RESUMO
The anti-inflammatory and immunomodulatory properties of high-dose omega-3 fatty acids and Vitamin D, and the initial encouraging results from case reports on the use of this supplementation in new-onset Type 1 Diabetes (T1D), support further testing of this combination strategy. This intervention appears to be well tolerated, affordable, and sufficiently safe to be further tested in randomized prospective trials to determine whether this combination therapy may be of assistance to halt progression of autoimmunity and/or preserve residual beta-cell function in subjects with new onset and established T1D of up to 10 years duration. In addition, the 1st PreDiRe T1D conference (Preventing Disease and its Recurrence in Type 1 Diabetes - see Editorial in this issue) was organized to discuss initial results and possible alternative/complementary strategies, for collaborative international expansion of these trials, to include strategies for disease prevention. Our POSEIDON clinical trial will test the use of high dose vitamin D3 and highly purified Omega-3 fatty acids in new onset and established T1D. The draft of the study protocol, in addition to the informed consent and assent, is now shared open access to facilitate its international implementation by interested physicians and centers that would like to further test this approach through clinical trials.
RESUMO
Several studies have evaluated the role of inflammation in type 1 diabetes (T1D). The safety profile and anti-inflammatory properties of high dose omega-3 fatty acids combined with Vitamin D supplementation make this therapy a possible candidate for T1D intervention trials. Herein, we describe the case of a 14-year-old boy with new onset T1D treated with high dose Omega-3 and vitamin D3. By 12 months, peak C-peptide increased to 0.55 nmol/L (1.66 ng/mL) corresponding to a 20% increment from baseline and AUC C-peptide was slightly higher compared to 9 months (0.33 vs. 0.30 nmol/L/min) although remaining slightly lower than baseline. Combination high-dose Omega-3 fatty acids and high-dose vitamin D3 therapy was well tolerated and may have beneficial effects on beta-cell function. Randomized controlled trials could be of assistance to determine whether this therapy may result in the preservation of beta-cell function in patients with new onset T1D.
Assuntos
Peptídeo C/metabolismo , Colecalciferol/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Adolescente , Linfócitos B/efeitos dos fármacos , Linfócitos B/fisiologia , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Humanos , Hipoglicemiantes , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Masculino , Resultado do TratamentoAssuntos
Herpesvirus Humano 4/fisiologia , Ilhotas Pancreáticas/virologia , Transplante de Rim , Latência Viral/fisiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Humanos , Terapia de Imunossupressão , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/etiologia , Fatores de RiscoRESUMO
To prevent graft rejection and avoid immunosuppression-related side-effects, we attempted to induce recipient chimerism and graft tolerance in islet transplantation by donor CD34+hematopoietic stem cell (HSC) infusion. Six patients with brittle type 1 Diabetes Mellitus received a single-donor allogeneic islet transplant (8611 +/- 2113 IEQ/kg) followed by high doses of donor HSC (4.3 +/- 1.9 x 10(6) HSC/kg), at days 5 and 11 posttransplant, without ablative conditioning. An 'Edmonton-like' immunosuppression was administered, with a single dose of anti-TNFalpha antibody (Infliximab) added to induction. Immunosuppression was weaned per protocol starting 12 months posttransplant. After transplantation, glucose control significantly improved, with 3 recipients achieving insulin-independence for a short time (24 +/- 23 days). No severe hypoglycemia or protocol-related adverse events occurred. Graft function was maximal at 3 months then declined. Two recipients rejected within 6 months due to low immunosuppressive trough levels, whereas 4 completed 1-year follow-up with functioning grafts. Graft failure occurred within 4 months from weaning (478 +/- 25 days posttransplant). Peripheral chimerism, as donor leukocytes, was maximal at 1-month (5.92 +/- 0.48%), highly reduced at 1-year (0.20 +/- 0.08%), and was undetectable at graft failure. CD25+T-lymphocytes significantly decreased at 3 months, but partially recovered thereafter. Combined islet and HSC allotransplantation using an 'Edmonton-like' immunosuppression, without ablative conditioning, did not lead to stable chimerism and graft tolerance.
Assuntos
Quimerismo , Diabetes Mellitus Tipo 1/cirurgia , Transplante de Células-Tronco Hematopoéticas , Transplante das Ilhotas Pancreáticas/imunologia , Tolerância ao Transplante/imunologia , Adulto , Antígenos CD34/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Transplante HomólogoRESUMO
The aim of this study was to develop a simple test for the assessment of islet graft dysfunction based on measures involving fasting C-peptide. Calculations were made to account for the dependence of C-peptide secretion on glucose concentration (C-peptide/glucose ratio [CP/G]) and adjusted for renal function by calculating the C-peptide/glucose-creatinine ratio (CP/GCr). Values from 22 recipients were analyzed at different times post-last islet infusion. Receiver operating characteristic curves were used to determine which of these measures best predicts high 90-minute glucose (90 min-Glc; >10 mmol/L) after a Mixed Meal Tolerance Test (MMTT). In this initial analysis, CP/G was found to be superior predicting high 90 min-Glc with a larger area under the ROC curve than C-peptide (p = 0.01) and CP/GCr (p = 0.06). We then correlated C-peptide and CP/G with islet equivalents--IEQ/kg infused, 90 min-Glc after MMTT and clinical outcome (beta-score). C-peptide and CP/G in the first 3 months post-last islet infusion correlated with IEQ/kg infused. CP/G correlated with 90 min-Glc and beta-score. C-peptide and CP/G are good indicators of islet mass transplanted. CP/G is more indicative of graft dysfunction and clinical outcome than C-peptide alone. The ease of calculation and the good correlation with other tests makes this ratio a practical tool when monitoring and managing islet transplant recipients.
Assuntos
Peptídeo C/sangue , Rejeição de Enxerto/sangue , Rejeição de Enxerto/fisiopatologia , Células Secretoras de Insulina/patologia , Transplante das Ilhotas Pancreáticas/fisiologia , Adulto , Glicemia/metabolismo , Creatinina/sangue , Feminino , Rejeição de Enxerto/diagnóstico , Humanos , Transplante das Ilhotas Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
This study analyzed quality of life in patients with type 1 diabetes that received islet transplantation. Twenty-three subjects were followed over 3 years. In addition to an interview, patients self-completed two standardized psychometric questionnaires, HSQ 2.0 and DQOL, before and after transplant, and scores were compared. Analysis was also adjusted for potential "confounders" such as graft dysfunction, insulin therapy and adverse events. DQOL: the Impact score significantly improved at all time points of the follow-up; satisfaction and worry scales also significantly improved at selected time points. Longitudinal analysis demonstrated that reintroduction of insulin had a negative effect on all three scales, but significant improvement in Impact scale persisted even after adjusting for this factor. HSQ 2.0: only the Health Perception scale preliminarily showed significant improvement at most time points. Longitudinal analysis showed loss of significance when insulin therapy was considered. Other scores were improved only at selected time points or not affected. Bodily pain scale showed deterioration at selected times. Interview: glucose control stability, not insulin independence, was reported as the main beneficial factor influencing QOL. In conclusion, islet transplantation has a positive influence on patients' QOL, despite chronic immunosuppression side effects. Re-introduction of insulin modifies QOL outcomes.