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Akari Inada

Publications and source records attributed to Akari Inada.

7 recordsLinked to original sources
PubMed2006

Timing and expression pattern of carbonic anhydrase II in pancreas.

In the search for genetic markers for assessing the role of duct cells in pancreas growth, we examined whether carbonic anhydrase II (CAII) has ductal cell specificity. We determined the distribution and timing of CAII expression in mouse pancreas from embryonic stage to adult. The pancreatic ducts only start expressing CAII at embryonic day (E) 18.5, with increases after birth. Around E15.5, glucagon-positive cells, but not insulin-positive cells, also express CAII, with further increases by adult. CAII expression was restricted to cells within ductal structures and glucagon-positive cells with no colocalization with any insulin-positive cells at any time. In the human pancreas, CAII expression is restricted to the ducts. Furthermore, the activity of a 1.6-kb fragment of the human promoter with Luciferase assays was moderately strong compared with the cytomegalovirus promoter in human pancreatic duct cell line (PANC-1). Thus, we believe that the CAII gene could serve as a useful pancreatic duct cell marker.

Animals↗
PubMed2006

How can we get more beta cells?

The need for a reliable source of functional beta cells has led to many new investigations in an effort to drive the differentiation of embryonic stem cells, of putative stem cells, or of pancreatic progenitor cells to form new beta cells. There appears to be a plasticity of pancreatic cells in vitro that may be exploited to generate the necessary beta cells. Major questions still remain: whether there are true pancreatic stem cells, what are the pancreatic progenitor cells after birth, and whether expanded beta cells themselves could serve as the source.

Cell Differentiation↗
PubMed2005

Induced ICER Igamma down-regulates cyclin A expression and cell proliferation in insulin-producing beta cells.

We have previously found that cyclin A expression is markedly reduced in pancreatic beta-cells by cell-specific overexpression of repressor inducible cyclic AMP early repressor (ICER Igamma) in transgenic mice. Here we further examined regulatory effects of ICER Igamma on cyclin A gene expression using Min6 cells, an insulin-producing cell line. The cyclin A promoter luciferase assay showed that ICER Igamma directly repressed cyclin A gene transcription. In addition, upon ICER Igamma overexpression, cyclin A mRNA levels markedly decreased, thereby confirming an inhibitory effect of ICER Igamma on cyclin A expression. Suppression of cyclin A results in inhibition of BrdU incorporation. Under normal culture conditions endogenous cyclin A is abundant in these cells, whereas ICER is hardly detectable. However, serum starvation of Min6 cells induces ICER Igamma expression with a concomitant very low expression level of cyclin A. Cyclin A protein is not expressed unless the cells are in active DNA replication. These results indicate a potentially important anti-proliferative effect of ICER Igamma in pancreatic beta cells. Since ICER Igamma is greatly increased in diabetes as well as in FFA- or high glucose-treated islets, this effect may in part exacerbate diabetes by limiting beta-cell proliferation.

Animals↗
PubMed2005

Establishment of a diabetic mouse model with progressive diabetic nephropathy.

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER Igamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Igamma transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER Igamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.

Albumins↗
PubMed2004

The pancreatic ductal epithelium serves as a potential pool of progenitor cells.

With the increasing success of islet transplantation, beta-cell replacement therapy has had renewed interest. To make such a therapy available to more than a few of the thousands of patients with diabetes, new sources of insulin-producing cells must become readily available. The most promising sources are stem cells, whether embryonic or adult stem cells. Clearly identifiable adult pancreatic stem cells have yet to be characterized. Although considerable evidence suggests their possibility, recent lineage-tracing experiments challenge their existence. Even in light of these lineage-tracing experiments, we suggest that evidence for neogenesis or new islet formation after birth remains strong. Our work has suggested that the pancreatic duct epithelium itself serves as a pool for progenitors for both islet and acinar tissues after birth and into adulthood and, thus, that the duct epithelium can be considered 'facultative stem cells'. We will develop our case for this hypothesis in this perspective.

Animals↗
PubMed2004

Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic beta cells.

Transcriptional control mediated by the cyclic AMP-responsive element (CRE) represents an important mechanism of gene regulation. To test our hypothesis that increased inducible cyclic AMP early repressor (ICER) Igamma inhibits function of CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic beta cells, we generated transgenic mice with beta-cell-directed expression of ICER Igamma, a powerful repressor that is greatly increased in diabetes. Three transgenic lines clearly show that increased ICER Igamma expression in beta cells results in early severe diabetes. From birth islets were severely disorganized with a significantly increased proportion of alpha cells throughout the islet. Diabetes results from the combined effects of impaired insulin expression and a decreased number of beta cells. The decrease in beta cells appears to result from impaired proliferation rather than from increased apoptosis after birth. Cyclin A gene expression is impaired by the strong inhibition of ICER; the suppression of cyclin A results in a substantially decreased proliferation of beta cells in the postnatal period. These results suggest that CRE and CRE-binding factors have an important role in pancreatic beta-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of beta-cell mass.

Animals↗