveness, and free fatty acid dynamics after human islet transplantation for type 1 diabetes. J. Clin. Endocrinol. Metab. 91(6), 2138–2144 (2006)

    Article  CAS  PubMed  Google Scholar 

  30. D. Hirsch, J. Odorico, N. Radke, M. Hanson, J.S. Danobeitia, D. Hullett, R. Alejandro, C. Ricordi, L.A. Fernandez, Correction of insulin sensitivity and glucose disposal after pancreatic islet transplantation: preliminary results. Diabetes Obes. Metab. 12(11), 994–1003 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. S.R. Vethakkan, J.M. Walters, J.L. Gooley, R.C. Boston, T.W. Kay, D.J. Goodman, A.J. Jenkins, G.M. Ward, Normalized NEFA dynamics during an OGTT after islet transplantation. Transplantation 94(7), e49–51 (2012)

    Article  PubMed  Google Scholar 

  32. Y.M. Wee, M.Y. Choi, C.H. Kang, Y.H. Kim, J.H. Kim, S.K. Lee, S.Y. Yu, S.C. Kim, D.J. Han, The synergistic effect of tautomycetin on cyclosporine A-mediated immunosuppression in a rodent islet allograft model. Mol. Med. 16(7-8), 298–306 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. B. Singh, A. Saxena, Surrogate markers of insulin resistance: a review. World J. Diabetes 1(2), 36–47 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  34. A.M. Szczesniak, R.F. Porter, J.T. Toguri, J. Borowska-Fielding, S. Gebremeskel, A. Siwakoti, B. Johnston, C. Lehmann, M.E. Kelly, Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy. Neuropharmacology 113(Pt B), 627–638 (2017)

    Article  CAS  PubMed  Google Scholar 

  35. Y.Y. Huang, X.Q. Huang, L.Y. Zhao, F.Y. Sun, W.L. Chen, J.Y. Du, F. Yuan, J. Li, X.L. Huang, J. Liu, X.F. Lv, Y.Y. Guan, J.W. Chen, G.L. Wang, ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice. Apoptosis 19(11), 1559–1570 (2014)

    Article  CAS  PubMed  Google Scholar 

  36. A.L. Carvalho, V.E. DeMambro, A.R. Guntur, P. Le, K. Nagano, R. Baron, F.J.A. de Paula, K.J. Motyl, High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice. J. Cell. Physiol. 233(2), 1585–1600 (2018)

    Article  CAS  PubMed  Google Scholar 

  37. J. Sun, X. Fu, Y. Liu, Y. Wang, B. Huo, Y. Guo, X. Gao, W. Li, X. Hu, Hypoglycemic effect and mechanism of honokiol on type 2 diabetic mice. Drug Des. Dev. Ther. 9, 6327–6342 (2015)

    CAS  Google Scholar 

  38. J. Wang, Y. Huang, K. Li, Y. Chen, D. Vanegas, E.S. McLamore, Y. Shen, Leaf extract from lithocarpus polystachyus rehd. Promote glycogen synthesis in T2DM mice. PLoS ONE 11(11), e0166557 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  39. J.Y. Du, C.C. **, G.H. Wang, X.Q. Huang, J.D. Cheng, X.J. Wen, X.M. Zhao, G.L. Wang, LNK deficiency aggravates palmitate-induced preadipocyte apoptosis. Biochem. Biophys. Res. Commun. 490(2), 91–97 (2017)

    Article  CAS  PubMed  Google Scholar 

  40. L. Wang, L. Qing, H. Liu, N. Liu, J. Qiao, C. Cui, T. He, R. Zhao, F. Liu, F. Yan, C. Wang, K. Liang, X. Guo, Y.H. Shen, X. Hou, L. Chen, Mesenchymal stromal cells ameliorate oxidative stress-induced islet endothelium apoptosis and functional impairment via Wnt4-β-catenin signaling. Stem Cell Res. Ther. 8(1), 188 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  41. J. Gu, Y. Cheng, H. Wu, L. Kong, S. Wang, Z. Xu, Z. Zhang, Y. Tan, B.B. Keller, H. Zhou, Y. Wang, Z. Xu, L. Cai, Metallothionein is downstream of Nrf2 and partially mediates sulforaphane prevention of diabetic cardiomyopathy. Diabetes 66(2), 529–542 (2017)

    Article  CAS  PubMed  Google Scholar 

  42. C. Zhang, J. Deng, D. Liu, X. Tuo, L. **ao, B. Lai, Q. Yao, J. Liu, H. Yang, N. Wang, Nuciferine ameliorates hepatic steatosis in high-fat diet/streptozocin-induced diabetic mice through a PPARα/PPARγ coactivator-1α pathway. Br. J. Pharmacol. 175(22), 4218–4228 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. M. Rodriguez-Sosa, T. Cabellos-Avelar, Y. Sanchez-Zamora, I. Juárez-Avelar, E. García-Reyes, A. Lira-León, J.D.C. Benítez-Flores, T. Pacheco-Fernández, M. Hiriart, E.B. Gutiérrez-Cirlos, Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function. Cytokine 99, 214–224 (2017)

    Article  CAS  PubMed  Google Scholar 

  44. D.R. Matthews, J.P. Hosker, A.S. Rudenski, B.A. Naylor, D.F. Treacher, R.C. Turner, Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7), 412–419 (1985)

    Article  CAS  PubMed  Google Scholar 

  45. D. Shin, Y.S. Eom, S. Chon, B.J. Kim, K.S. Yu, D.H. Lee, Factors influencing insulin sensitivity during hyperinsulinemic-euglycemic clamp in healthy Korean male subjects. Diabetes Metab. Syndr. Obes. 12, 469–476 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. M. Kanauchi, N. Tsujimoto, T. Hashimoto, Validation of simple indices to assess insulin sensitivity based on the oral glucose tolerance test in the Japanese population. Diabetes Res. Clin. Pract. 55(3), 229–235 (2002)

    Article  CAS  PubMed  Google Scholar 

  47. J.K. Sethi, A.J. Vidal-Puig, Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J. Lipid Res. 48(6), 1253–1262 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. D.F. Lazar, A.R. Saltiel, Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat. Rev. Drug Discov. 5(4), 333–342 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript.

Funding

This research was performed with grants from the National Research Foundation of Korea (2017R1D1A1B03031027) and Asan Institute for Life Sciences (2020-0022).

Author information

Author notes

  1. These authors contributed equally: Monica Young Choi, Seong Jun Lim

Authors and Affiliations

  1. Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Monica Young Choi, Seong Jun Lim, Mi Joung Kim, Yu-Mee Wee, Hyunwook Kwon, Young Hoon Kim, Duck Jong Han & Sung Shin

  2. Asan Diabetes Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Chang Hee Jung

Authors
  1. Monica Young Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seong Jun Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mi Joung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu-Mee Wee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyunwook Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chang Hee Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Young Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Duck Jong Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sung Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SS, CHJ, KYH, and DJH conceived and designed the research. MYC, Y-MW, and MJK performed the experiments. All authors analysed the data and edited and revised the manuscript. MYC and SJL prepared the figures. SS, CHJ, and HK drafted the manuscript. SS is the guarantor of this work.

Corresponding author

Correspondence to Sung Shin.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Choi, M.Y., Lim, S.J., Kim, M.J. et al. Islet isograft transplantation improves insulin sensitivity in a murine model of type 2 diabetes. Endocrine 72, 660–671 (2021). https://doi.org/10.1007/s12020-021-02655-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-021-02655-8

Keywords

Search

Navigation