Insulin requirements and residual beta-cell function 12 months after concluding immunotherapy in type I diabetic patients treated with combined azathioprine and thymostimulin administration for one year.
An increase in clinical and functional remissions with immunosuppression, as well as abnormal T-cell function, in Type I diabetic patients has been reported in the early stages of diabetes. A controlled trial with azathioprine and thymostimulin in separate and combined administration was performed in 45 recently diagnosed Type I diabetic patients. Phenotyping of the T-lymphocyte subsets, levels of CD25 positive cells and interleukin-2 production by patients' lymphocytes, as well as remission rate and stimulated C-peptide levels, were serially assessed. Remission was defined as mean weekly glycemic profiles less than or equal to 7 mmole/l, serial HbA1 values in the normal range and no insulin requirements for at least 2 consecutive months. At 3,6,9 and 12 months of immunotherapy, remission occurred respectively in 0%, 8.3%, 16.6% and 0% of the conventionally treated diabetic controls and in 42.8%, 50%, 42.8% and 36.2% of the subjects submitted to combined azathioprine and thymostimulin administration. Patients receiving azathioprine or thymostimulin alone did not achieve better remission rates than controls. C-peptide levels were significantly higher (above 0.6 pmol/ml) in patients with remission than in those not in remission (P less than 0.02) throughout the trial. Excessive interleukin-2 production in recently diagnosed diabetics returned to normal levels in patients in remission. In the group receiving combined therapy, 38.5%, 25% and 23% were still in clinical remission at 6, 9 and 12 months after drug withdrawal. Twelve months after stopping treatment, patients who had remitted exhibited significantly lower insulin requirements and greater endogenous insulin secretion than those who had not remitted; the former also maintained near normal glycemic control. No side effects were detected except mild and transient leucopenia in a reduced number of patients receiving azathioprine. Remission was related to the time of beginning immunotherapy after the onset of diabetes (17.1 +/- 7 vs 42.5 +/- 15 days; P less than 0.01) and to age (17.7 +/- 5.6 vs 13 +/- 7 years; P less than 0.05). Interleukin-2 production seems to be negatively associated with clinical remission in the early stages of diabetes. Results suggest a complementary effect of the drugs used in this study that may enhance long-term remission in recently diagnosed Type I diabetic patients.
Moncada
E
E
Department of Endocrinology, University of Navarra, Pamplona, Spain.
Subirá
M L
ML
Oleaga
A
A
Goñi
F
F
Sánchez-Ibarrola
A
A
Monreal
M
M
Sevilla
M
M
Goñi
M J
MJ
Yoldi
A
A
Terán
D
D
D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage / Q000627:therapeutic use*; D002096:C-Peptide / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D007328:Insulin / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D015375:Receptors, Interleukin-2; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013949:Thymus Extracts / Q000008:administration & dosage / Q000627:therapeutic use*
D002096:C-Peptide; D007328:Insulin; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D013949:Thymus Extracts; C031407:thymostimulin; D001379:Azathioprine