Store-operated Ca entry (SOCE) is a dynamic process that leads to refilling of endoplasmic reticulum (ER) Ca stores through reversible gating of plasma membrane Ca channels by the ER Ca sensor Stromal Interaction Molecule 1 (STIM1). Pathogenic reductions in β-cell ER Ca have been observed in diabetes. However, a role for impaired SOCE in this phenotype has not been tested. We measured the expression of SOCE molecular components in human and rodent models of diabetes and found a specific reduction in STIM1 mRNA and protein levels in human islets from donors with type 2 diabetes (T2D), islets from hyperglycemic streptozotocin-treated mice, and INS-1 cells (rat insulinoma cells) treated with proinflammatory cytokines and palmitate. Pharmacologic SOCE inhibitors led to impaired islet Ca oscillations and insulin secretion, and these effects were phenocopied by β-cell STIM1 deletion. STIM1 deletion also led to reduced ER Ca storage and increased ER stress, whereas STIM1 gain of function rescued β-cell survival under proinflammatory conditions and improved insulin secretion in human islets from donors with T2D. Taken together, these data suggest that the loss of STIM1 and impaired SOCE contribute to ER Ca dyshomeostasis under diabetic conditions, whereas efforts to restore SOCE-mediated Ca transients may have the potential to improve β-cell health and function.

Aims/Introduction: The distinct effects of different statins on glycemic control have not been fully evaluated. In this open-label, prospective, cross-over clinical trial, we compared the effects of pitavastatin and atorvastatin on glycemic control in type 2 diabetic patients with hypercholesterolemia. Materials and Methods: A total of 28 Japanese type 2 diabetics with hypercholesterolemia treated with rosuvastatin (2.5 mg/day) for at least 8 weeks were recruited to this quasi-randomized cross-over study. At study entry, the patients assigned to sequence 1 received pitavastatin (2 mg/day) for 12 weeks in period 1 and atorvastatin (10 mg/day) for another 12 weeks in period 2, whereas patients assigned to sequence 2 received atorvastatin (10 mg/day) for 12 weeks in period 1 and pitavastatin (2 mg/day) for another 12 weeks in period 2. Blood samples were collected at three visits (baseline, after 12 and 24 weeks). Results: Lipid control was similar in both statins. The difference in glycated hemoglobin between pitavastatin and atorvastatin treatments was À0.18 (95% confidence interval À0.34 to À0.02; P = 0.03). Compared with atorvastatin, pitavastatin treatment significantly lowered the levels of glycoalbumin, fasting glucose and homeostasis model assessment of insulin resistance. Conclusions: Our results showed that treatment with pitavastatin had a more favorable outcome on glycemic control in patients with type 2 diabetes compared with atorvastatin. This trial was registered with UMIN (no. 000003554). (J Diabetes Invest

Serotonin signaling plays key roles in augmentation of pancreatic b-cell function during pregnancy. Increased expression of tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme for serotonin synthesis by lactogenic hormones, is involved in this phenomenon. To investigate its mechanisms, we here performed 5 0 -RACE and identified b-cell-specific transcription initiation sites for Tph1. Prolactin enhanced the expression of mRNA containing these exons; however, reporter gene plasmids containing the proximal 5 0 -flanking region of these exons did not show prolactin responsiveness in MIN6 cells.Prolactin-induced Tph1 expression was inhibited by a Jak2 inhibitor and was partially inhibited by an MEK1/2 or PI3K inhibitor. Therefore, we analyzed interferon g-activated sequences (GAS) and found GAS-A about 9-kbp upstream of the transcription start site. The reporter gene plasmid containing the GAS-A region linked to a heterologous promoter showed increased promoter activity by prolactin, which was inhibited by the forced expression of a dominant-negative mutant form of Stat5A and a Jak2 inhibitor. Chromatin immunoprecipitation analysis showed that prolactin treatment augmented Stat5 binding to the GAS-A region in MIN6 cells, as well as in isolated mouse islets, and that Stat5 recognized the GAS-A region in pregnant mouse islets. In addition, the transactivation activity of Stat5 was enhanced by prolactin through the Erk and PI3K pathways in MIN6 cells. Finally, serotonin expression was attenuated in islets of b-cell-specific Stat5-deficient mice compared with that of control littermates during pregnancy. Our findings suggest that prolactin-induced Tph1 expression is mediated by the activation of Jak2/Stat5, Erk, and PI3K pathways in b cells.Key Words

Background: SET7/9 regulates expression of NF-B target genes in non-␤ cells. Results: SET7/9 knockdown attenuated cytokine-induced expression of inducible nitric-oxide synthase and apoptosis in ␤ cells. Conclusion: SET7/9 regulates Nos2 expression through methylation of H3K4 in ␤ cells. Significance: SET7/9 contributes to proinflammatory cytokine signaling in the pancreatic ␤ cell.

The proliferation of pancreatic β cells is enhanced to enable an increase in β-cell mass and to compensate for insulin resistance during pregnancy. To elucidate the mechanisms involved, we previously investigated islets from pregnant and nonpregnant mice by gene expression profiling and found that the expression of postsynaptic density-95/Discs large/zonula occludens-1 (PDZ)–binding kinase (Pbk), a member of the mitogen-activated protein kinase kinase family, is increased in pregnant mouse islets compared with control mouse islets. Among the pregnancy hormones, treatment with estradiol upregulated Pbk expression. Inhibition of Pbk expression using a small interfering RNA for Pbk reduced bromodeoxyuridine incorporation in mouse insulinoma 6 cells, which was accompanied by a decreased expression of Ccnb1, a regulatory gene involved in mitosis. Ccnb1 expression was augmented in mouse islets during pregnancy. The forced expression of Pbk using an adenovirus system in isolated mouse islets increased Ccnb1 expression, and the Pbk inhibitor HI-TOPK-032 suppressed Ccnb1 expression in islets isolated from pregnant mice. Our results suggest that Pbk contributes to the expansion of islets during pregnancy and that Ccnb1 may assist Pbk in its role in β-cell proliferation.