Cryolife.ipos.com.hk

C-Peptide Levels and Insulin Independence Following
Autologous Nonmyeloablative Hematopoietic Stem Cell
Transplantation in Newly Diagnosed Type 1 Diabetes
Mellitus
Carlos E. B. Couri; Maria C. B. Oliveira; Ana B. P. L. Stracieri; et al. JAMA. 2009;301(15):1573-1579 (doi:10.1001/jama.2009.470) Transplantation; Transplantation, Other; Endocrine Diseases; Diabetes Mellitus C-Peptide Levels and Insulin Independence
Following Autologous Nonmyeloablative
Hematopoietic Stem Cell Transplantation
in Newly Diagnosed Type 1 Diabetes Mellitus
Carlos E. B. Couri, MD, PhD
Context In 2007, the effects of the autologous nonmyeloablative hematopoietic stem
cell transplantation (HSCT) in 15 patients with type 1 diabetes mellitus (DM) were re- ported. Most patients became insulin free with normal levels of glycated hemoglobinA1c (HbA1c) during a mean 18.8-month follow-up. To investigate if this effect was due to preservation of beta-cell mass, continued monitoring was performed of C-peptide levels after stem cell transplantation in the 15 original and 8 additional patients.
Objective To determine C-peptide levels after autologous nonmyeloablative HSCT
in patients with newly diagnosed type 1 DM during a longer follow-up.
Design, Setting, and Participants A prospective phase 1/2 study of 23 patients
with type 1 DM (aged 13-31 years) diagnosed in the previous 6 weeks by clinical find- ings with hyperglycemia and confirmed by measurement of serum levels of anti– glutamic acid decarboxylase antibodies. Enrollment was November 2003-April 2008,with follow-up until December 2008 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeira˜o Preto, Ribeira˜o Preto, Brazil. Hematopoietic stem cells were mobilized via the 2007 protocol.
Main Outcome Measures C-peptide levels measured during the mixed-meal tol-
erance test, before, and at different times following HSCT. Secondary end points in-
cluded morbidity and mortality from transplantation, temporal changes in exogenousinsulin requirements, and serum levels of HbA Results During a 7- to 58-month follow-up (mean, 29.8 months; median, 30 months),
20 patients without previous ketoacidosis and not receiving corticosteroids during the preparative regimen became insulin free. Twelve patients maintained this status for a mean 31 months (range, 14-52 months) and 8 patients relapsed and resumed insulin use at low dose (0.1-0.3 IU/kg). In the continuous insulin–independent group, HbA1c levels were less than 7.0% and mean (SE) area under the curve (AUC) of C-peptide levels increased significantly from 225.0 (75.2) ng/mL per 2 hours pretransplantation to 785.4 (90.3) ng/mL viable beta-cell function), the lower the per 2 hours at 24 months posttransplantation (PϽ.001) and to 728.1 (144.4) ng/mL per2 hours at 36 months (P=.001). In the transient insulin–independent group, mean (SE) AUC of C-peptide levels also increased from 148.9 (75.2) ng/mL per 2 hours pretrans- plantation to 546.8 (96.9) ng/mL per 2 hours at 36 months (P=.001), which was sus- tained at 48 months. In this group, 2 patients regained insulin independence after treat- ment with sitagliptin, which was associated with increase in C-peptide levels. Two patients clinical trials analyzing the effects of dif- developed bilateral nosocomial pneumonia, 3 patients developed late endocrine dys- function, and 9 patients developed oligospermia. There was no mortality.
Conclusion After a mean follow-up of 29.8 months following autologous nonmy-
tion is an achievable target in different eloablative HSCT in patients with newly diagnosed type 1 DM, C-peptide levels in- creased significantly and the majority of patients achieved insulin independence with Trial Registration clinicaltrials.gov Identifier: NCT00315133
gous nonmyeloablative hematopoieticstem cell transplantation (HSCT),4 in Author Affiliations are listed at the end of this article.
Corresponding Author: Julio C. Voltarelli, MD, PhD, Re-
gional Blood Center (Hemocentro), Campus USP, 14051-
140 Ribeira˜o Preto, Brazil ([email protected]).
2009 American Medical Association. All rights reserved.
(Reprinted) JAMA, April 15, 2009—Vol 301, No. 15 1573
C-PEPTIDE LEVELS AND INSULIN FOLLOWING STEM CELL TRANSPLANTATION ther immune suppressive medications.
if patients presented clinical findings of and of the Brazilian Ministry of Health.
the patients were younger than 18 years.
Study Design
docrinologists of the team (C.E.B.C.).
Stem Cell Mobilization Regimen
of dietary or lifestyle alterations.
(Leucin, Laboratory Bergamo, Sa˜o Paulo, Study Patients
of Medicine of Ribeira˜o Preto, Ribeira˜o taneously starting 1 day after cyclophos- for not fulfilling protocol criteria or for criteria were patients of both sexes, aged 12 to 35 years, with a clinical and labo- 10 cells/µL of whole blood. Apheresis was glutamic acid decarboxylase antibodies.
sulin titration was based on fasting glu- diac, psychiatric, or hepatic disease; or Conditioning (Immune Ablative)
vert to millimoles per liter, multiply by 1574 JAMA, April 15, 2009—Vol 301, No. 15 (Reprinted)
2009 American Medical Association. All rights reserved.
C-PEPTIDE LEVELS AND INSULIN FOLLOWING STEM CELL TRANSPLANTATION 4 patients for at least 1 year. In the patients Genzyme Polyclonals SAF, Marcyl’Etoile, France) was administered at a dose of 0.5 6.0%, respectively, at 3, 12, 24, 36, and 48 months after transplantation (PϽ.001 fore stem cell infusion. Except for the first characteristic of increased risk for type avoiding the use of glucocorticoids. Stem PϽ.001) and at 36 months after trans- hours, P=.001) (FIGURE).
Statistical Analysis
tory tract infection. Daily insulin doses tiple regression of mixed effects for pe- plantation. To present the mean variation of HbA1c levels with time, a model of lin- [96.9] ng/mL per 2 hours, P=.001) that ear regression of random effects was con- pecia (TABLE 2). With regard to severe
adverse effects, 2 patients presented bi- per 2 hours, P=.22, between 36 and 48 months after transplantation) (Figure).
resents a random effect in each patient.
sent residuals that are normally distrib- ware, version 8 (SAS Institute Inc, Cary, North Carolina). Statistical significance oligospermia. Two patients fathered chil- variables are shown in TABLE 1. This
is a very selected group of patients, pre- vious diabetic ketoacidosis. All patients ogenous insulin use, 4 patients for at least 3 years, 3 patients for at least 2 years, and 2009 American Medical Association. All rights reserved.
(Reprinted) JAMA, April 15, 2009—Vol 301, No. 15 1575
C-PEPTIDE LEVELS AND INSULIN FOLLOWING STEM CELL TRANSPLANTATION levels was 1069.6 ng/mL per 2 hours.
Table 1. Pretreatment and Follow-up Characteristics of Patients With Type 1 Diabetes Mellitus Undergoing Autologous Nonmyeloablative
Hematopoietic Stem Cell Transplantation
At Diagnosis
Duration
Hemoglobin A1c
of Symptoms
Insulin Dose
Glucose,
at Pretrans-
of Hyper-
Premobilization,
Insulin,
plantation, %
glycemia, d
Abbreviations: C, continuously; GAD, glutamic acid decarboxylase; NS, not suspended; T, transiently.
SI conversion factor: To convert glucose to mmol/L, multiply by 0.0555.
a Body mass index was calculated as weight in kilograms divided by height in meters squared.
b Months since mobilization regimen.
c Patients 1 and 21 presented with diabetic ketoacidosis.
d Patients 1 and 20 used corticosteroids in the conditioning regimen.
e Denotes patients who self-identified as having both black and white racial parentage.
f Patient 2 became insulin free for 47 months after transplantation when he resumed insulin use. Four months after resuming insulin, oral sitagliptin (100 mg/d) was prescribed and patient became insulin free again 2 months later and is still insulin free for 5 months.
g Patient 4 became insulin free for 43 months after transplantation when he resumed insulin use. Two months after resuming insulin, oral sitagliptin (100 mg/d) was prescribed and patient became insulin free again 1 month later and is still insulin free for 6 months.
h For the continuously insulin-free group, mean (SD) was 31 (13.1) months and for the transiently insulin-free group, mean (SD) was 17.7 (16.9) months.
1576 JAMA, April 15, 2009—Vol 301, No. 15 (Reprinted)
2009 American Medical Association. All rights reserved.
C-PEPTIDE LEVELS AND INSULIN FOLLOWING STEM CELL TRANSPLANTATION changes in lifestyle. In our current study, increase of beta-cell function.3,9-18 More- sustained beta-cell function, cases of ex- ogenous insulin suspension were rare.
trol. To confirm that this is a treatment ings of a group of 15 patients with newly effect that improves beta-cell mass rather in spite of progressive increase in daily transiently insulin free. However, one of the limitations of our previous study was viduals, the increments still reached sig- Table 2. Transplantation Complications
Mobilization
Minor Conditioning
Major Conditioning
Patient No.
Complications
Complicationsa
Complications
Late Complications
a All patients except 4, 5, 7, and 8 presented with nausea; vomiting presented in all patients except 4 and 6; and all presented with alopecia.
b Patient 2 fathered a child 2 years after transplantation.
c Patient 13 fathered a child 2 years after transplantation.
2009 American Medical Association. All rights reserved.
(Reprinted) JAMA, April 15, 2009—Vol 301, No. 15 1577
C-PEPTIDE LEVELS AND INSULIN FOLLOWING STEM CELL TRANSPLANTATION nificance at 36 months with sustained in- class of oral antihyperglycemic agents.19 effects, 2 patients had bilateral pneumo- pha cells, and increase beta-cell mass in rash, or urticaria. Those adverse effects are not negligible but may outweigh long- versely related to C-peptide levels,1 it is probable that even those patients who re- sumed insulin are at lower risk for long- levels in parallel with further increase in insulin production. In addition, sitaglip- C-peptide levels along the follow-up.
larger group of patients with a longer fol- peptidil peptidase 4 (sitagliptin), a novel Figure. Time Course of Total Area Under the Curve (AUC) of C-Peptide Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously
Insulin Free and in 8 Patients Transiently Insulin Free
Statistical analysis was performed using a model of multiple regression of mixed effects. For the C-peptide AUC levels in 12 patients continuously insulin free, data from1 patient at 6 months and from 2 patients at 36 months after transplantation were not available (PϽ.001 between pretreatment and 6 months; P=.001 betweenpretreatment and 12 months; PϽ.001 between pretreatment and 24 months; PϽ.001 between pretreatment and 36 months; P=.10 between 12 and 24 months aftertransplantation; P=.58 between 24 and 36 months after transplantation). For the C-peptide AUC levels in 8 patients transiently insulin free, data from 1 patient at 24months after transplantation were not available (PϽ.001 between pretreatment and 36 months; P=.22 between 36 and 48 months after transplantation). To convertC-peptide to nmol/L, multiply by 0.331.
1578 JAMA, April 15, 2009—Vol 301, No. 15 (Reprinted)
2009 American Medical Association. All rights reserved.
C-PEPTIDE LEVELS AND INSULIN FOLLOWING STEM CELL TRANSPLANTATION Study concept and design: Couri, Oliveira, Foss-Freitas, zilian Ministry of Health, FAEPA-HCRP, FUNDHERP, CAPES, FAPESP, CNPq, FINEP, Genzyme Corpora- Acquisition of data: Couri, Oliveira, Moraes, Pieroni, tion, and Johnson & Johnson-LifeScan–Brazil.
Madeira, Simo˜es, Foss, Voltarelli.
Role of the Sponsors: The funding organizations did
Analysis and interpretation of data: Couri, Stracieri, not participate in the design and conduct of the study, Barros, Malmegrim, Martinez, Foss, Voltarelli.
in the collection, management, analysis, and inter- Drafting of the manuscript: Couri.
pretation of the data, or in the preparation, review, Author Affiliations: Departments of Clinical Medi-
Critical revision of the manuscript for important in- cine (Drs Couri, Oliveira, Stracieri, Moraes, Pieroni, Bar- tellectual content: Couri, Oliveira, Stracieri, Moraes, Additional Contributions: We thank Sebastia˜o L.
ros, Madeira, Malmegrim, Foss-Freitas, Simo˜es, Foss, Pieroni, Barros, Madeira, Malmegrim, Foss-Freitas, Branda˜o Filho, technician from the Endocrinology and Voltarelli) and Social Medicine (Dr Martinez), Simo˜es, Martinez, Foss, Burt, Voltarelli.
and Metabolism Laboratory, for performing School of Medicine of Ribeira˜o Preto, University of Sa˜o Statistical analysis: Couri, Martinez.
C-peptide tests; the multiprofessional team of the Paulo, Ribeira˜o Preto, Brazil; and Division of Immu- Bone Marrow Transplantation Unit; and the notherapy, Northwestern University Feinberg School Administrative, technical, or material support: Couri, Regional Blood Center of the Hospital das Clı´nicas of Medicine, Chicago, Illinois (Dr Burt).
of Ribeira˜o Preto, University of Sa˜o Paulo, Sa˜o Author Contributions: Dr Voltarelli had full access to all
Study supervision: Couri, Simo˜es, Foss, Burt, Voltarelli.
Paulo, Brazil. No individuals named received any of the data in the study and takes responsibility for the Financial Disclosures: None reported.
compensation from a funding sponsor for their con- integrity of the data and the accuracy of the data analysis.
Funding/Support: This work was supported by the Bra-
REFERENCES
1. The Diabetes Control and Complications Trial Re-
11. Cook JJ, Hudson I, Harrison LC, et al. Double-
19. Aschner P, Kipnes MS, Lunceford JK, Sanchez M,
search Group. Effect of intensive therapy on residual blind controlled trial of azathioprine in children with Mickel C, Williams-Herman DE; Sitagliptin Study 021 beta-cell function in patients with type 1 diabetes in newly diagnosed type I diabetes. Diabetes. 1989; Group. Effect of the dipeptidyl peptidase-4 inhibitor the Diabetes Control and Complications Trial. Ann In- sitagliptin as monotherapy on glycemic control in pa- tern Med. 1998;128(7):517-523.
12. Silverstein J, Maclaren N, Riley W, Spillar R,
tients with type 2 diabetes. Diabetes Care. 2006; 2. Couri CEB, Foss MC, Voltarelli JC. Secondary pre-
Radjenovic D, Johnson S. Immunosupression with aza- vention of type 1 diabetes mellitus: stopping im- tioprine and prednisone in recent-onset insulin- 20. Mari A, Sallas WM, He YL, et al. Vildagliptin, a
mune destruction and promoting ␤-cell regeneration.
dependent diabetes mellitus. N Engl J Med. 1988; dipeptidyl peptidase-IV inhibitor, improves model- Braz J Med Biol Res. 2006;39(10):1271-1280.
assessed beta-cell function in patients with type 2 3. Staeva-Vieira T, Peakman M, von Herrath M. Trans-
13. Canadian-European Randomized Control Trial
diabetes. J Clin Endocrinol Metab. 2005;90(8): lational mini-review series on type-1 diabetes: immune- Group. Cyclosporin-induced remission of IDDM af- based therapeutic approaches for type 1 diabetes. Clin ter early intervention: association of 1 yr of cyclospo- 21. Herman GA, Bergman A, Stevens C, et al. Effect
Exp Immunol. 2007;148(1):17-31.
rin treatment with enhanced insulin secretion. Diabetes.
of single oral doses of sitagliptin, a dipeptidyl pepti- 4. Burt RK, Slavin S, Burns WH, Marmont AM. In-
dase-4 inhibitor, on incretin and plasma glucose lev- duction of tolerance in autoimmune diseases by he- 14. Herold KC, Hagopian W, Auger JA, et al. Anti-
els after an oral glucose tolerance test in patients with matopoietic stem cell transplantation: getting closer CD3 monoclonal antibody in new-onset type 1 dia- type 2 diabetes. J Clin Endocrinol Metab. 2006; to a cure? Blood. 2002;99(3):768-784.
betes mellitus. N Engl J Med. 2002;346(22):1692- 5. Voltarelli JC, Couri CE, Stracieri AB, et al. Autolo-
22. Herman GA, Stevens C, Van Dyck K, et al. Phar-
gous nonmyeloablative hematopoietic stem cell trans- 15. Keymeulen B, Vandemeulebroucke E, Ziegler AG,
macokinetics and pharmacodynamics of sitagliptin, an plantation in newly diagnosed type 1 diabetes mellitus.
et al. Insulin needs after CD3-antibody therapy in new- inhibitor of dipeptidyl peptidase IV, in healthy sub- JAMA. 2007;297(14):1568-1576.
onset type 1 diabetes. N Engl J Med. 2005;352 jects: results from two randomized, double-blind, pla- 6. Ross LF, Philipson LH. Ethics in hematopoietic stem
cebo-controlled studies with single oral doses. Clin cell transplantation in type 1 diabetes mellitus. JAMA.
16. Raz I, Elias D, Avron A, Tamir M, Metzger M,
Pharmacol Ther. 2005;78(6):675-688.
2007;298(3):285-, author reply 285-286.
Cohen IR. ␤-cell function in newly-onset type 1 dia- 23. Kim SJ, Nian C, Doudet DJ, McIntosh CH. Dipep-
7. Skyler JS. Cellular therapy for type 1 diabetes: has
betes and immunomodulation with a heatshock tidyl peptidase IV inhibition with MK0431 improves the time come? JAMA. 2007;297(14):1599-1600.
protein peptide (DiaPep277): a randomised, double- islet graft survival in diabetic NOD mice partially 8. Cerna´ M. Genetics of autoimmune diabetes mellitus.
blind, phase II trial. Lancet. 2001;358(9295):1749- via T-cell modulation. Diabetes. 2009;58(3):641- Wien Med Wochenschr. 2008;158(1-2):2-12.
9. Elliott RB, Crossley JR, Berryman CC, James AG.
17. Saudek F, Havrdova T, Boucek P, Karasova L,
24. Au WY, Lie AK, Kung AW, Liang R, Hawkins BR,
Partial preservation of pancreatic ␤-cell function in chil- Novota P, Skibova J. Polyclonal anti-T-cell therapy for Kwong YL. Autoimmune thyroid dysfunction after he- dren with diabetes. Lancet. 1981;19:631-632.
type 1 diabetes mellitus of recent onset. Rev Diabet matopoietic stem cell transplantation. Bone Marrow 10. Harrison LC, Colman PG, Dean B, Baxter R, Martin
Transplant. 2005;35(4):383-388.
FI. Increased in remission rate in newly diagnosed type 18. Ludvigsson J, Faresjö M, Hjorth M, et al. GAD treat-
25. Eisenbarth GS, Gottlieb PA. Autoimmune poly-
I diabetic subjects treated with azathioprine. Diabetes.
ment and insulin secretion in recent-onset type 1 endocrine syndromes. N Engl J Med. 2004;350 diabetes. N Engl J Med. 2008;359(18):1909-1920.
2009 American Medical Association. All rights reserved.
(Reprinted) JAMA, April 15, 2009—Vol 301, No. 15 1579

Source: http://cryolife.ipos.com.hk/site/UserFiles/jrublk/File/Diabetes%20type%201%20cord%20blood%20treatment_clinical%20trial.pdf