Loss of huntingtin-associated protein 1 impairs insulin secretion from pancreatic β-cells

Hap1 was originally identified as a neuronal protein that interacts with huntingtin, the Huntington’s disease (HD) protein. Later studies revealed that Hap1 participates in intracellular trafficking in neuronal cells and that this trafficking function can be adversely affected by mutant huntingtin. Hap1 is also present in pancreatic β-cells and other endocrine cells; however, the role of Hap1 in these endocrine cells remains unknown. Using the Cre-loxP system, we generated conditional Hap1 knockout mice to selectively deplete the expression of Hap1 in mouse pancreatic β-cells. Mutant mice with Hap1 deficiency in pancreatic β-cells had impaired glucose tolerance and decreased insulin release in response to intraperitoneally injected glucose. Using cultured pancreatic β-cell lines and isolated mouse pancreatic islets, we confirmed that decreasing Hap1 could reduce glucose-mediated insulin release. Electron microscopy suggested that there was a reduced number of insulin-containing vesicles docked at the plasma membrane of pancreatic islets in Hap1 mutant mice following intraperitoneal glucose injection. Glucose treatment decreased the phosphorylation of Hap1A in cultured β-cells and in mouse pancreatic tissues. Moreover, this glucose treatment increased Hap1’s association with kinesin light chain and dynactin p150, both of which are involved in microtubule-dependent trafficking. These studies suggest that Hap1 is important for insulin release from β-cells via dephosphorylation that can regulate its intracellular trafficking function.     

NDRG2 is highly expressed in pancreatic β cells and involved in protection against lipotoxicity

The N-myc downstream-regulated gene 2 (NDRG2) is involved in cell differentiation and apoptosis, but its function in the pancreas remains to be established. Herein we examine the expression and function of NDRG2 in the endocrine pancreas. NDRG2 immunoreactivity was localized mainly in the cytoplasm of pancreatic β cells. When β-TC3 cells were exposed chronically to high levels of free fatty acid (FFA), cell viability was impaired, and Akt and NDRG2 phosphorylation were reduced. NDRG2 is a potential substrate of protein kinase Akt. Overexpression of constitutively active Akt enhanced NDRG2 phosphorylation and abolished the apoptosis induced by FFA in β-TC3 cells, whereas NDRG2 knock-down attenuated Akt-mediated protection of β cells against fatty acid-triggered apoptosis. Collectively, these data indicate that NDRG2 acts as a key molecule in pancreatic β cells and is involved in the Akt-mediated protection of β cells against lipotoxicity.     

Glucagon and pancreatic polypeptide immunoreactivities co-exist in a population of rat islet cells

In mammalian pancreas, glucagon and pancreatic polypeptide have been shown to be present in distinct cell types. The present communication reports that, in rat pancreas, in addition to glucagon and pancreatic polypeptide cell populations, there is a small population of cells which contain both glucagon and pancreatic polypeptide immunoreactivities.     

Prevention or acceleration of type 1 diabetes by viruses

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells. Even though extensive scientific research has yielded important insights into the immune mechanisms involved in pancreatic β-cell destruction, little is known about the events that trigger the autoimmune process. Recent epidemiological and experimental data suggest that environmental factors are involved in this process. In this review, we discuss the role of viruses as an environmental factor on the development of type 1 diabetes, and the immune mechanisms by which they can trigger or protect against this pathology.     

Glucagon and pancreatic polypeptide immunoreactivities co-exist in a population of rat islet cells

Summary In mammalian pancreas, glucagon and pancreatic polypeptide have been shown to be present in distinct cell types. The present communication reports that, in rat pancreas, in addition to glucagon and pancreatic polypeptide cell populations, there is a small population of cells which contain both glucagon and pancreatic polypeptide immunoreactivities.     

Ontogenic development of peptide hormones in the mammalian fetal pancreas

Summary The ontogeny of insulin, glucagon, PP and somatostatin in the mammalian fetal pancreas has been examined in recent years largely by immunocytochemistry and in some instances by radioimmunoassay. Complete ontogenic data are available only for the rat, human pig and sheep. Figure 3 compares the time of appearance of the endocrine cell-types within the fetal pancreas when the periods of gestation of the four species are converted to a uniform scale. The striking ontogenic difference in the rat probably reflects the immaturity of the rodent fetus at birth compared with the human, pig and sheep. In the fetal pancreas, differences in cell number of glucagon and PP cells in the dorsal and ventral lobes become apparent from an early gestational period. Factors responsible for the functional and structural maturation of the fetal pancreatic endocrine cells and the processes involved in pancreatic organogenesis are poorly understood. Studies in these areas would have clinical implications since it may be possible in the future to employ agents for selective replication of fetal -cells for transplantation in patients with Type I diabetes, bearing in mind that such cells must have the capacity to respond to normal stimuli and repressors when transplanted. The presence of the other islet cell-types may be obligatory for these appropriate responses. This would require a more complete knowledge of those factors which produce the normal selectivity of the four hormonal cell-types.     

The pleiotropic roles of ADAM9 in the biology of solid tumors

A disintegrin and a metalloprotease (ADAM) 9 is a metzincin cell-surface protease involved in several biological processes such as myogenesis, fertilization, cell migration, inflammatory response, proliferation, and cell–cell interactions. ADAM9 has been found over-expressed in several solid tumors entities such as glioma, melanoma, prostate cancer, pancreatic ductal adenocarcinoma, gastric, breast, lung, and liver cancers. Immunohistochemical analyses highlight ADAM9 expression by actual cancer cells and associate its abundant presence with clinicopathological features such as shortened overall survival, poor tumor grade, de-differentiation, therapy resistance, and metastasis formation. In each of these tumors, ADAM9 may contribute to tumor biology via proteolytic or non-proteolytic mechanisms. For example, in liver cancer, ADAM9 has been found to shed MHC class I polypeptide-related sequence A, contributing towards the evasion of tumor immunity. ADAM9 may also contribute to tumor biology in non-proteolytic ways probably through interaction with different integrins. For example, in melanoma, the interaction between ADAM9 and β1 integrins facilitates tumor stroma cross talks, which then promotes invasion and metastasis via the activation of MMP1 and MMP2. In breast cancer, the interaction between β1 integrins on endothelial cells and ADAM9 on tumor cells facilitate tumor cell extravasation and invasion to distant sites. This review summarizes the present knowledge on ADAM9 in solid cancers, and the different mechanisms which it employ to drive tumor progression.     

Breaking T cell tolerance to beta cell antigens by merocytic dendritic cells

In type 1 diabetes (T1D), a break in central and peripheral tolerance results in antigen-specific T cells destroying insulin-producing, pancreatic beta cells. Herein, we discuss the critical sub-population of dendritic cells responsible for mediating both the cross-presentation of islet antigen to CD8⁺ T cells and the direct presentation of beta cell antigen to CD4⁺ T cells. These cells, termed merocytic dendritic cells (mcDC), are more numerous in non-obese diabetic (NOD), and antigen-loaded mcDC rescue CD8⁺ T cells from peripheral anergy and deletion, and stimulate islet-reactive CD4⁺ T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDC can break peripheral T cell tolerance to beta cell antigens in vivo and induce rapid onset T cell-mediated T1D in young NOD mouse. Thus, the mcDC subset appears to represent the long-sought critical antigen-presenting cell responsible for breaking peripheral tolerance to beta cell antigen in vivo.     

Transformation, in vitro, of cerebral hamster cells by polyoma virus]

A cell line called HCxPy was obtained in vitro by transformation of dissociated hamster brain cell cultures by polyoma virus. The first foci of transformed cells became evident 90 to 120 days after viral infection. This cell line is now at the 46th passage. The cells appear tumorigenic for hamsters after subcutaneous and intracerebral injection. They carry the polyoma virus T and cell surface antigens. Good evidence for astrocytic differentiation can be found by morphological examination of the tumours and of the cultured cells.     

Über eine selektive Mitosehemmung und -schädigung bei jungen Ratten durch Synthalin A

Summary A single subcutaneous injection of synthalin-A does not affect the cytoplasma ofA-cells in pancreatic islets of the rat during the 1^st–5^th day of life, in contrast to adult animals. Selective action was found on mitoticA-cells: reduction of mitotic frequency to 25% of the normal rate, and pathological mitoses in the sense of the so-called primary effect. The mitoses ofB-cells, exocrine pancreatic cells and intestinal epithelia seemed to be unchanged, although the mitotic rate was higher than inA-cells.     

Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. To improve diagnosis and treatment, key mechanisms of deregulated molecular functions have to be identified. Using microarray analysis, the expression patterns of 5600 human genes were assessed in PDAC by comparison with the normal pancreas and chronic pancreatitis (CP). The expression of 467 of 5600 genes was increased in PDAC in comparison to the normal pancreas, and the expression of 120 of these genes was not increased in CP. In addition, 341 of 5600 genes were expressed at decreased levels in PDAC tissues, of which 96 were decreased in comparison to both normal and CP tissues. Thus, a total of 808 of 5600 human genes were differentially expressed in pancreatic cancer. The identification of a large panel of altered genes in PDAC will stimulate additional studies that will lead to improved understanding of the molecular mechanisms underlying pancreatic malignant growth.     

Hedgehog signaling in pancreas development and disease

Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic cancer. Received 5 August 2005; received after revision 4 November 2005; accepted 22 November 2005     

Effect of pancreatic duct ligation on exocrine pancreatic function and structure in the rabbit

4 weeks after pancreatic duct ligation in the rabbit, fecal and luminal chymotrypsin were detected in concentrations similar to the control group. Pancreatic changes in the ligated group were marked dilatation of the main pancreatic duct, proliferation and distention of ductules and fibrosis. Despite pancreatic duct ligation and fibrosis, proteolytic enzymes continued to secrete into the duodenal lumen. These results suggest that pancreatic duct ligation in the rabbit is not associated with total pancreatic insufficiency.