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At least 1,423 records · Page 79Linked to original sources
PubMed1997

Non-insulin-dependent diabetes mellitus--a collision between thrifty genes and an affluent society.

Non-insulin-dependent diabetes mellitus (NIDDM) is one of the most common non-communicable diseases in the world. It has become obvious that NIDDM is the result of a collision between thrifty genes and an affluent society. Genes predisposing to NIDDM might have been survival genes for our ancestors, helping them to store energy during long periods of starvation. When these genes are exposed to a sedentary lifestyle and high caloric intake typical to the Western world, they predispose to obesity and insulin resistance. NIDDM results when beta cells cannot compensate for insulin resistance by increasing insulin secretion. Therefore, at least two inherited defects can be expected in NIDDM, one causing obesity and insulin resistance and the other inability to increase insulin secretion. In reality there may be more inherited defects. It has become quite clear that diabetes cannot simply be divided into NIDDM and insulin-dependent diabetes mellitus (IDDM). The disease is more heterogeneous; unmasking this heterogeneity and identifying new subgroups of diabetes presents a challenge to modern molecular biology.

Animals↗
PubMed2004

Chronic effects of fatty acids on pancreatic beta-cell function: new insights from functional genomics.

Type 2 diabetes can be viewed as a failure of the pancreatic beta-cell to compensate for peripheral insulin resistance with enhanced insulin secretion. This failure is explained by both a relative loss of beta-cell mass as well as secretory defects that include enhanced basal secretion and a selective loss of sensitivity to glucose. These features are reproduced by chronic exposure of beta-cells to fatty acids (FAs), suggesting that hyperlipidemia might contribute to decompensation. Using MIN6 cells pretreated for 48 h with oleate or palmitate, we have previously defined alterations in global gene expression by transcript profiling and described additional secretory changes to those already established (Busch A-K, Cordery D, Denyer G, Biden TJ: Diabetes 51:977-987, 2002). In contrast to a modest decoupling of glucose-stimulated insulin secretion, FA pretreatment markedly enhanced the secretory response to an acute subsequent challenge with FAs. We propose that this apparent switch in sensitivity from glucose to FAs would be an appropriate response to hyperlipidemia in vivo and thus plays a positive role in beta-cell compensation for insulin resistance. Altered expression of dozens of genes could contribute to this switch, and allelic variations in any of these genes could (to varying degrees) impair beta-cell compensation and thus contribute to conditions ranging from impaired glucose tolerance to frank diabetes.

Animals↗
PubMed1997

A truncated Reelin protein is produced but not secreted in the 'Orleans' reeler mutation (Reln[rl-Orl]).

Reelin is the protein defective in reeler mutant mice [I. Bar, C. Lambert de Rouvroit, I. Royaux, D.B. Krizman, C. Dernoncourt, D. Ruelle, M.C. Beckers, A.M. Goffinet, A YAC contig containing the reeler locus with preliminary characterization of candidate gene fragments, Genomics 26 (1995) 543-549; G. D'Arcangelo, G.G. Miao, S.C. Chen, H.D. Soares, J.I. Morgan, T. Curran, A protein related to extracellular matrix proteins deleted in the mouse mutant reeler, Nature 374 (1995) 719-723; S. Hirotsune, T. Takahara, N. Sasaki, K. Hirose, A. Yoshiki, T. Ohashi, M. Kusakabe, Y. Murakami, M. Muramatsu, S. Watanabe, K. Nakao, M. Katsuki, Y. Hayashizaki, The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons, Nature Genet. 10 (1995) 77-83]. In the Orleans allele of reeler (symbol: Reln[rl-Orl]), a 220 nucleotide deletion is present in the 3' region of the Reelin message, resulting in a frame shift with production of a predicted protein amputated from its C-terminal amino acids. In this study, we first show that the predicted truncated protein indeed exists in Orleans reeler mice, using several anti-Reelin antibodies. Three antibodies are directed against epitopes located in the N-terminal region of the protein, namely: monoclonal antibody CR-50 [M. Ogawa, T. Miyata, K. Nakajima, K. Yagyu, M. Seike, K. Ikenaka, H. Yamamoto, K. Mikoshiba, The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons, Neuron 14 (1995) 899-912] (epitope region between Reelin residues 251-407), monoclonal antibody G10 (epitope located between amino acids 199 and 244) and the polyclonal antipeptide rp4 (positions 381-399). A fourth antibody, antipeptide rp5, reacts with the C-terminal (3443-3461) Reelin sequence. In normal embryos, all four antibodies stained cells in the marginal zone with features of Cajal-Retzius cells. While N-terminal specific antibodies detected Reelin immunoreactivity in mouse embryos homozygous for the reeler-Orleans mutation, no staining was obtained with the rp5 antibody, showing the presence of a truncated protein. Moreover, although Reelin could be detected at the surface of living Cajal-Retzius cells of normal mice, it was not revealed after vital staining of embryonic cortex from Orleans reeler mice. These results indicate that the C-terminal region of Reelin is essential for its secretion and suggest that the Orleans reeler phenotype is due to defective Reelin secretion rather than to secretion of an inactive protein.

Amino Acid Sequence↗
PubMed1994

Effects of obesity on bile formation and biliary lipid secretion in the genetically obese JCR:LA-corpulent rat.

Obesity, a known risk factor in cholesterol gallstone disease, is a favorable factor in the formation of bile supersaturated with cholesterol. Previous studies have been indirect and limited to human beings. To better define the hepatic secretory defect, we directly measured bile secretion and bile salt kinetics in a genetically obese rat. Common bile duct cannulations and 24-hr bile collections were performed on 11 obese (homozygous for the cp gene) and 11 lean (heterozygous cp) female rats of the JCR:LA-cp strain. In absolute terms, obese rats had normal bile salt secretion rates, 28% larger bile salt pools and 45% greater bile salt synthesis than lean controls. Obese rats had twice the total liver DNA content of lean controls, indicating twice the liver cell number. In terms relative to liver cell number, bile salt synthesis per milligram DNA was no different in the obese rats and controls. Biliary secretion under basal conditions, when expressed per total DNA content, was significantly decreased in the obese rats. Bile salt and phospholipid secretion per milligram DNA were decreased 54% and 49%, respectively, whereas a lesser 31% reduction in cholesterol secretion resulted in an increased cholesterol saturation index. The bile salt secretion rate and bile flow per milligram DNA were both decreased by half in obese rats, a cholestatic state likely reflecting the accumulation of intracellular microvesicular fat and mitochondrial damage. The secretory defect in this model of obesity is therefore less bile salt and phospholipid in relation to the cholesterol secreted per liver cell.

Animals↗
PubMed2005

The aging reproductive neuroendocrine axis.

It is well known that the reproductive system is one of the first biological systems to show age-related decline. While depletion of ovarian follicles clearly relates to the end of reproductive function in females, evidence is accumulating that a hypothalamic defect is critical in the transition from cyclicity to acyclicity. This minireview attempts to present a concise review on aging of the female reproductive neuroendocrine axis and provide thought-provoking analysis and insights into potential future directions for this field. Evidence will be reviewed, which shows that a defect in pulsatile and surge gonadotropin hormone-releasing hormone (GnRH) secretion exists in normal cycling middle-aged female rats, which is thought to explain the significantly attenuated pulsatile and surge luteinizing hormone (LH) secretion at middle-age. Evidence is also presented, which supports the age-related defect in GnRH secretion as being due to a reduced activation of GnRH neurons. Along these lines, stimulation of GnRH secretion by the major excitatory transmitter glutamate is shown to be significantly attenuated in middle-aged proestrous rats. Corresponding age-related defects in other major excitatory regulatory factors, such as catecholamines, neuropeptide Y, and astrocytes, have also been demonstrated. Age-related changes in hypothalamic concentrations of neurotransmitter receptors, steroid receptors, and circulating steroid hormone levels are also reviewed, and discussion is presented on the complex interrelationships of the hypothalamus-pituitary-ovarian (HPO) axis during aging, with attention to how a defect in one level of the axis can induce defects in other levels, and thereby potentiate the dysfunction of the entire HPO axis.

Aging↗
PubMed2001

Chromosomal aberrations in sporadic pituitary tumors.

Pituitary adenomas are common intracranial neoplasms that may be hormone-secreting or nonfunctional. Genetic defects associated with some pituitary tumors have been identified, although our understanding of the underlying molecular mechanisms remains incomplete. We have studied 75 sporadic pituitary tumors, representing the major clinical subtypes, by comparative genomic hybridization (CGH) with the aim of assessing for DNA copy number changes. CGH revealed chromosomal imbalances in 34 adenomas (45.3%), whereby gains were 4.9 times more frequently observed than losses. Most of the genetic alterations detected by CGH affected entire chromosomes (108/131, 82.4%). Gain of genetic material was observed predominantly on chromosomes X (24/75, 32%), 19 (12/75, 16%), 12 (6/75, 6.7%), 7 and 9 (5/75, 6.7%), whereas loss of DNA sequences most frequently affected chromosomes 11 (4/75, 5.3%), 13 and 10 (3/75, 4%). There were no significant differences in the CGH results for the individual clinical subtypes of pituitary tumors. These results reveal a nonrandom pattern of chromosomal alterations in pituitary tumors, in particular gains of entire chromosomes, and this may contribute to the development of such neoplasms.

Adenoma↗
PubMed1977

The thyroid in the spontaneously hypertensive rat: a light and electron microscopic study.

The present study was undertaken to seek ultrastructural changes in the thyroid gland of the spontaneously hypertensive rat which would contribute to the understanding of previously reported abnormalities in thyroid function. Light and electron microscopic observations and measurements of plasma T3 and systolic blood pressure were recorded from a colony of Wistar Kyoto rats (WKY) and of spontaneously hypertensive rats (SHR). The systolic blood pressure of SHR was significantly higher than that of WKY but the plasma T3 levels of the two groups did not differ significantly. After administration of propylthiouracil (PTU), serum T3 levels and systolic pressure of both groups decreased. The size of the thyroid follicles in SHR was highly variable throughout the gland, and the colloid contained unevenly dense areas and cell debris. The follicular cells contained slightly dilated rough surfaced endoplasmic reticulum (ER) and numerous pleomorphic bodies of uneven density. After treatment with PTU, the vessels between the follicles of SHR did not become as dilated as those in WKY but the fine structure of follicular cells in SHR was similar to that of WKY and was characteristic of the typical thyroid response to PTU administration. We suggest that the thyroid in SHR does not respond adequately to the elevated TSH levels reported to be present in these animals, although it can respond to the highly elevated TSH levels which occur with PTU administration. This impairment most probably involves defects in synthesis and/or secretion of thyroid hormones in response to TSH stimulation.

Animals↗
PubMed1988

Changes in B lymphocyte function in rheumatoid arthritis and lupus nephritis after total lymphoid irradiation.

Patients with rheumatoid arthritis and patients with lupus nephritis underwent total lymphoid irradiation (TLI). Peripheral blood mononuclear cells from these patients showed a decrease in pokeweed mitogen-induced immunoglobulin secretion after TLI. A defect in non-T cells contributed to the decreased response. No defect in the response of non-T cells to T cell-independent activators of B cells, Staphylococcus aureus Cowan 1 and Epstein-Barr virus, was observed after TLI. We conclude that TLI induces a selective deficit in B cells, which respond to T cell-dependent mitogen stimulation.

Arthritis, Rheumatoid↗
PubMed2006

Transgenic expression of a CD83-immunoglobulin fusion protein impairs the development of immune-competent CD4-positive T cells.

The murine transmembrane glycoprotein CD83 is an important regulator for both thymic T cell maturation and peripheral T cell response. CD83 deficiency leads to a block in the thymic maturation of CD4-positive T cells, and interference with peripheral CD83/CD83 ligand interaction by addition of soluble CD83 suppresses immune responses in vivo and in vitro. Here we report the generation of a mouse transgenic for a fusion protein consisting of the extracellular domain of murine CD83 fused to the constant part of human IgG1 heavy chain. Thymic selection of CD4-positive T cells was unchanged in CD83Ig transgenic and in CD83Ig/OT-2 double-transgenic mice. However, thymic and peripheral CD4-positive T cells derived from CD83Ig/OT-2 transgenic mice displayed a reduced cytokine response to antigenic stimulation in vitro, whereas CD83Ig/OT-1-derived CD8-positive T cells showed normal cytokine secretion. The T cell defect was relevant in vivo, since a sub-lethal infection with Trypanosoma cruzi led to an increased parasitemia and reduced survival rate of CD83Ig transgenic mice compared to wild-type C57BL/6 mice. In contrast, in vivo application of recombinant CD83Ig did not result in an increase in parasitemia. Taken together our data suggest that thymic selection in the presence of CD83Ig leads to an intrinsic T cell defect of CD4-positive T cells resembling the phenotype described for CD4-positive T cells derived from CD83-deficient mouse strains.

Animals↗
PubMed1975

Secretion analysis: secretin testing in pancreatic cancer.

Modern testing of pancreatic function and the diagnosis of pancreatic disease is facilitated by the addition of augmented stimulus to the standard stimulus used in secretin testing. The combined standard-augmented secretin test protocol enables not only diagnosis using the classical patterns of secretion (qualitative and quantitative defects), but also permits delineation of secretory capacity. In the abnormal patient, the augmented test increases the defect in the characteristic diagnostic parameter. Thus, there is fixation of flow in pancreatic cancer and fixation of bicarbonate in pancreatic inflammation.

Amylases↗
PubMed2002

Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is an idiopathic disease characterized by the accumulation of surfactant in the pulmonary airspaces. The development of a PAP-like syndrome in the GM-CSF knockout mouse and resolution of disease by local GM-CSF expression strongly implicates GM-CSF in surfactant homeostasis and disease pathogenesis. Based on murine data, GM-CSF therapy was administered to PAP patients, with a subset responding to therapy. The lack of response to GM-CSF therapy in some patients is unexplained. In adult idiopathic PAP there appears to be no intrinsic cellular defect in synthesizing or secreting GM-CSF and/or function in the GM-CSF receptor. Subsequent studies have shown the presence of circulating, neutralizing anti-GM-CSF antibodies in all adult PAP patients studied to date. Whether the anti-GM-CSF is causally related to the PAP disease and whether it should be the target of manipulation remains to be determined. The present study quantified the anti-GM-CSF levels sequentially in PAP patients receiving GM-CSF therapy. The data indicate that titers of circulating anti-GM-CSF predict response to GM-CSF therapy. In addition, we present data from a patient undergoing plasmapheresis in which anti-GM-CSF titer decreased with improvement in the lung disease. Together, these data support the hypothesis that PAP is an anti-GM-CSF autoimmune disease due to the development of antibodies, which results in the deactivation or neutralization of GM-CSF.

Adolescent↗
PubMed2000

Overexpression of human amyloid precursor protein in Drosophila.

Amyloid precursor protein (APP) is the precursor of the beta-amyloid peptide which is associated with Alzheimer's disease. The physiological function of APP is not well understood. We have established model system for the analysis of APP function in Drosophila. In neural cells, overexpressed human APP was transported to the synaptic terminal in a manner similar to its localization in human neurons, which suggested that the Drosophila protein transport system localizes human APP appropriately. Expression of APP in imaginal discs resulted in a defect in adult cuticle secretion and a blistered wing phenotype. The severity of the wing blister phenotype was proportional to the APP expression level. These results suggested the presence in Drosophila wing tissue of a protein or protein(s) which can interact with APP.

Amyloid beta-Protein Precursor↗
PubMed1999

Analyses of proteins involved in vesicular trafficking in platelets of mouse models of Hermansky Pudlak syndrome.

Hermansky Pudlak syndrome (HPS) is an autosomal recessive inherited disorder characterized by defects in synthesis and/or secretion of three related subcellular organelles: melanosomes, platelet-dense granules, and lysosomes. In the mouse, mutant forms of any of 14 separate genes result in an HPS-like phenotype. The mouse pearl and mocha genes encode subunits of the AP3 adaptor protein complex, confirming that HPS mutations involve proteins regulating intracellular vesicular trafficking. Therefore, expression of several additional proteins involved in vesicular transport was examined by immunoblotting of platelet extracts from HPS mutant and control mice. Platelet levels of SCAMPS (secretory carrier membrane proteins), Rab11, Rab31, NSF (N-ethylmaleimide-sensitive fusion protein), syntaxin 2, syntaxin 4, munc18c, and p115/TAP (p115/transcytosis-associated protein) were not significantly altered in several different HPS mutants. However, gunmetal (gm/gm) platelets contained decreased amounts of SNAP-23. The Snap23 gene was mapped to mouse chromosome 5, demonstrating it cannot encode the gm gene, which maps to chromosome 14. It is likely therefore that the gm gene functions upstream of SNAP-23 in vesicular trafficking.

Albinism, Oculocutaneous↗
PubMed1989

Cloning and characterization of the SKI3 gene of Saccharomyces cerevisiae demonstrates allelism to SKI5.

We have identified a mutant strain of the yeast Saccharomyces cerevisiae which overproduces killer toxin. This strain contains a single mutation which fails to complement defects in both the SKI3 and SKI5 genes, while a cloned copy of this gene complements both the ski3 and ski5 defects. The level of secreted toxin from a cDNA based plasmid is not increased in a ski3 strain, showing that the overproduction phenotype is dependent upon an increased level of M1 dsRNA.

Alleles↗
PubMed1977

Immunoglobulin deficiency diseases of the intestine.

Marshak has emphasized the role of the gastrointestinal tract as a major immunologic organ and described the radiologic findings of immunoglobulin deficiency diseases of the small intestine. According to his classification the radiologic findings include multiple nodular defects, edema and increased secretions associated with Giardiasis, a sprue-like pattern, and thickened folds. In this report, the role of the intestine in the immune response is briefly reviewed and several of the radiologic features of immune deficiency diseases and those of benign nodular lymphoid hyperplasia are illustrated.

Adolescent↗
PubMed1994

Assessment of growth hormone insulin like growth factor-I axis in Down's syndrome.

As GH therapy has been reported to increase growth velocity in children with Down's syndrome (DS), we studied the GH-IGF-I axis in some DS patients affected by growth retardation without serious congenital malformation, malnutrition or pathological thyroid or adrenal function. IGF-I and IGF-II were evaluated in 39 patients in basal conditions. The patients were subsequently divided into two groups with respect to the IGF-I basal value: Group 1 (GR 1) consisting of patients with abnormally low basal IGF-I concentration as compared to age matched control subjects, group 2 (GR 2) consisting of patients with IGF-I in the normal range. In 6 GR 1 patients and 12 GR 2 patients we evaluated GH and IGF-I concentrations after stimulation with arginine (0.5 g/kg bw), and recombinant GH (4 IU im). In the same patients, GH radioreceptor assay and serum GH-binding protein were evaluated. In all patients IGF-II proved normal (534 +/- 23 ng/ml; mean +/- SE), while IGF-I was pathological in 36% of subjects. The cause of the defective IGF-I secretion in these patients does not seem to depend on an impaired GH axis, as no significant difference in arginine-stimulated GH peak values was seen between GR 1 (29.6 +/- 5.3 ng/ml) and GR 2 (15.1 +/- 2.24 ng/ml). IGF-I concentration evaluated 12, 24, and 48 h after arginine stimulation was significantly increased only in GR 2 patients (peak value: 0.95 +/- 0.1, p = 0.0003 vs baseline; GR 1: 0.34 +/- 0.05 U/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier Proteins↗
PubMed2006

ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura.

The activity of ADAMTS13, the von Willebrand factor cleaving protease, is deficient in patients with thrombotic thrombocytopenic purpura (TTP). In the present study, the phenotype of ADAMTS13 in TTP and in normal plasma was demonstrated by immunoblotting. Normal plasma (n = 20) revealed a single band at 190 kD under reducing conditions using a polyclonal antibody, and a single band at 150 kD under non-reducing conditions using a monoclonal antibody. ADAMTS13 was not detected in the plasma from patients with congenital TTP (n = 5) by either antibody, whereas patients with acquired TTP (n = 2) presented the normal phenotype. Following immunoadsorption of immunoglobulins, the ADAMTS13 band was removed from the plasma of the patients with acquired TTP, but not from that of normal individuals. This indicates that ADAMTS13 is complexed with immunoglobulin in these patients. The lack of ADAMTS13 expression in the plasma from patients with hereditary TTP may indicate defective synthesis, impaired cellular secretion, or enhanced degradation in the circulation. This study differentiated between normal and TTP plasma, as well as between congenital and acquired TTP. This method may, therefore, be used as a complement in the diagnosis of TTP.

ADAM Proteins↗
PubMed2005

Bile salt diarrhea.

Alterations in bile acid metabolism and in the enterohepatic circulation are often associated with chronic diarrhea and should be considered when more common causes of chronic diarrhea have been excluded. Bile acid diarrhea most often occurs in disease or resection of the terminal ileum, in which there is increased exposure of the colonic mucosa to bile salts with consequent activation of fluid and electrolyte secretion. Congenital or acquired defects in the enterohepatic circulation of bile acids also may lead to diarrhea. Although multiple diagnostic tests may be considered to confirm abnormal fecal bile acid losses, the most critical elements of the clinical evaluation of suspected bile acid diarrhea are a careful history to exclude more common causes of chronic diarrhea and a diagnostic trial of bile acid-binding resins.

Bile Acids and Salts↗