RESUMO
Insulin is a key hormone for maintaining glucose homeostasis in organisms. In general, deficiency of insulin synthesis and secretion results in type I diabetes, whereas insulin resistance leads to type 2 diabetes. Cell division cycle 42 (CDC42), a member of Rho GTPases family, has been shown as an essential regulator in the second phase of glucose-induced insulin secretion in pancreatic islets ß cells in vitro. However, the effect of CDC42 on insulin expression has not been explored. Here we reported that the glucose-induced insulin expression and secretion were significantly inhibited in mice lacking CDC42 gene in pancreatic ß cells (Rip-CDC42cKO) in vivo and in vitro. Deletion of CDC42 gene in pancreatic ß cells did not affect survival or reproduction in mice. However, the Rip-CDC42cKO mice showed the systemic glucose intolerance and the decrease of glucose-induced insulin secretion without apparent alterations of peripheral tissues insulin sensitivity and the morphology of islets. Furthermore, we demonstrated that deletion of CDC42 gene in pancreatic ß cells significantly attenuated the insulin expression through inhibiting the ERK1/2-NeuroD1 signaling pathway. Taken together, our study presents novel evidence that CDC42 is an important modulator in glucose-induced insulin expression as well as insulin secretion in pancreatic ß cells.
Assuntos
Glucose/farmacologia , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Insulina/genética , Proteína cdc42 de Ligação ao GTP/genética , Animais , Células Cultivadas , Deleção de Genes , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Insulina/metabolismo , Resistência à Insulina/genética , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
OBJECTIVE: To explore the changes in the threshold of auditory brainstem response (ABR) and [Ca(2+)]I and calmodulin (CaM) in cochlear nucleus of newborn mice infected by murine cytomegalovirus (MCMV) in the brain. METHODS: Sixty-nine newborn mice were randomized into model group and control group. The model group (54 mice) was established by intracranial injection with MCMV viral suspension 20 l and the same volume of 0.9% sodium chloride was injected in the control group (15 mice). After 1 month, the ABR was tested in a sound-electric screen environment and the threshold was recorded. Then intracellular free calcium [Ca(2+)]i and the mRNA level of CaM in the cochlear nucleus were assayed by flow cytometry and RT-PCR. RESULTS: Compare to the control group [(64.0 ± 1.3) dBSPL], the threshold of ABR in the model group [(84.5 ± 2.7) dBSPL] was increased (F = 2.789,P = 0.000). Moreover, in the model group the intracellular free calcium [Ca(2+)]i and the mRNA level of CaM in the cochlear nucleus were increased (F = 1.290, P = 0.000; F = 4.252, P = 0.023), and the differences were statistically significant. CONCLUSIONS: The intracranial injection of MCMV can lead to abnormal changes in the threshold of ABR in mice, and the change of [Ca(2+) ]I/CaM in cochlear nucleus may be the important pathological basis of sensorineural hearing loss induced by MCMV infection.
