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Clinical and Experimental Medicine

, Volume 15, Issue 1, pp 41–45 | Cite as

Novel therapy for insulin-dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells

  • S. D. DaveEmail author
  • A. V. Vanikar
  • H. L. Trivedi
  • U. G. Thakkar
  • S. C. Gopal
  • T. Chandra
Original Article

Abstract

Insulin-dependent diabetes mellitus (IDDM) is a metabolic disease usually resulting from autoimmune-mediated β-cell destruction requiring lifetime exogenous insulin replacement. Mesenchymal stem cells (MSC) hold promising therapy. We present our experience of treating IDDM with co-infusion of in vitro autologous adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). This was an Institutional Review Board approved prospective non-randomized open-labeled clinical trial after informed consent from ten patients. ISC were differentiated from autologous adipose tissue-derived MSC and were infused with bone marrow-derived HSC in portal, thymic circulation by mini-laparotomy and in subcutaneous circulation. Patients were monitored for blood sugar levels, serum C-peptide levels, glycosylated hemoglobin (Hb1Ac) and glutamic acid decarboxylase (GAD) antibodies. Insulin administration was made on sliding scale with an objective of maintaining FBS < 150 mg/dL and PPBS around 200 mg/dL. Mean 3.34 mL cell inoculums with 5.25 × 104 cells/μL were infused. No untoward effects were observed. Over a mean follow-up of 31.71 months, mean serum C-peptide of 0.22 ng/mL before infusion had sustained rise of 0.92 ng/mL with decreased exogenous insulin requirement from 63.9 international units (IU)/day to 38.6 IU/day. Improvement in mean Hb1Ac was observed from 10.99 to 6.72 %. Mean GAD antibodies were positive in all patients with mean of 331.10 IU/mL, which decreased to mean of 123 IU/mL. Co-infusion of autologous ISC with HSC represents a viable novel therapeutic option for IDDM.

Keywords

Insulin-secreting cells Adipose tissue Mesenchymal stem cells Hematopoietic stem cells Insulin-dependent diabetes mellitus 

Abbreviations

BM

Bone marrow

CBM

Cultured bone marrow

DKA

Diabetic ketoacidosis

FBS

Fasting blood sugar levels

GAD

Glutamic acid decarboxylase

Hb1Ac

Glycosylated hemoglobin

HSC

Hematopoietic stem cells

ISC

Insulin-secreting cells

MSC

Mesenchymal stem cells

PPBS

Postprandial blood sugar level

IDDM

Insulin-dependent diabetes mellitus

Notes

Acknowledgments

The authors thank the staff and technicians of IKDRC-ITS, India, for all the technical help. The authors also thank Shobhana Sengunthar for providing statistical analysis.

Conflict of interest

None.

References

  1. 1.
    Starzl TE (2001) The “privileged” liver and hepatic tolerogenicity. Liver Transpl 7(10):918–920CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Sprent J, Kishimoto H (2001) The thymus and central tolerance. Philos Trans R Soc Lond B Biol Sci 356(1409):609–616CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Castano L, Eisenbarth GS (1990) Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol 8:647–679CrossRefPubMedGoogle Scholar
  4. 4.
    Dave SD, Vanikar AV, Trivedi HL (2012) Ex vivo generation of glucose sensitive insulin secreting mesenchymal stem cells derived from human adipose tissue. Indian J Endocr Metab 16(1):S65–S69CrossRefGoogle Scholar
  5. 5.
    Trivedi HL, Vanikar AV, Thakker UG, Feroze A, Dave SD et al (2008) Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin. Transpl Proc 40(4):1135–1139CrossRefGoogle Scholar
  6. 6.
    Vanikar AV, Dave SD, Thakkar UG, Trivedi HL (2010) Co-transplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus. Stem Cells Int Article ID 582382 5 pagesGoogle Scholar
  7. 7.
    Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH et al (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 97:7999–8004CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB et al (2000) Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 6:278–282CrossRefPubMedGoogle Scholar
  9. 9.
    Yang L, Li S, Hatch H, Ahrens K, Cornelius JG et al (2002) In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA 99:8078–8083CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Suzuki A, Nakauchi H, Taniguchi H (2002) Glucagon-like peptide 1 (1-37) converts intestinal epithelial cells into insulin-producing cells. Proc Natl Acad Sci USA 100:5034–5039CrossRefGoogle Scholar
  11. 11.
    Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA et al (2000) Insulin secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–162CrossRefPubMedGoogle Scholar
  12. 12.
    Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R et al (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394CrossRefPubMedGoogle Scholar
  13. 13.
    Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL et al (2001) Insulin production by human embryonic stem cells. Diabetes 50:1691–1697CrossRefPubMedGoogle Scholar
  14. 14.
    Lee RH, Seo MJ, Reger RL et al (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/SCID mice. Proc Natl Acad Sci 103:17438CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Urban VS, Kiss J, Kovacs J, Gocza E, Vas V et al (2008) Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 26:244–253CrossRefPubMedGoogle Scholar
  16. 16.
    Brusko TM (2009) Mesenchymal stem cells: a potential border patrol for transplanted islets? Diabetes 58(8):1728–1729CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH (2008) Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for insulin dependent diabetes. Diabetes 57:1759–1767CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110:3499–3506CrossRefPubMedGoogle Scholar
  19. 19.
    Volarevic V, Al-Qahtani A, Arsenijevic N, Pajovic S, Lukic ML (2010) Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity 43:255–263CrossRefPubMedGoogle Scholar
  20. 20.
    da Silva Meirelles L, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119(11):2204–2213CrossRefGoogle Scholar
  21. 21.
    Zhang N, Li J, Luo R, Jiang J, Wang JA (2008) Bone marrow mesenchymal stem cells induce angiogenesis and attenuate the remodeling of diabetic cardiomyopathy. Exp Clin Endocrinol Diabetes 116:104–111CrossRefPubMedGoogle Scholar
  22. 22.
    Couri CEB, Voltarelli JC (2009) Stem cell therapy for insulin dependent diabetes mellitus: a review of recent clinical trials. Diabetol Metab Syndr 1:19CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Timper K, Sebok D, Eberhardt M, Linscheid P, Christ-Crain M et al (2006) Human adipose-tissue derived mesenchymal stem cells differentiate into insulin, somatostatin and glucagon expressing cells. Biochem Biophys Res Commun 341(4):1135–1140CrossRefPubMedGoogle Scholar
  24. 24.
    Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W et al (2001) Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50:521–533CrossRefPubMedGoogle Scholar
  25. 25.
    Okura H, Komoda H, Fumimoto Y, Lee C, Nishida T et al (2009) Transdifferentiation of human adipose tissue-derived stromal cells into insulin-producing clusters. J Artif Organs 12(2):123–130CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2013

Authors and Affiliations

  • S. D. Dave
    • 1
    Email author
  • A. V. Vanikar
    • 1
  • H. L. Trivedi
    • 2
    • 3
  • U. G. Thakkar
    • 3
  • S. C. Gopal
    • 4
  • T. Chandra
    • 5
  1. 1.Stem Cell Lab, Transplantation Biology Research Centre, Department of Pathology, Laboratory Medicine, Transfusion Services and ImmunohematologyG. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre (IKDRC)-Dr. H.L. Trivedi Institute of Transplantation Sciences (ITS)AhmedabadIndia
  2. 2.Department of Nephrology and Transplantation MedicineIKDRC-ITSAhmedabadIndia
  3. 3.Department of Stem Cell Therapy and Regenerative MedicineIKDRC-ITSAhmedabadIndia
  4. 4.Department of SurgeryBanaras Hindu UniversityVaranasiIndia
  5. 5.Department of Transfusion MedicineKing George Medical UniversityLucknowIndia

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