RESUMO
AIMS/INTRODUCTION: To elucidate the relationship between titers of islet autoantibodies, the C-X-C motif chemokine 10 - a circulating chemokine that activates T-helper 1 cells leading to ß-cell destruction - and ß-cell function in type 1 diabetes. MATERIALS AND METHODS: In total, 58 type 1 diabetes patients positive for glutamic decarboxylase-65 autoantibodies (GADA)-radioimmunoassay (mean age 54.1 years; 27 acute-onset cases and 31 slowly progressive cases) were enrolled; serum C-X-C motif chemokine 10 (n = 50), zinc transporter 8 autoantibodies (n = 50) and GADA (n = 58) by an enzyme-linked immunosorbent assay, and insulinoma-associated antigen-2 autoantibodies by radioimmunoassay (n = 50) were measured. The ratio of 100 × random C-peptide (ng/mL)-to-plasma glucose levels (mg/dL; C-peptide index [CPI]) was measured. RESULTS: The CPI significantly decreased in both groups with the progression of disease duration. GADA titers by radioimmunoassay and enzyme-linked immunosorbent assay were strongly correlated with the CPI in acute-onset type 1 diabetes patients with a shorter disease duration (≤10 years), but not in those with a longer duration or slowly progressive type 1 diabetes. Neither insulinoma-associated antigen-2 nor zinc transporter 8 autoantibodies titers were correlated with the CPI. Serum C-X-C motif chemokine 10 levels in both groups were significantly higher than in non-diabetic controls, and persisted at high levels even in those with chronic duration. CONCLUSIONS: Among islet autoantibodies, the intensity of the humoral immune response, as defined by GADA titers, reflected the degree of residual ß-cell function in acute-onset type 1 diabetes patients with short duration. Prolonged disease activity might accelerate ß-cell impairment in both subtypes of type 1 diabetes.
Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Glutamato Descarboxilase/imunologia , Secreção de Insulina , Ilhotas Pancreáticas/fisiopatologia , Adulto , Estudos de Casos e Controles , Quimiocina CXCL10/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de TempoRESUMO
D-type cyclins play a pivotal role in G(1)-S progression of the cell cycle, and their expression is frequently deregulated in cancer. Cyclin D1 has a half-life of only ~30 min as a result of its ubiquitylation and proteasomal degradation, with various F-box proteins, including Fbxo4, Fbxw8, Skp2, and Fbxo31, having been found to contribute to its ubiquitylation. We have now generated Fbxo4-deficient mice and found no abnormalities in these animals. Cyclin D1 accumulation was thus not observed in Fbxo4(-/-) mouse tissues. The half-life of cyclin D1 in mouse embryonic fibroblasts (MEFs) prepared from Fbxo4(-/-), Fbxw8(-/-), and Fbxo4(-/-); Fbxw8(-/-) mice also did not differ from that in wild-type MEFs. Additional depletion of Skp2 and Fbxo31 in Fbxo4(-/-); Fbxw8(-/-) MEFs by RNA interference did not affect cyclin D1 stability. Although Fbxo31 depletion in MEFs increased cyclin D1 abundance, this effect appeared attributable to upregulation of cyclin D1 mRNA. Furthermore, abrogation of the function of the Skp1-Cul1-F-box protein (SCF) complex or the anaphase-promoting complex/cyclosome (APC/C) complexes did not alter the half-life of cyclin D1, whereas cyclin D1 degradation was dependent largely on proteasome activity. Our genetic analyses thus do not support a role for any of the four F-box proteins examined in cyclin D1 degradation during normal cell cycle progression. They suggest the existence of other ubiquitin ligases that target cyclin D1 for proteolysis.