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5 results on '"Saeko Moriuchi"'

1. Comprehensive Search for GPCR Compounds which Can Enhance MafA and/or PDX-1 Expression Levels Using a Small Molecule Compound Library

Author

Hideaki Kaneto, Atsushi Obata, Masashi Shimoda, Tomohiko Kimura, Yoshiyuki Obata, Tomoko Ikeda, Saeko Moriuchi, Shuhei Nakanishi, Tomoatsu Mune, and Kohei Kaku

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

It has been shown that chronic hyperglycemia gradually decreases insulin biosynthesis and secretion which is accompanied by reduced expression of very important insulin gene transcription factors MafA and PDX-1. Such phenomena are well known as β-cell glucose toxicity. It has been shown that the downregulation of MafA and/or PDX-1 expression considerably explains the molecular mechanism for glucose toxicity. However, it remained unknown which molecules can enhance MafA and/or PDX-1 expression levels. In this study, we comprehensively searched for G protein-coupled receptor (GPCR) compounds which can enhance MafA and/or PDX-1 expression levels using a small molecule compound library in pancreatic β-cell line MIN6 cells and islets isolated from nondiabetic C57BL/6 J mice and obese type 2 diabetic C57BL/KsJ-db/db mice. We found that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells. We confirmed that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in islets from nondiabetic mice as well. Furthermore, these reagents more clearly enhanced MafA, PDX-1, or insulin expression levels in islets from obese type 2 diabetic db/db mice in which MafA and PDX-1 expression levels are reduced due to glucose toxicity. In conclusion, fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells and islets from nondiabetic mice and obese type 2 diabetic db/db mice. To the best of our knowledge, this is the first report showing some molecule which can enhance MafA and/or PDX-1 expression levels. Therefore, although further extensive study is necessary, we think that the information in this study could be, at least in part, useful at some point such as in the development of new antidiabetes medicine based on the molecular mechanism of β-cell glucose toxicity in the future.

Published
2023
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2. Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic β-cells in db/db mice: The earlier and longer, the better

Author

Kenji Kohara, Tomohiko Kimura, Atsushi Obata, Shuhei Nakanishi, Saeko Moriuchi, Hideaki Kaneto, Tomoatsu Mune, Hidenori Hirukawa, Yukiko Kanda-Kimura, Yuka Nogami, Masashi Shimoda, Kohei Kaku, and Seizo Okauchi

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Time Factors, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Mice, Obese, Mice, Transgenic, Drug Administration Schedule, Diabetes Mellitus, Experimental, Diabetes Complications, Mice, 03 medical and health sciences, Endocrinology, Early Medical Intervention, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Animals, Sorbitol, Sodium-Glucose Transporter 2 Inhibitors, Cells, Cultured, geography, geography.geographical_feature_category, business.industry, Pancreatic islets, Insulin, Advanced stage, Luseogliflozin, Islet, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Cytoprotection, Apoptosis, Disease Progression, SGLT2 Inhibitor, business
Abstract

Aims We compared the protective effects of sodium glucose co-transporter (SGLT) 2 inhibitor luseogliflozin on pancreatic β-cells between early and advanced stages of diabetes and between short- and long-term use. Materials and methods Diabetic db/db mice were treated with luseogliflozin for 2 weeks in an early stage of diabetes (7-9 weeks of age) and an advanced stage of diabetes (16-18 weeks) for a longer period of time (7-18 weeks). We performed various morphological analyses of pancreatic islets and examined gene expression profiles in islets after such treatment. Results In diabetic db/db mice, insulin biosynthesis and secretion were markedly increased by luseogliflozin in an early stage of diabetes but not in an advanced stage. In addition, β-cell mass was preserved by luseogliflozin only in an early stage. Furthermore, when db/db mice were treated with luseogliflozin for a longer period of time, starting from an early stage, β-cell function and mass were markedly preserved even after a longer period of time compared to untreated db/db mice. Conclusion Luseogliflozin exerts more protective effects in an early stage of diabetes compared to an advanced stage, and longer-term use of luseogliflozin exerts more beneficial effects on pancreatic β-cells compared to short-term use.

Published
2018
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3. Suppression of free fatty acid receptor 1 expression in pancreatic β-cells in obese type 2 diabetic db/db mice: a potential role of pancreatic and duodenal homeobox factor 1

Author

Hideaki Kaneto, Hidenori Hirukawa, Tomohiko Kimura, Kenji Kohara, Tomoatsu Mune, Kohei Kaku, Seizo Okauchi, Masashi Shimoda, Saeko Moriuchi, and Atsushi Obata

Subjects
Male, endocrine system, medicine.medical_specialty, Small interfering RNA, Endocrinology, Diabetes and Metabolism, Regulator, 030209 endocrinology & metabolism, digestive system, Cell Line, Receptors, G-Protein-Coupled, 03 medical and health sciences, Mice, 0302 clinical medicine, Endocrinology, Free fatty acid receptor 1, Internal medicine, Insulin-Secreting Cells, Insulin Secretion, medicine, Animals, Obesity, RNA, Messenger, RNA, Small Interfering, Receptor, Transcription factor, Homeodomain Proteins, Messenger RNA, Chemistry, Disease Models, Animal, Diabetes Mellitus, Type 2, Cell culture, 030220 oncology & carcinogenesis, Trans-Activators, PDX1
Abstract

It is known that long-chain fatty acids bind to free fatty acid receptor 1 (Ffar1), also known as G protein-coupled receptor 40 (GPR40), and amplify glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells and that Ffar1 agonists facilitates insulin secretion and ameliorates glycemic control. On the other hands, pancreatic and duodenal homeobox factor 1 (Pdx1) is an important transcription factor for various β-cell-related genes including insulin gene and thereby contributes to the maintenance of mature β-cell function. The aim of this study was to evaluate how Ffar1 expression in β-cells is altered under diabetic conditions. In this study, we used male obese type 2 diabetic mice and control mice. We evaluated Ffar1 and Pdx1 mRNA and protein expression levels in both mice. In addition, we examined whether Pdx1 is a possible regulator of Ffar1 expression using small interfering RNA for Pdx1 (siPdx1) in β-cell-derived cell line. As the results, Ffar1 mRNA and protein expression in β-cells were significantly lower in obese type 2 diabetic db/db mice compared to control mice which was accompanied by the decreased expression of Pdx1. In addition, down-regulation of Pdx1 expression using siPdx1 suppressed Ffar1 expression. Furthermore, adenoviral Pdx1 overexpression significantly increased Ffar1 expression. In conclusion, Ffar1 expression is markedly down-regulated under diabetic conditions which is accompanied by decreased expression of Pdx1. Furthermore, it is likely that Pdx1 is a regulator of Ffar1 expression in β-cells.

Published
2018

4. Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity

Author

Kenji Kohara, Tomohiko Kimura, Hidenori Yoshitaka, Atsushi Obata, Genta Chikazawa, Kentaro Tamura, Arudo Hiraoka, Guy A. Rutter, Saeko Moriuchi, Hideaki Kaneto, Gabriela da Silva Xavier, Hidenori Hirukawa, Atsuhisa Ishida, Tomoatsu Mune, Kohei Kaku, Seizo Okauchi, Ikki Shimizu, and Masashi Shimoda

Subjects
0301 basic medicine, Male, Small interfering RNA, Receptor expression, lcsh:Medicine, ADHESION, Body Mass Index, Gene expression, RNA, Small Interfering, Receptor, lcsh:Science, Aged, 80 and over, Multidisciplinary, GLUCAGON-LIKE PEPTIDE-1, digestive, oral, and skin physiology, Arteriosclerosis, Arteries, Middle Aged, Multidisciplinary Sciences, AGONIST, medicine.anatomical_structure, Science & Technology - Other Topics, CORONARY-ARTERY-DISEASE, Female, Tunica Media, Transcription Factor 7-Like 2 Protein, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, endocrine system, Endothelium, TYPE-2 DIABETES-MELLITUS, Down-Regulation, Article, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, Downregulation and upregulation, BETA-CELL FUNCTION, Internal medicine, medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, Obesity, Glucagon-like peptide 1 receptor, Aged, Science & Technology, business.industry, lcsh:R, medicine.disease, ENDOTHELIAL-CELLS, TCF7L2, 030104 developmental biology, Endocrinology, ATHEROSCLEROSIS, LIRAGLUTIDE, lcsh:Q, Endothelium, Vascular, business, Tunica Intima
Abstract

It has been thought that incretin signaling prevents arteriosclerosis, and very recently anti-arteriosclerotic effects through GLP-1 receptor were finally demonstrated in clinical human study. The purpose of this study was to investigate how vascular GLP-1 receptor expression is influenced in human subjects. First, we evaluated GLP-1 receptor expression in human arteries in immunostaining. Next, we separated the artery into the intima and media, and evaluated gene expression levels of various factors. We divided the subjects into obesity and non-obesity group and compared their expression levels between them. Finally, we evaluated which factors determine vascular GLP-1 receptor expression. GLP-1 receptor expression in intima and media was lower in obesity group compared to non-obesity group which was correlated with the alteration of TCF7L2 expression. Multiple regression analyses showed that BMI was an independent determining factor for GLP-1 receptor expression in the intima and media. Furthermore, using small interfering RNA method and TCF7L2-EGFP adenovirus, we showed that TCF7L2 was involved in GLP-1 receptor expression in human vascular cells. Taken together, vascular GLP-1 receptor and TCF7L2 expression was significantly down-regulated in human subjects with obesity. In addition, it is likely that TCF7L2 functions as a modulator of vascular GLP-1 receptor expression.

Published
2018

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