Pharmacological challenges to oncogenic Ras-expressing cancer cells have shown a novel type of cell death, ferroptosis, which requires intracellular iron. In the present study, we assessed ferroptosis following treatment of human fibrosarcoma HT1080 cells with several inhibitors of lysosomal activity and found that they prevented cell death induced by the ferroptosis-inducing compounds erastin and RSL3. Fluorescent analyses with a reactive oxygen species (ROS) sensor revealed constitutive generation of ROS in lysosomes, and treatment with lysosome inhibitors decreased both lysosomal ROS and a ferroptotic cell-death-associated ROS burst. These inhibitors partially prevented intracellular iron provision by attenuating intracellular transport of transferrin or autophagic degradation of ferritin. Furthermore, analyses with a fluorescent sensor that detects oxidative changes in cell membranes revealed that formation of lipid ROS in perinuclear compartments probably represented an early event in ferroptosis. These results suggest that lysosomal activity is involved in lipid ROS-mediated ferroptotic cell death through regulation of cellular iron equilibria and ROS generation.

Metabolic regulation in mammals requires communication between multiple organs and tissues. The rise in the incidence of obesity and associated metabolic disorders, including type 2 diabetes, has renewed interest in interorgan communication. We used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiological compensation for insulin resistance. We found that hepatic activation of extracellular regulated kinase (ERK) signaling induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.

OBJECTIVE Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic β-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic β-cell functions both in vivo and in vitro. RESEARCH DESIGN AND METHODS First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine β-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells. RESULTS Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-β 1 , but not with a protein kinase A inhibitor, H-89, inhibited IL-6–induced enhancement of GSIS. An inositol triphosphate (IP 3 ) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6. CONCLUSIONS The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic β-cells and enhances GSIS. The PLC-IP 3 –dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS.

No abstract

We conducted a cross-sectional community survey in northern Japan to assess the relationship between personality and home blood pressure value. The Japanese version of the short-form Eysenck personality questionnaire was used to assess personality. A total of 999 people selected from the general population participated. We showed that the personality extroversion score positively affected the systolic blood pressure value, whereas no significant relationship was observed between personality psychoticism or neuroticism and blood pressure value. This study is the first to clarify the relationship between personality assessed by the Eysenck personality questionnaire and blood pressure measured in a non-medical setting. When physicians investigate the pathogenesis of essential hypertension, they should take psychological factors into consideration, as well as the many environmental and genetic factors.

No abstract

Aim: In the pathogenesis of atherosclerosis, autoantibodies have two-facedness of progression and protection. Previous reports have indicated that low autoantibody levels against apolipoprotein B-100 (apo B-100) could increase the risk of atherosclerotic cardiovascular diseases (CVD) in healthy subjects. In this study, we investigated the relationship between circulating anti-apo B-100 autoantibodies and the clinical parameters in Japanese diabetic patients with or without CVD.Methods: We measured the serum levels of anti-apo B-100 autoantibodies against native and malondialdehyde (MDA)-modified p45 or p210 epitopes, as well as anti-apo E autoantibodies, using enzyme-linked immunosorbent assay.Results: In patients with CVD, the circulating levels of IgG against native p45, MDA-modified p45, and MDA-modified p210 (IgGN-45, IgGMDA-45, and IgGMDA-210) were significantly lower than those in patients without CVD, whereas no difference was observed in anti-apo E autoantibody levels. In addition, IgMN-45, IgMMDA-45, and IgGMDA-45 were negatively correlated with LDL-C levels, whereas IgGN-45 and IgGN-210 were positively correlated with HbA1c levels. No correlation was observed between autoantibody levels and diabetic microangiopathy. In the statin-treated subgroup, IgGMDA-45 and IgGMDA-210 were significantly lower in patients with CVD than in those without CVD.Conclusion: Measurement of serum anti-apo B-100 autoantibodies can be useful for the evaluation of CVD risk in patients with diabetes receiving statin treatment.

Glucagon-like peptide 1 (GLP-1) is a hormone, inducing glucose-dependent stimulation of insulin secretion from beta cells. Liraglutide acts as a GLP-1 receptor agonist.To assess the effect of liraglutide on the beta cell function, we performed oral glucose tolerance tests in 7 subjects with type 2 diabetes before and after treatment of liraglutide. Moreover, we performed same study again in 4 subjects at 6 months after induction. Liraglutide significantly increased area under the Curve (AUC) of plasma insulin level after glucose loading and significantly decreased AUC of plasma glucose level, compared with before induction. HOMA-beta was significantly increased, whereas insulinogenic index was not changed. HOMA-R was not affected but Matsuda index was significantly decreased after induction of liraglutide. Disposition index was not altered significantly, but tendency of improvement was observed. Glucose tolerance tests revealed that those effects of liraglutide were continued for 6 months after induction. These results showed that treatment of liraglutide could improve insulin secretion but early phase of insulin secretion was not improved. The results suggest that liraglutide is likely to improve beta-cell function, but this effect is still inadequate by six-month treatment.