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The Immune Mechanism and Effect of Rosiglitazone in Adults with Latent Autoimmune Diabetes (LADA)

Author: YangZhiFang
Tutor: ZhouZhiGuang
School: Central South University
Course: Internal Medicine
Keywords: Diabetes , autoimmune , occult Rosiglitazone Islet function Treatment Lymphocyte CD4 ~ CD25 ~ FOXP3 CD4 ~
CLC: R587.1
Type: PhD thesis
Year: 2007
Downloads: 112
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Abstract


Part 1 Rosiglitazone preserves isletβcellfunction of adult-onset latent autoimmune diabetesin 3 years follow-up studyObjective: To investigate the effects of rosiglitazone on isletβcellfunction and the strategy for treating LADA.Methods: LADA patients, defined as GAD-Ab positive, with a fastingC-peptide (FCP) of 0.2nmol/L or more, were enrolled and evaluated to bedivided to receive oral hypoglycemic agents or insulin therapy. Then,those patients in oral hypoglycemic agents group randomly assigned toreceive sulfonylureas (SUs group, n=15) or rosiglitazone (RSG group, n=15) therapy, metformin added if needed. Those patients in insulin groupwere randomly assigned to receive subcutaneous insulin alone (n=12) orrosiglitazone combined with insulin (n=12). The DQA1 and DQB1genotypes were analysed with sequence-based typing. Plasma glucose,HbA1c, fasting C-peptide (FCP) and C-peptide after 2 h 75-g glucoseload (PCP) were determined every 6 months. GAD-Ab and C-peptidewere measured with radioligand assay and radioimmune assayrespectively.Results: 1) During 3 years’ follow-up, noβcell function failure occurredin the patients of group received oral hypoglycemic agents. The HbA1clevels (5.95±0.57% vs 8.31±2.75%, P<0.05)and FCP levels (0.69±0.27nmol/L vs 0.83±0.24nmol/L, P<0.05) were lower in RSG group patientsin the first 6 months, accompanying with the improvement ofHOMA2-IR(1.71±0.52mmol~*mU/L~2 vs 2.19±0.79mmol~*mU/L~2, P<0.05). The PCP and△CP (△CP=PCP-FCP) levels in RSG group patientssustained, which were higher than those in SUs group (PCP,3.15±1.95nmol/L vs 1.99±0.76 nmol/L, P<0.05), (△CP, 2.45±1.87nmol/L vs 1.32±0.70 nmol/L, P<0.05) at 18 months, then the differences wenton. HOMA2-%B in RSG group were higher than those in SUs group inthe 18th month (82.78±52.9% vs 52.5126.77%, P<0.05) and in the 36thmonth (73.46±36.87% vs 43.27±30.48%, P<0.05).2) During 3 years’ follow-up,βcell function failure occurred in 9LADA patients of group received insulin. The FCP levels(0.34±0.28nmol/L vs 0.54±0.31 nmol/L, P<0.05) in INS+RSG groupwere decreased until the 36th month. However, the FCP levels(0.38±0.29nmol/L vs 0.57±0.46nmol/L, P<0.05)in INS group showedapparent decrease after the 6th month. The FCP levels in INS+RSG groupwere higher than those in INS group after the 12th month. The PCP levelsand△CP levels in INS+RSG group sustained, whereas the PCP levels(0.71±0.72nmol/L vs 1.35±0.94nmol/L, P<0.01) and△CP levels(0.44±0.58nmol/L vs 0.78±0.70nmol/L, P<0.05) in INS group weredecreased after the 12th month. The PCP levels (after the 12th month)and△CP levels (after the 18th month) in INS+RSG group were higherthan those in INS group.Conclusions: Rosiglitazone had beneficial effects on isletβcell functionin LADA patients. Part 2 The CD4~+ regulatory T cells in adults with latentautoimmune diabetesObjective: To study the percentage of peripheral blood CD4~+CD25~+ Tcells and the expression of FOXP3 mRNA in the patients with latentautoimmune diabetes in adults (LADA).Methods: Fresh peripheral blood samples were obtained from 67 patientswith LADA, 30 patients with type 2 diabetes and 30 matched healthynondiabetic control subjects without diabetic family history. Two-colorstaining (anti-CD4, anti-CD25, anti-CD3, anti-CDS) flow cytometricanalysis was employed to measure the CD4~+CD25~+ T Cells of peripheralblood. The CD4~+ T cells were purified with anti-CD4-Dynal magneticbeads and Detach-a-Bead antibodies. Using real time-PCR tested theexpression of FOXP3 mRNA in CD4~+ T Cells.Results: 1) Patients with LADA had higher percentage of CD4~+CD25~+ Tcells (4.1±1.9% vs 2.8±1.5%, P<0.01) and CD4~+CD25~+of CD4~+ T cells(11.9±5.0% vs 8.2±3.7%, P<0.01) and CD8~+ T cells (24.6±6.8% vs19.4±7.1%, P<0.01 ) and lower of CD4~+/CD8~+ ratio(1.5±0.5 vs 1.9±0.6,P<0.01) in comparison with control subjects.2) Patients with LADA had lower expression of FOXP3 mRNAin CD4~+ T cells compared to the control subjects (0.52-fold, P<0.01,n=10).Conclusion: Though the percentage of CD4~+CD25~+ T cells elevated, theexpression of FOXP3 mRNA in CD4~+ T cells was lower in patients withLADA. The regulatory T cells may be defective in LADA patients. Part 3 Rosiglitazone upregulates FOXP3 mRNA expressionof CD4~+ T cells in adults with latent autoimmune diabetesObjective: To investigate the effect of rosiglitazone on the CD4~+regulatory T cells in the patients with latent autoimmune diabetes inadults(LADA).Methods: The CD4~+ T cells from LADA patients were isolated, andexpression of FOXP3 mRNA, along with PPAR_γmRNA and TGF-β1mRNA, was determined. The effect of rosiglitazone on CD4~+ T cells wasmeasured in vivo before and after rosiglitazone treatment and in in vitrocultures for 48h. Cell viability was assessed by tetrazolium salt3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazoliumbromide bromide(MTT) assay. The proliferation assay was assessed with [~3HI thymidine.Two-color staining (anti-CD4, anti-CD25) flow cytometric analysis wasemployed to measure the percentage of CD4~+CD25~+ T cells of peripheralblood.Results: PPAR_γmRNA is expressed in peripheral CD4~+T Lymphocytes.1) Rosiglitazone inhibited PHA-induced human CD4~+T cell activation indose dependent fashion. The percentage of CD4~+CD25~+ T cells showedno significant change after the peripheral blood culture with 1uM and10uM rosiglitazone. The concentration of 10uM rosiglitazone inducedFOXP3 mRNA expression in in vitro cultures (3.27fold, P<0.05),whereas TGF-β1 mRNA expression did not change. Furthermore, onlythe concentration of 1uM rosiglitazone promoted FOXP3 mRNAexpression if adding IL-2 (10U/mL) in in vitro cultures (3.48fold,P<0.05).2) FOXP3 mRNA expression was significantly elevated in the CD4~+Tcells of LADA patients receiving rosiglitazone treatment for 6 months(2.2fold, P<0.05), although there were no increase in the CD4~+CD25~+ T cells.Conclusion: Rosiglitazone promotes FOXP3 mRNA expression inCD4~+ T cells in vivo and in vitro, improving the defective of theregulatory T cells.

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetes
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