Biomedical subjects

Taka-aki Matsuoka

Publications and source records attributed to Taka-aki Matsuoka.

12 recordsLinked to original sources

PubMed2006

Marked increase of insulin gene transcription by suppression of the Rho/Rho-kinase pathway.

The hallmarks of type 2 diabetes are pancreatic beta-cell dysfunction and insulin resistance. It has been suggested that Rho/Rho-kinase is a mediator of insulin signaling, and thereby involved in the development of insulin resistance, regulation of insulin action, and glucose homeostasis, but the role of Rho/Rho-kinase in beta-cells remained unknown. The aim of this study was to examine the possible role of Rho/Rho-kinase in beta-cell function. Immunostaining showed that RhoA was expressed in mature beta-cells, with higher expression observed in beta-cells of diabetic C57BL/KsJ-db/db mice compared to non-diabetic mice. In addition, to examine the functional role of Rho/Rho-kinase in beta-cells, we evaluated the effect of Rho-kinase inhibitors on insulin biosynthesis. Northern blot analysis showed that insulin mRNA levels were markedly increased by Rho-kinase inhibitors, Y-27632 and fasudil, in beta-cell-derived HIT-T15 cells. Furthermore, using the luciferase reporter gene assay, insulin promoter activity was also dramatically increased by Y-27632, which was associated with an increase in the insulin mRNA level. These results suggest that suppression of Rho/Rho-kinase increases insulin promoter activity, which leads to an increase in insulin mRNA level. Taken together, Rho/Rho-kinase is activated in beta-cells under diabetic conditions and suppression of the Rho/Rho-kinase pathway increases insulin gene transcription. These results imply that Rho/Rho-kinase activation is involved in the suppression of insulin expression found in diabetes and that suppression of the Rho/Rho-kinase pathway could be a useful tool to augment insulin gene transcription.

Animals↗

PubMed2006

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation.

The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches. The transgenic pancreas was markedly small with the replacement of acinar cells by duct-like structures, accompanied by activated Stat3. Genetic ablation of Stat3 in the transgenic pancreas profoundly suppressed the metaplastic phenotype. These results provide a mechanism of pancreatic metaplasia by which persistent PDX-1 expression cell-autonomously induces acinar-to-ductal transition through Stat3 activation.

Animals↗

PubMed2006

Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance.

Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion and/or beta-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy.

Animals↗

PubMed2005

Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance.

Animals↗

PubMed2005

A crucial role of MafA as a novel therapeutic target for diabetes.

MafA, a recently isolated pancreatic beta-cell-specific transcription factor, is a potent activator of insulin gene transcription. In this study, we show that MafA overexpression, together with PDX-1 (pancreatic and duodenal homeobox factor-1) and NeuroD, markedly increases insulin gene expression in the liver. Consequently, substantial amounts of insulin protein were induced by such combination. Furthermore, in streptozotocin-induced diabetic mice, MafA overexpression in the liver, together with PDX-1 and NeuroD, dramatically ameliorated glucose tolerance, while combination of PDX-1 and NeuroD was much less effective. These results suggest a crucial role of MafA as a novel therapeutic target for diabetes.

Adenoviridae↗

PubMed2005

PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance.

Diabetes is the most prevalent and serious metabolic disease, and the number of diabetic patients worldwide is increasing. The reduction of insulin biosynthesis in pancreatic beta-cells is closely associated with the onset and progression of diabetes, and thus it is important to search for ways to induce insulin-producing cells in non-beta-cells. In this study, we showed that a modified form of the pancreatic and duodenal homeobox factor 1 (PDX-1) carrying the VP16 transcriptional activation domain (PDX-1/VP16) markedly increases insulin biosynthesis and induces various pancreas-related factors in the liver, especially in the presence of NeuroD or neurogenin 3 (Ngn3). Furthermore, in streptozotocin-induced diabetic mice, PDX-1/VP16 overexpression, together with NeuroD or Ngn3, drastically ameliorated glucose tolerance. Thus PDX-1/VP16 expression, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. This approach warrants further investigation and may have utility in the treatment of diabetes.

Adenoviridae↗

PubMed2004

Involvement of endoplasmic reticulum stress in insulin resistance and diabetes.

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic beta-cell dysfunction are the hallmarks of the disease. In this study, we have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes.

Animals↗

PubMed2004

Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide.

The JNK pathway is known to be activated in several tissues in the diabetic state, and is possibly involved in the development of insulin resistance and suppression of insulin biosynthesis. Here we show a potential new therapy for diabetes using cell-permeable JNK-inhibitory peptide. Intraperitoneal administration of the peptide led to its transduction into various tissues in vivo, and this treatment markedly improved insulin resistance and ameliorated glucose tolerance in diabetic mice. These data indicate that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK-inhibitory peptide may have promise as a new therapeutic agent for diabetes.

Amino Acid Sequence↗

PubMed2004

The MafA transcription factor appears to be responsible for tissue-specific expression of insulin.

Insulin gene expression is regulated by several islet-enriched transcription factors. However, MafA is the only beta cell-specific activator. Here, we show that MafA selectively induces endogenous insulin transcription in non-beta cells. MafA was also first detected in the insulin-producing cells formed during the second and predominant phase of beta cell differentiation, and absent in the few insulin-positive cells found in Nkx6.1(-/-) pancreata, which lack the majority of second-phase beta cells. These results demonstrate that MafA is a potent insulin activator that is likely to function downstream of Nkx6.1 during islet insulin-producing cell development.

Animals↗

PubMed2004

Oxidative stress and the JNK pathway as a potential therapeutic target for diabetes.

Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Possibly due to low levels of antioxidant enzyme expressions, beta-cells are vulnerable to oxidative stress. When beta-cell-derived cell lines or isolated rat islets were exposed to oxidative stress, insulin gene expression was markedly decreased. Furthermore, when diabetic C57BL/ KsJ-db/db mice were treated with antioxidants, glucose tolerance was ameliorated. Histological analyses of the pancreata revealed that the beta-cell mass is significantly larger in the mice treated with the antioxidants. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA. As a possible mechanism underlying the phenomena, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), an important transcription factor for the insulin gene, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. Furthermore, oxidative stress induces nucleocytoplasmic translocation of PDX-1 through activation of the c-Jun N-terminal kinase (JNK) pathway, which leads to suppression of insulin gene expression. Taken together, oxidative stress and consequent activation of the JNK pathway are involved in progression of beta-cell dysfunction found in diabetes, and thus are a therapeutic target for diabetes.

Active Transport, Cell Nucleus↗

PubMed2003

Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells.

The C1/RIPE3b1 (-118/-107 bp) binding factor regulates pancreatic-beta-cell-specific and glucose-regulated transcription of the insulin gene. In the present study, the C1/RIPE3b1 activator from mouse beta TC-3 cell nuclear extracts was purified by DNA affinity chromatography and two-dimensional gel electrophoresis. C1/RIPE3b1 binding activity was found in the roughly 46-kDa fraction at pH 7.0 and pH 4.5, and each contained N- and C-terminal peptides to mouse MafA as determined by peptide mass mapping and tandem spectrometry. MafA was detected in the C1/RIPE3b1 binding complex by using MafA peptide-specific antisera. In addition, MafA was shown to bind within the enhancer region (-340/-91 bp) of the endogenous insulin gene in beta TC-3 cells in the chromatin immunoprecipitation assay. These results strongly suggested that MafA was the beta-cell-enriched component of the RIPE3b1 activator. However, reverse transcription-PCR analysis demonstrated that mouse islets express not only MafA but also other members of the large Maf family, specifically c-Maf and MafB. Furthermore, immunohistochemical studies revealed that at least MafA and MafB were present within the nuclei of islet beta cells and not within pancreas acinar cells. Because MafA, MafB, and c-Maf were each capable of specifically binding to and activating insulin C1 element-mediated expression, our results suggest that all of these factors play a role in islet beta-cell function.

Amino Acid Sequence↗

PubMedDate not supplied

Oxidative stress and pancreatic beta-cell dysfunction.

Oxidative stress is induced under diabetic conditions through various pathways, including the electron transport chain in mitochondria and the nonenzymatic glycosylation reaction, and is likely involved in progression of pancreatic beta-cell dysfunction developing in diabetes. beta-Cells are vulnerable to oxidative stress, possibly due to low levels of antioxidant enzyme expression. When oxidative stress was induced in vitro in beta cells, the insulin gene promoter activity and mRNA levels were suppressed, accompanied by the reduced activity of pancreatic and duodenal homeobox factor-1 (PDX-1) (also known as IDX-1/STF-1/IPF1), an important transcription factor for the insulin gene. The suppression of oxidative stress by a potent antioxidant, N-acetyl-l-cysteine or probucol, led to the recovery of insulin biosynthesis and PDX-1 expression in nuclei and improved glucose tolerance in animal models for type 2 diabetes. As a possible cause of this, we recently found that PDX-1 was translocated from the nucleus to the cytoplasm in response to oxidative stress. Furthermore, the addition of a dominant-negative form of c-Jun N-terminal kinase (JNK) inhibited the oxidative stress-induced PDX-1 translocation, suggesting an essential role of JNK in mediating the phenomenon. Taken together, the oxidative stress-mediated activation of the JNK pathway leads to nucleocytoplasmic translocation of PDX-1 and thus is likely involved in the progression of beta-cell dysfunction found in diabetes.

Animals↗