Type II diabetic Goto-Kakizaki (GK) rats were insulin-resistant in euglycemic-hyperinsulinemic clamp studies. We therefore examined insulin signaling systems in control Wistar and diabetic GK rats. Glycerol-3-phosphate acyltransferase (G3PAT), which is activated by headgroup mediators released from glycosyl-phosphatidylinositol (GPI), was activated by insulin in intact and cell-free adipocyte preparations of control, but not diabetic, rats. A specific chiro-inositol-containing inositol phosphoglycan (IPG) mediator, prepared from beef liver, bypassed this defect and comparably activated G3PAT in cell-free adipocyte preparations of both diabetic GK and control rats. A myo-inositol-containing IPG mediator did not activate G3PAT. Relative to control adipocytes, labeling of GPI by [3H]glucosamine was diminished by 50% and insulin failed to stimulate GPI hydrolysis in GK adipocytes. In contrast to GPI-dependent G3PAT activation, insulin-stimulated hexose transport was intact in adipocytes and soleus and gastrocnemius muscles of the GK rat, as was insulin-induced activation of mitogen-activated protein kinase and protein kinase C. We conclude that (i) chiro-inositol-containing IPG mediator activates G3PAT during insulin action, (ii) diabetic GK rats have a defect in synthesizing or releasing functional chiro-inositol-containing IPG, and (iii) defective IPG-regulated intracellular glucose metabolism contributes importantly to insulin resistance in diabetic GK rats.

Adipocytes↗

PubMed1994

Increased expression of nucleoside diphosphate kinases/nm23 in human diploid fibroblasts transformed by SV40 large T antigen or 60Co irradiation.

When the expression levels of nucleoside diphosphate (NDP) kinase/nm23 were examined in four human normal diploid fibroblast cell lines in comparison with their corresponding immortalized cells transformed by SV40 large T antigen or 60Co irradiation, mRNA levels of the two isoforms (NDP kinase A/nm23-H1, NDP kinase B/nm23-H2) were increased in the immortalized cell lines. The increase was found to be associated with increased translation products. Furthermore, the cell extracts prepared from these immortalized cell lines demonstrated slightly higher enzyme activity than those from their normal counterparts. Neither the growth state nor the in vitro aging largely affected their expression in a normal cell line (TIG-3) examined. The results suggest possible involvement of NDP kinases/nm23 in acquiring an infinite growth property of these cells.

Antigens, Polyomavirus Transforming↗

PubMed1994

Ultrasonic diagnosis of torsion of the wandering spleen.

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Adult↗

PubMed1994

Inhibition with N-acetylcysteine of enhanced production of tumor necrosis factor in streptozotocin-induced diabetic rats.

We previously reported that the in vivo production of the tumor necrosis factor alpha (TNF) was significantly enhanced after the onset of diabetes in spontaneous type 1 and 2 diabetic animals. In this report we confirmed the enhanced production of TNF in streptozotocin (STZ)-induced diabetes and then attempted to suppress the enhanced TNF production with N-acetylcysteine (NAC), a precursor of glutathione synthesis. The lipopolysaccharide-induced serum TNF activities were significantly enhanced in STZ-induced diabetic rats (6-18 weeks of age) compared with those of nondiabetic rats throughout the 12-week experiment. A single, oral administration of NAC (200 or 1000 mg/kg body wt) significantly suppressed the enhanced TNF production in the diabetic rats compared with that in untreated rats in a dose-dependent manner. On the other hand, in the long-term (6 or 12 weeks) administrations, smaller doses of NAC (50 or 200 mg/kg/day) also significantly inhibited the enhanced production of TNF regardless of the dose of NAC. NAC administration, however, did not suppress the TNF production of nondiabetic rats. The long-term NAC administration affected neither body weight nor levels of serum glucose, fructosamine, albumin, and triglyceride. These results show that NAC administration significantly suppressed the enhanced TNF production in diabetic rats and indicate that NAC might be useful in preventing TNF-mediated pathological conditions in diabetes.

Acetylcysteine↗

PubMed1994

Biliary lipid composition in heterozygous familial hypercholesterolemia and influence of treatment with probucol.

The lipid composition of fasting duodenal bile was determined in 11 healthy subjects with normolipidemia and 15 patients with heterozygous familial hypercholesterolemia (FH) (12 with type IIa, three with type IIb). The age distribution among the groups of subjects was similar. In the patients with heterozygous FH type IIa, the mean value for molar percentage of cholesterol and lithogenic index (LI) of bile were significantly higher than those of controls (8.4 +/- 1.0%, 1.47 +/- 0.18 calculated by Hegard, Dam, and Holzbach vs 4.3 +/- 0.4%, 0.81 +/- 0.07, respectively). The value of LI in the patients with FH type IIb was also found to be significantly higher than that of the controls. In the patients with heterozygous FH type IIa, we observed both a significant decrease in the molar percentages of glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycolithocholic acid, and a significant increase of taurochenodeoxycholic acid compared to the corresponding values in the controls. Bile analysis of six patients was reexamined during probucol treatment after 16 weeks. Probucol significantly lowered serum cholesterol levels. However, biliary lipid composition and individual bile acid proportions was not altered by the treatment. The results suggest that most of the patients with heterozygous FH have supersaturated bile and are predisposed to cholesterol gallstone formation. In addition, the mechanism by which probucol lowers serum cholesterol appears to be independent of any change in the metabolism of biliary lipid.

Adult↗

PubMed1994

Anti-idiotypic antibody production in hepatitis B vaccine recipients.

Antibodies against hepatitis B surface antigen and against anti-hepatitis B surface antigen idiotype were assayed after immunization with hepatitis B vaccine both in sera, by enzyme-linked immunosorbent assay (ELISA), and in peripheral blood mononuclear cells, by enzyme-linked immunospot (ELISPOT) assay. After vaccination of 19 subjects, antibody to the idiotype of anti-hepatitis B surface antigen was detected in none of the sera tested with ELISA, but anti-idiotypic antibody-secreting cells were detected by ELISPOT assay in 4 (36.4%) of the 11 vaccine recipients who were positive for anti-hepatitis B surface antigen with ELISPOT assay. On the other hand, these cells were detected in none of those who remained seronegative for anti-hepatitis B surface antigen, or in the 7 normal subjects or the 2 chronic hepatitis type C patients. These results suggest that anti-idiotypic antibody production is more sensitively detected by ELISPOT assay than by ELISA, and anti-idiotypic antibodies to anti-hepatitis B surface antigen may be present in those with anti-hepatitis B surface antigen.

Adult↗

PubMed1994

Small duct cholangitis induced by N-formyl L-methionine L-leucine L-tyrosine in rats.

Primary sclerosing cholangitis (PSC) frequently accompanies inflammatory bowel diseases. In an attempt to increase our understanding of the pathogenesis of PSC, we studied bile duct changes in rats with colitis which had been given N-formyl L-methionine L-leucine L-tyrosine (fMLT) rectally; fMLT is one of the chemotactic peptides produced by Escherichia coli, and is secreted into the bile by hepatocytes after it enters the portal blood. Transrectal administration of fMLT induced a marked inflammation in the portal triad and mild hepatocyte necrosis on the 4th day. The infiltrating leukocytes in the portal tract were mostly mononuclear cells, which densely infiltrated around the bile ducts. These mononuclear cells appeared to attach to bile duct epithelial cells, and they were more numerous in the smaller bile ducts. Electron microscopy revealed that lymphocytes were in direct contact with bile duct lining cells and that some epithelial cells had degenerated or collapsed. These results suggest that this E. coli-derived peptide may induce cholangitis in the small bile duct through cell-mediated mechanisms. Since these pathologic changes resemble those of the bile duct observed in the early stage of PSC, it can be concluded that bacterial chemotactic peptides may play a role in the pathogenesis of small-duct PSC.

Animals↗

PubMed1994

Infrequent stromal expression of gelatinase A and intact basement membrane in intraductal neoplasms of the pancreas.

BACKGROUND/AIMS: Basement membrane disruption is a characteristic of invasive carcinoma. Gelatinases (also called type IV collagenases) that degrade type IV collagen are believed to play an important role in tumor invasion and metastasis. Intraductal neoplasm (IDN) of the pancreas is a unique tumor that grows intraductally with an infrequent stromal invasion. However, in IDN, basement membrane anomaly and gelatinase expression have not been clarified. The aim of this study was to examine the relationships between basement membrane disruption and the expression of gelatinase A in relation to the biological behavior of IDN or pancreatic duct cell carcinoma (DCC). METHODS: Disruption of basement membrane and expression of gelatinase A were immunohistochemically investigated in 14 cases of IDN and 16 cases of DCC. RESULTS: Basement membrane was intact in all cases of IDN, whereas focal to severe disruption was observed in DCC. Stromal expression of gelatinase A was higher in DCC than in IDN, and the intensity of expression was related to the degree of disruption of the basement membrane in DCC. CONCLUSIONS: Stromal expression of gelatinase A and disruption of basement membrane, common characteristics of invasive cancer, were not prominent in IDN. This may be related to the benign biological behavior of IDN.

Aged↗

PubMed1994

ICA and organ-specific autoantibodies among Japanese patients with early-onset insulin-dependent diabetes mellitus--the JDS study.

The Japan Diabetes Society (JDS) conducted a multicenter study on the immunogenetics of insulin-dependent diabetes mellitus (IDDM) among Japanese. The previous report of the JDS study described HLA types and other immunogenetic markers in Japanese patients with IDDM. In the present report, the autoimmunity of Japanese patients was studied by measuring ICA and other organ-specific autoantibodies in patients with different durations of IDDM. The prevalences of ICA were the highest in the first year after diagnosis (73.1%) and decreased to 58.0%, 18.3% and 2.8% in 1-5 years, 5-10 years and 10 years or more after diagnosis, respectively (P < 0.01), while the prevalences of the other organ specific autoantibodies increased gradually with duration of IDDM from 20% in the first year to 35% in 10 years or more after diagnosis (P < 0.05). There were no sex differences in the prevalences of ICA but those of other organ-specific autoantibodies were significantly higher in female patients than in male patients (P < 0.01). The prevalence of ICA was not correlated with sex, age at onset or HLA types. In one of the subjects, a girl, the titers of ICA increased in parallel with a decrease in insulin secretion before the development of overt IDDM and declined thereafter. These findings suggest that IDDM might develop when the autoimmunity specific to pancreatic islets is triggered in people with underlying autoimmunity as shown by the presence of organ-specific autoantibodies other than ICA.

Adolescent↗

PubMed1994

5-Aminosalicylic acid inhibits leukotriene B4 omega-hydroxylase activity in human polymorphonuclear leukocytes.

omega-Oxidation is regarded as the major pathway for the metabolism and inactivation of leukotriene B4 (LTB4). To investigate the action of 5-aminosalicylic acid (5-ASA) on LTB4 omega-hydroxylase activity, we incubated human polymorphonuclear leukocytes (PMNLs) with 3H-labeled LTB4 after pre-incubation with various concentrations of 5-ASA. omega-oxidation metabolites were separated by high performance liquid chromatography and each radioactivity was measured by a liquid scintilation counter. LTB4 omega-hydroxylase activity was inhibited by 5-ASA in a concentration-dependent fashion. The 50% inhibitory dose was about 50 mumol/l, which is within the concentration range found in the colonic mucosa. Our findings may be valuable in elucidating the potentially critical aspect of 5-ASA treatment in ulcerative colitis (UC).

Aminosalicylic Acids↗

PubMed1994

Diabetes mellitus.

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Animals↗

PubMed1994

Effects of galanin on amylase secretion from dispersed rat pancreatic acini.

Dispersed rat pancreatic acini were used to determine the effect of galanin on the exocrine pancreas and on basal and secretagogue-stimulated amylase secretion. Basal amylase secretion and amylase release stimulated by cholecystokinin octapeptide, bombesin, 12-o-tetradecanoyl-phorbol-13-acetate (TPA), secretin, and vasoactive intestinal peptide were not affected by galanin in doses ranging from 10(-12) to 10(-6) M. Galanin, however, significantly inhibited the amylase release stimulated by sub- and supramaximal doses of carbachol. A time course study showed that the inhibition by galanin occurred during the sustained phase of carbachol-stimulated amylase secretion. The inhibitory action of galanin disappeared in acini obtained from animals pretreated with pertussis toxin (PTX). These results suggest that galanin inhibits carbachol-stimulated amylase secretion through a mechanism related to a PTX-sensitive G protein.

Amylases↗