Glucagon-like peptide-1 (GLP-1) and its analog exendin-4 (EX) have been considered as a growth factor implicated in pancreatic islet mass increase and -cell proliferation. This study aimed to investigate the effect of EX on cyclin D1 expression, a key regulator of the cell cycle, in the pancreatic -cell line INS-1. We demonstrated that EX significantly increased cyclin D1 mRNA and subsequently its protein levels. Although EX induced phosphorylation of Raf-1 and extracellular-signal-regulated kinase (ERK), both PD98059 and exogenous ERK1 had no effect on the cyclin D1 induction by EX. Instead, the cAMP-elevating agent forskolin induced cyclin D1 expression remarkably and this response was inhibited by pretreatment with H-89, a protein kinase A (PKA) inhibitor. Promoter analyses revealed that the cAMP-responsive element (CRE) site (at position -48; 5 -TAACGTCA-3 ) of cyclin D1 gene was required for both basal and EX-induced activation of the cyclin D1 promoter, which was confirmed by site-directed mutagenesis study. For EX to activate the cyclin D1 promoter effectively, CRE-binding protein (CREB) should be phosphorylated and bound to the putative CRE site, according to the results of electrophoretic mobility shift and chromatin immunoprecipitation assays. Lastly, a transfection assay employing constitutively active or dominant-negative CREB expression plasmids clearly demonstrated that CREB was largely involved in both basal and EX-induced cyclin D1 promoter activities. Taken together, EXinduced cyclin D1 expression is largely dependent on the cAMP/PKA signaling pathway, and EX increases the level of phosphorylated CREB and more potently transactivates cyclin D1 gene through binding of the CREB to the putative CRE site, implicating a potential mechanism underlying -cell proliferation by EX.

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BackgroundWe have developed a new arthroscope with a field of view of 150°. This requires less motion to maneuver, and the optical error is decreased. It also improves how novices learn arthroscopy. We hypothesized that surgical performance using this arthroscope is superior to a conventional arthroscope. This study tested the hypothesis using motion analysis and a new validated parameter, “dimensionless squared jolt” (DSJ).MethodsWe compared the surgical performance using between the wide-angle and the conventional arthroscope among 14 novice orthopedic residents who performed three standardized tasks three times with each arthroscope. The tasks simulated arthroscopic rotator cuff repair surgical skills. Their motion was analyzed using an optical tracking system. The differences in performance parameters, such as time taken, average acceleration of the hands (m/s2), the number of movements, and the total path length (m) including DSJ between the two arthroscopes, were investigated using paired t-tests.ResultsAll the estimated values for the tasks using the 150° arthroscope were lower than those for the 105° arthroscope. There were statistically significant differences in performance between the two arthroscopes only for DSJ (p = 0.014) and average acceleration (p = 0.039).ConclusionsDSJ and average acceleration are reliable parameters for representing hand-eye coordination. The surgical performance of novice arthroscopists was better with the new wide-angle arthroscope than with the conventional arthroscope.