Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients.

AIMS/HYPOTHESIS: Exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, is reported to have modest anti-inflammatory effects in addition to that of improving beta cell survival. We therefore sought to determine whether exendin-4 decreases expression of the gene encoding chemokine (C-X-C motif) ligand (CXCL)10, which plays a role in initiating insulitis in type 1 diabetes. METHODS: The expression of CXCL10 in human islets was determined at the mRNA level by real-time RT-PCR analysis and at the protein level by western blotting. The level of CXCL10 in culture medium was measured by ELISA. Pathway-specific gene expression profiling was carried out to determine the expression of a panel of genes encoding chemokines and cytokines in human islets exposed to cytokines. RESULTS: IFN-γ induced expression of CXCL10 through activation of signal transducer and activator of transcription-1 (STAT-1). A combination of cytokines (IL-1ß, TNF-α and IFN-γ) showed strong synergy in the induction of numerous chemokines and cytokines through nuclear factor kappa B and STAT-1. Exendin-4 suppressed basal expression of several inflammatory mediators. In combination with phosphodiesterase inhibitors, exendin-4 also decreased IFN-γ-induced CXCL10 expression in human islets and in MIN6 cells (a mouse beta cell line), and its secretion into the culture medium. Exendin-4 action was mimicked by forskolin, an activator of adenylyl cyclase, and by dibutyryl cyclic AMP. Protein kinase A was not involved in mediating exendin-4 action on CXCL10. The mechanism of exendin-4's anti-inflammatory action involved decreases in STAT-1 levels. CONCLUSIONS/INTERPRETATION: These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival.

Design considerations in development of a prototype, piezoelectric internal fixation plate: a preliminary report.

The piezoelectric internal fixation plate represents a new concept in orthopaedic implants. The purpose of this device is to provide stable bone fixation while delivering internally generated, microampere direct currents to prevent or treat nonunion of a fracture or osteotomy. Clinically, currents of this type have been effective in treatment of nonunion, but application has required separate, implanted, or external battery or radiofrequency powered circuits. The "piezoplate" being developed contains an integral piezoelectric element that generates current in response to either physiological loading such as weightbearing or to externally applied ultrasound. Currents are processed by a rectifying circuit for delivery to bone by electrodes. Specially designed series/parallel piezoelectric elements and dual processing circuits are required to generate optimum rectified currents from the low-frequency, high-voltage signals generated by weightbearing, as well as the high-frequency, low-voltage signals produced by ultrasound. This paper reports on the current status of development and describes design parameters of this device which combines the modalities of mechanical fixation and electrical stimulation in a single implant.