Abstract. Sulfonylurea is one of the commonly used anti-diabetic drugs that stimulate insulin secretion from β-cells. Despite their glucose lowering effects in type 2 diabetes mellitus, long-term treatment brought on secondary failure characterized by β-cell exhaustion and apoptosis. ER stress induced by Ca 2+ depletion in endoplasmic reticulum (ER) is speculated be one of the causes of secondary failure, but it remains unclear. Glucagon like peptide-1 (GLP-1) has anti-apoptotic effects in β-cells after the induction of oxidative and ER stress. In this study, we examined the antiapoptotic action of a GLP-1 analogue in β-cell lines and islets against ER stress induced by chronic treatment of sulfonylurea. HIT-T15 and dispersed islet cells were exposed to glibenclamide for 48 h, and apoptosis was evaluated using Annexin/PI flow cytometry. Expression of the ER stressrelated molecules and sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) 2/3 was determined by real-time PCR and western blot analysis. Chronic exposure to glibenclamide increased apoptosis by depletion of ER Ca 2+ concentration through reduced expression of SERCA 2/3. Pretreatment with Exendin-4 had an anti-apoptotic role through ER stress modulation and ER Ca 2+ replenishing by SERCA restoration. These findings will further the understanding of one cause of glibenclamide-induced β-cell loss and therapeutic availability of GLP-1-based drugs in secondary failure by sulfonylurea during treatment of diabetes.

Secretagogue-stimulated intracellular Ca2+ signals are fundamentally important for initiating the secretion of the fluid and ion component of saliva from parotid acinar cells. The Ca2+ signals have characteristic spatial and temporal characteristics, which are defined by the specific properties of Ca2+ release mediated by inositol 1,4,5-trisphosphate receptors (InsP3R). In this study we have investigated the role of adenine nucleotides in modulating Ca2+ release in mouse parotid acinar cells. In permeabilized cells, the Ca2+ release rate induced by submaximal [InsP3] was increased by 5 mM ATP. Enhanced Ca2+ release was not observed at saturating [InsP3]. The EC50 for the augmented Ca2+ release was ∼8 μM ATP. The effect was mimicked by nonhydrolysable ATP analogs. ADP and AMP also potentiated Ca2+ release but were less potent than ATP. In acini isolated from InsP3R-2-null transgenic animals, the rate of Ca2+ release was decreased under all conditions but now enhanced by ATP at all [InsP3]. In addition the EC50 for ATP potentiation increased to ∼500 μM. These characteristics are consistent with the properties of the InsP3R-2 dominating the overall features of InsP3R-induced Ca2+ release despite the expression of all isoforms. Finally, Ca2+ signals were measured in intact parotid lobules by multiphoton microscopy. Consistent with the release data, carbachol-stimulated Ca2+ signals were reduced in lobules exposed to experimental hypoxia compared with control lobules only at submaximal concentrations. Adenine nucleotide modulation of InsP3R in parotid acinar cells likely contributes to the properties of Ca2+ signals in physiological and pathological conditions.

GABA could be secreted from beta-cells into the islet-acinar portal system after administration of glutainine, and could enhance the CCK-stimulated exocrine secretion through GABA(A) receptors. Thus, GABA in islet beta-cells is a hormone modulating pancreatic exocrine secretion.

This study was conducted to investigate the reliability and validity of the Korean version of the DSM-5 Level 2 Cross-Cutting Symptom Measure-inattention [Swanson, Nolan and Pelham, version IV (SNAP-IV)] and anger [Patient-Reported Outcome Measurement Information System (PROMIS) Anger] for parents and guardians of children aged 6-17 years. Methods:We included 104 children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD), ADHD with anxiety and depression, depressive disorder, anxiety disorder, and tic disorder with somatic symptoms (ADHD=41, depression=9, anxi-ety=14, ADHD+anxious depression=11, tic+somatic symptoms=29). Their ages ranged from 8 years to 15 years. The participants' mothers completed the SNAP-IV, PROMIS Anger scale, Korean version of the IOWA Conners Rating Scale (K-IOWA), and Korean ADHD Rating Scale (K-ARS) so that the reliability and validity of the SNAP-IV and PROMIS Anger scales, which are DSM-5 scales for assessing inattention and anger of children and adolescents, could be examined. Results: The reliability coefficient of SNAP-IV (Cronbach's α) was 0.94. The correlation coefficients between SNAP-IV, K-IOWA inattention, and K-ARS inattention scores ranged from 0.73 to 0.86. The mean SNAP-IV scores of the ADHD and the ADHD+anxious depression groups were significantly higher than those of the anxiety and the tic+somatic symptoms groups. The reliability coefficient of the PROMIS Anger was 0.91. The correlation coefficient between PROMIS Anger and K-IOWA oppositional/defiant scores was 0.75. The PROMIS Anger mean score of the ADHD+anxious depression group tended to be higher than that of the other groups. Conclusion:These results suggest that the Korean version of the DSM-5 Level 2 Cross-Cutting Symptom Measure-inattention and anger for parent and guardian of child age 6-17 might be a reliable and valid test and may be useful for screening children and adolescents with ADHD.

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