C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus.
BACKGROUND
In 2007, the effects of the autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in 15 patients with type 1 diabetes mellitus (DM) were reported. Most patients became insulin free with normal levels of glycated hemoglobin A(1c) (HbA(1c)) 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.


METHODS
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 findings 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 Ribeirão Preto, Ribeirão Preto, Brazil. Hematopoietic stem cells were mobilized via the 2007 protocol.


METHODS
C-peptide levels measured during the mixed-meal tolerance test, before, and at different times following HSCT. Secondary end points included morbidity and mortality from transplantation, temporal changes in exogenous insulin requirements, and serum levels of HbA(1c).


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, HbA(1c) 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 per 2 hours at 24 months posttransplantation (P < .001) and to 728.1 (144.4) ng/mL per 2 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 pretransplantation to 546.8 (96.9) ng/mL per 2 hours at 36 months (P = .001), which was sustained at 48 months. In this group, 2 patients regained insulin independence after treatment with sitagliptin, which was associated with increase in C-peptide levels. Two patients developed bilateral nosocomial pneumonia, 3 patients developed late endocrine dysfunction, and 9 patients developed oligospermia. There was no mortality.


CONCLUSIONS
After a mean follow-up of 29.8 months following autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM, C-peptide levels increased significantly and the majority of patients achieved insulin independence with good glycemic control.


BACKGROUND
clinicaltrials.gov Identifier: NCT00315133.
Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Carlos E B
CE
Couri
Maria C B
MC
Oliveira
Ana B P L
AB
Stracieri
Daniela A
DA
Moraes
Fabiano
F
Pieroni
George M N
GM
Barros
Maria Isabel A
MI
Madeira
Kelen C R
KC
Malmegrim
Maria C
MC
Foss-Freitas
Belinda P
BP
Simões
Edson Z
EZ
Martinez
Milton C
MC
Foss
Richard K
RK
Burt
Júlio C
JC
Voltarelli
D000293:Adolescent; D000328:Adult; D002096:C-Peptide / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000628:therapy*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D011446:Prospective Studies; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D055815:Young Adult
D002096:C-Peptide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin